Lung water estimation using an external sensing catheter.
A method for measuring pulmonary oedema (ETVL) is described using sodium ions as the intravascular indicator and heat as the extravascular indicator. The technique offers the advantage of virtually unlimited repeatability, relatively uncomplicated instrumentation and no blood loss. There is also the potential for differentiating between pulmonary oedema and pulmonary congestion and determining the efficacy of therapy. A sensing catheter to detect blood conductivity and temperature changes is required. Ideally the sensing catheter should be situated at a point just distal to the aortic valve. However, a commercially manufactured detecting catheter we had built proved troublesome to insert because of its relatively large diameter. Therefore, an external sensing catheter has been constructed to measure ETVL and the values obtained have been compared with those from an internal catheter. There was no difference between the internal and external catheter QT, but ETVL was consistently overestimated by 2.46 +/- 0.26 ml/kg. However, this value can be related to the internal value and can be used for clinical studies.


From volcanoes to the bench: Advantages of novel hyperthermoacidic archaeal proteases for proteomics workflows.
Here we introduce hyperthermoacidic archaeal proteases (HTA-Proteases©) isolated from organisms that thrive in nearly boiling acidic volcanic springs and investigate their use for bottom-up proteomic experiments. We find that HTA-Proteases have novel cleavage specificities, show no autolysis, function in dilute formic acid, and store at ambient temperature for years. HTA-Proteases function optimally at 70-90 °C and pH of 2-4 with rapid digestion kinetics. The extreme HTA-Protease reaction conditions actively denature sample proteins, obviate the use of chaotropes, are largely independent of reduction and alkylation, and allow for a one-step/five-minute sample preparation protocol without sample manipulation, dilution, or additional cleanup. We find that brief one-step HTA-Protease protocols significantly increase proteome and protein sequence coverage with datasets orthogonal to trypsin. Importantly, HTA-Protease digests markedly increase coverage and identifications for ribonucleoproteins, histones, and mitochondrial membrane proteins as compared to tryptic digests alone. In addition to increased coverage in these classes, HTA-Proteases and simplified one-step protocols are expected to reduce technical variability and advance the fields of clinical and high-throughput proteomics. This work reveals significant utility of heretofore unavailable HTA-Proteases for proteomic workflows. We discuss some of the potential for these remarkable enzymes to empower new proteomics methods, approaches, and biological insights. SIGNIFICANCE: Here we introduce new capabilities for bottom-up proteomics applications with hyperthermoacidic archaeal proteases (HTA-Proteases©). HTA-Proteases have novel cleavage specificity, require no chaotropes, and allow simple one-step/five-minute sample preparations that promise to reduce variability between samples and laboratories. HTA-Proteases generate unique sets of observable peptides that are non-overlapping with tryptic peptides and significantly increase sequence coverage and available peptide targets relative to trypsin alone. HTA-Proteases show some bias for the detection and coverage of nucleic acid-binding proteins and membrane proteins relative to trypsin. These new ultra-stable enzymes function optimally in nearly boiling acidic conditions, show no autolysis, and do not require aliquoting as they are stable for years at ambient temperatures. Used independently or in conjunction with tryptic digests, HTA-Proteases offer increased proteome coverage, unique peptide targets, and brief one-step protocols amenable to automation, rapid turnaround, and high-throughput approaches.


From chaos to chaos. An analysis of a discrete age-structured prey-predator model.
Discrete age-structured density-dependent one-population models and discrete age-structured density-dependent prey-predator models are considered. Regarding the former, we present formal proofs of the nature of bifurcations involved as well as presenting some new results about the dynamics in unstable and chaotic parameter regions. Regarding the latter, we show that increased predation may act both as a stabilizing and a destabilizing effect. Moreover, we find that possible periodic dynamics of low period, either exact or approximate, may not be generated by the predator, but it may be generated by the prey. Finally, what is most interesting from the biological point of view, is that given that the prey, in absence of the predator, exhibits periodic or almost periodic oscillations of low period, then the introduction of the predator does not alter this periodicity in any substantial way until the stabilizing effect of increased predation becomes so strong that a stable equilibrium is achieved.


Differential modulation of mediator release from human basophils and mast cells by mizolastine.
Basophils and mast cells play a major role in the pathogenesis of allergic disorders by releasing several proinflammatory mediators. Some histamine H1 receptor antagonists exert anti-inflammatory activities by modulating mediator release from basophils and mast cells. To study the in vitro effects of mizolastine, an H1 receptor antagonist, on the release of eicosanoids, histamine and IL-4 from human basophils and lung mast cells. Mizolastine (10(-7)-10(-5) M) concentration-dependently inhibited the release of cysteinyl leukotriene C4 from anti-IgE-stimulated basophils (IC(50): 3.85+/-0.28 microM) and mast cells (IC(50): 3.92+/-0.41 microM). The same concentrations of mizolastine did not affect anti-IgE-induced prostaglandin D2 release from lung mast cells. In contrast, mizolastine enhanced up to 80% IgE-mediated histamine release (EC(50): 4.63+/-0.14 microM) from basophils, but not from mast cells and it significantly potentiated IL-4 release from basophils induced by anti-IgE. Mizolastine did not affect histamine release from basophils induced by formyl peptide, whereas it inhibited cysteinyl leukotriene C4 release (IC(50): 1.86+/-0.24 microM). Blockade of cytosolic phospholipase A2 and arachidonic acid mobilization by pyrrolidine-1 did not alter the effect of mizolastine on histamine release from basophils, thereby excluding accumulation of arachidonic acid metabolic intermediates as the cause of this effect. Mizolastine did not influence anti-IgE-induced activation of extracellular signal-regulated kinase-1 and -2 (ERK-1 and -2) in human basophils. Mizolastine efficiently inhibits LTC4 synthesis in human basophils and mast cells presumably by interfering with 5-lipoxygenase. In contrast, it enhances histamine and IL-4 release only from anti-IgE-stimulated basophils. Therefore, mizolastine differentially regulates the production of mediators from basophils and mast cells in a cell- and stimulus-specific fashion.


Surgical salvage therapy for malignant intrathoracic metastases from nonseminomatous germ cell cancer of testicular origin: analysis of a single-institution experience.
Cisplatin-based chemotherapy followed by surgical extirpation of residual benign disease represents the usual sequence of curative therapy for metastatic nonseminomatous germ cell cancer of testicular origin. Occasionally, residual disease is malignant in the form of either a persistent nonseminomatous germ cell cancer tumor or degeneration into non-germ cell cancer. We reviewed our institution's experience with patients undergoing salvage operations to remove malignant intrathoracic metastases. From 1981 through 2001, 438 patients with nonseminomatous germ cell cancer had operations to remove residual intrathoracic disease after cisplatin-based chemotherapy at Indiana University Hospital. A subset of 134 patients who underwent 186 surgical procedures to remove malignant metastases is the basis of this review. Fifty-nine patients had removal of pulmonary metastases, 49 had removal of mediastinal metastases, and 26 had removal of both pulmonary and mediastinal metastases. Surgical pathology demonstrated 84 patients with persistent nonseminomatous germ cell cancer tumors, 38 with degeneration into non-germ cell cancer, and 12 with both malignant pathologic categories. There were 4 (3.7%) operative deaths. The overall median survival was 5.6 years, with 55 (42.3%) patients alive and well after a mean follow-up of 5.1 years. Seventeen variables were analyzed by using Cox regression. Of these, older age, pulmonary metastases (vs mediastinal metastases), and 4 or more (vs 1) total intrathoracic metastases were significantly (P < or = .01) predictive of inferior long-term survival. Salvage thoracic surgery to remove malignant metastases from nonseminomatous germ cell cancer tumors of testicular origin can result in long-term survival in select patients. We identified variables that influence survival in this subset.


Effect of increasing heart rate on left ventricular performance in patients with normal cardiac function.
The influence of an increase in heart rate on left ventricular (LV) contractile performance was assessed in patients with normal LV function. In 19 patients (3 men, 16 women) ages 55 +/- 9 years (mean +/- standard deviation) with normal global and segmental LV function and normal coronary arteries, LV dP/dt max was measured at baseline heart rate and during atrial pacing at baseline +5, baseline +25 and baseline +45 beats/min. In 10 of the patients, intravascular volume was not altered during pacing and, as a result, echocardiographically measured LV end-diastolic dimension decreased (5.4 +/- 0.4 at baseline vs 4.9 +/- 0.5 cm at baseline +45 beats/min, p less than 0.05). In these patients, LV dP/dt max increased modestly (1,571 +/- 237 at baseline vs 1,760 +/- 199 mm Hg/s at baseline +45 beats/min, p less than 0.05). In the other 9 patients, intravascular volume was expanded rapidly (by saline infusion) during pacing and, as a result, LV end-diastolic dimension was held constant (5.2 +/- 0.6 at baseline vs 5.1 +/- 0.6 cm at baseline +45 beats/min, difference not significant). In these patients, LV dP/dt max increased substantially with pacing (1,505 +/- 228 at baseline vs 2,050 +/- 258 mm Hg/s at baseline +45 beats/min, p less than 0.05). Thus, an increase in heart rate induces a modest increase in LV dP/dt max in patients in whom LV preload (as reflected by end-diastolic dimension) is allowed to decrease; in contrast, it causes a marked increase in LV dP/dt max in those in whom LV preload is maintained constant.


A comparative study of the characteristics of hate speech propagators and their behaviours over Twitter social media platform.
The internet and social media have facilitated diverse communication genres, enabling widespread and rapid opinions-sharing. However, hate speech imposes a contemporary challenge on individuals and communities, given the user anonymity, freedom, and inadequate regulation. Therefore, it is imperative to identify the perpetrators responsible for spreading hate content and examine their behaviour to prevent and mitigate the negative impact. This study aimed to compare the characteristics of hate speech propagators and their behaviour with non-hate users on Twitter for the first time in Sri Lanka. The intrinsic and extrinsic profile features were extensively analyzed, employing Sinhala and English text analysis techniques. A corpus of 102882 posts from 530 hate and non-hate Twitter user profiles was selected for the study. This study investigates the unique characteristics of hate speech propagators and non-hate users by examining their profile self-presentation, conducting social network analysis, and analyzing sentiment and emotion through linguistic analysis. Hate users often refrained from expression, with infrequent account verification and geotagging. They tend to have a higher follower and following counts and more favourites, group memberships, and statuses than non-hate users. However, general Twitter user engagement with hate users was significantly low, with fewer likes, retweets, and replies. The limited involvement of normal users with hate content indicates that audiences can be effectively utilized to combat hate speech. The sentiment analysis between languages showed polarisation of negative tweets towards Sinhala, with the synergistic effect of English language users using positive sentiment to spread hate content. The novel findings shed light on the characteristics of hate users, facilitating their early detection and moderation of hate speech and aiding in developing algorithms to rank and categorize hate users using artificial intelligence. Moreover, it can be used for policy reforms, awareness programmes, and building social cohesion while combating hate speech.


A scientific basis for the risk assessment of vinyl chloride. Developed jointly by the members of the Committee on the Evaluation of Carcinogenic Substances, National Health Council of The Netherlands.
In July 1984 the Minister of Welfare, Public Health and Culture, representing the Dutch government, sent a request to the Health Council of The Netherlands to advise on the health risks presented by environmental exposure to several carcinogenic substances. One of these substances was vinyl chloride (VC). On the basis of a working document prepared by the National Institute of Public Health and Environmental Hygiene, a committee of the Health Council of The Netherlands prepared a report concerning a health risk assessment of VC which was published in May 1986. A short review is presented of the available data and the considerations that formed the basis for the risk assessment of the carcinogenicity of VC to humans. The advice was based mainly on human data from epidemiological studies of workers occupationally exposed to VC. The committee concludes that continuous exposure to 0.001 mg/m3 VC corresponds to an additional cancer mortality risk of 10(-6) per lifetime. The Dutch government considers this additional risk to the general population to be acceptable.


Rapid alcohol determination in plasma and urine by column liquid chromatography with biosensor detection.
An enzyme based amperometric biosensor used as a selective and sensitive detection unit in column liquid chromatography for the determination of ethanol and methanol in biological fluids such as plasma and urine is described. The reagentless enzyme electrode is based on the co-immobilisation of alcohol oxidase and horseradish peroxidase in carbon paste. The selectivity of the biosensor was found to vary when four various alcohol oxidase enzyme preparations from Candida boidinii, Pichia pastoris, and Hansenula polymorpha were used in the biosensors described. High sensitivity could be obtained for a number of alcohols, organic acids, and aldehydes. Optimisation regarding the sensitivity and selectivity of the four alcohol oxidase co-immobilised biosensors are outlined. A fast and reliable liquid chromatographic separation system with a PLRP-S polymer based separation column used with a phosphate buffer as the mobile phase was optimised using the best biosensor which was based on alcohol oxidase from P. pastoris and which showed the highest turnover rate for alcohols, as the detector for the determination of ethanol and methanol in human urine and plasma samples. The selectivity and stability of the biosensor were retained by working at an applied potential of -50 mV versus Ag/AgCl, the optimal operational potential, and by the casting of a protective membrane on the electrode surface. High selectivity of the enzyme electrode was also found towards other easily oxidisable interfering species normally present in biological fluids. It was found that stable and reliable determinations of ethanol and methanol in plasma and urine could be performed with only a simple dilution and centrifugation step prior to injection into the liquid chromatographic system. An analysis time of 4 min was required for the assay, with a sample throughput of 13 samples h(-1).


Stepped-care in obesity treatment: matching treatment intensity to participant performance.
This investigation examined the effectiveness of a self-help (SH), stepped-care (SC) weight loss program. Based on a failure to achieve pre-assigned weight loss goals, participants were eligible to be stepped-up from a SH program to two levels of treatment intensity (weight loss group [WLG]; individual counseling [IC]) beyond SH. The primary outcome was change in body weight. Fifty-three overweight/obese adults (BMI≥27 kg/m(2); mean BMI of 37.3, SD=6.6, 89% Caucasian, and 77% female) participated in an 18-week weight loss intervention. During several phases of the investigation, those stepped-up to more intensive treatment lost comparable weight to those who were not stepped-up. Nevertheless, by the end of treatment, individuals who remained in SH (M=8.6%) lost a significantly greater percentage of weight than individuals who received SH+IC (M=4.7%; p<.05) and individuals in SH+IC lost a significantly greater percentage of weight than individuals who received SH+WLG+IC (M=1.6%; p<.05). While some individuals benefited from being stepped-up to greater intensity treatment, other individuals experienced little benefit. The application of SC principles to the treatment of obesity needs further study.


Factors associated with use of emergency medical services in patients with acute stroke.
The aim of this study was to investigate the factors associated with use of emergency medical services (EMS) in patients with acute stroke. Prospective data on consecutive patients with acute stroke who presented to the emergency department of a university medical center from January 1, 2010, to July 31, 2011, were analyzed. Patients were excluded if they had an unknown residence, had onset of stroke at a nursing home or hospital, or were transferred from another hospital. Variables for all patients with stroke and ischemic stroke who did and did not use EMS were compared. In total, 1344 patients (60% male; mean age, 68.7 years) were included. Use of EMS (n = 409; 30.4%) was significantly associated with a higher level of education (≧6 years vs <6 years; odds ratio [OR], 1.69; 95% confidence interval [CI], 1.25-2.29), a higher National Institutes of Health Stroke Scale score (OR, 1.08; 95% CI, 1.05-1.11), altered consciousness (OR, 1.88; 95% CI, 1.25-2.84), and atrial fibrillation (OR, 2.43; 95% CI, 1.71-3.44) after adjustment. For patients with ischemic stroke, use of EMS was significantly higher in cases of cardioembolism (OR, 3.04; 95% CI, 1.40-6.60) and large artery atherothrombosis (OR, 2.10; 95% CI, 1.22-3.62) than lacunar infarction. Patients with stroke who have altered consciousness, a higher level of education, a higher National Institutes of Health Stroke Scale score, atrial fibrillation, and cardioembolic stroke were more likely to use EMS.


Kiwifruit decreases blood pressure and whole-blood platelet aggregation in male smokers.
Lifestyle modifications to reduce risk factors for cardiovascular diseases such as blood pressure (BP) and smoking have been emphasized. Fruits and vegetables may modify such risk factors. The major aim of this randomized, controlled trial was to investigate the effects of (1) kiwifruits and (2) an antioxidant-rich diet compared with (3) a control group on BP and platelet aggregation (that is, whole-blood platelet aggregation) after 8 weeks in male smokers (age 44-74 years, n=102). The kiwifruit group received 3 kiwifruits per day, whereas the antioxidant-rich diet group received a comprehensive combination of antioxidant-rich foods. In the kiwifruit group, reductions of 10 mm Hg in systolic BP and 9 mm Hg in diastolic BP were observed (P=0.019 and P=0.016 (change from baseline in the kiwifruit group compared with change from baseline in the control group)). In the antioxidant-rich diet group, a reduction of 10 mm Hg in systolic BP was observed among hypertensives (P=0.045). Additionally, a 15% reduction in platelet aggregation and an 11% reduction in angiotensin-converting enzyme activity was observed in the kiwifruit group (P=0.009 and P=0.034). No effects on these parameters were observed in the antioxidant-rich diet group. This study suggest that intake of kiwifruit may have beneficial effects on BP and platelet aggregation in male smokers.


Lipid-A-antibodies--indicators for the risk of renal scarring in children with urinary tract infection.
The levels of IgG- and IgM-antibodies against lipid A were determined by an ultramicro-ELISA in 54 children between 2 months and 13 years of age with non-obstructive urinary tract infections at the onset of the infection and subsequently after 3, 6 and 12 months. Children older than 2 years who later developed renal scarring as shown by intravenous pyelograms had higher levels of IgG antibodies than those without scars. This correlation was not found in children younger than 2 years of age. IgM-antibody levels did not correlate with the risk of scar formation. We conclude that the IgG-antibody level against lipid A is a useful indicator for early recognition of children over the age of two years who will later develop renal scars. The ultramicro-ELISA technique makes screening for children at risk possible at a low cost.


Be a leading candidate.
Nerves can take hold and speech become garbled when you are put on the spot. Here, we offer expert advice on being the best you can be at a job interview.


Substrate Targeted Ablation of Atrial Fibrillation Guided by High Density Voltage Mapping: Long-Term Results.
Long-term ablation results for atrial fibrillation (AF) have been disappointing, particularly for non-paroxysmal AF (NPAF). We hypothesize fibrosis in paroxysmal AF (PAF) and NPAF would be reflected in voltage fragmentation and visualized by high density mapping. Targeted ablation of discrete low voltage bridges (LVB) would eliminate endocardial fragmentation and should have a positive effect on long-term sinus rhythm (SR) survival. To assess the efficacy of LVB ablation on SR survival in patients with PAF and NPAF, as well as, determine its impact on P wave duration (PWD) and LA volume (LAV). 56 patients (29PAF/26NPAF) had a voltage gradient map (VGM) created, high and low voltage limits were adjusted to image LVB. Ablation was performed until no LVB were observed. Baseline PWD and LAV were obtained and reassessed 6 months' post ablation. Patients were followed for 5 years with intermittent monitors. Termination of AF in NPAF was 88%. PWD normalized in PAF and were normal in NPAF post ablation. LAV decreased significantly in NPAF. At 5 years, SR was observed in 89% of PAF and 67% of NPAF. 1. LVB ablation terminates AF in NPAF 88%; 2. Both PWD and LAV were improved; 3. Maintenance of SR was observed in 89% and 67% (PAF vs NPAF); 4. The present study demonstrates efficacy of a simplified, individualized, and unified methodology for AF ablation.


Patient profiles on outcomes in patients hospitalized for heart failure: a 10-year history of the Malaysian population.
Heart failure (HF) affects an estimated 38 million people worldwide and is the leading cause of hospitalization among adults and the elderly. Evidence suggests that there may be regional and ethnic differences in the prevalence, outcomes and management of HF. The aim of this study was to understand the disease burden and treatment patterns of patients hospitalized for HF in multi-ethnic Malaysia. A retrospective, non-interventional study was conducted utilizing 10 years of medical records from the National Heart Institute Malaysia (IJN) from 1 January 2009 to 31 December 2018. Of the 4739 patients in the IJN database, 3923 were eligible and were included in this analysis. The study recorded a high male prevalence (72.3%) with a mean age of 62.0 (±13.26) years. The 30-day and 1-year rehospitalization rate was 6.8% and 24.7%, respectively. In-hospital mortality was 7.2% with 27.0% due to cardiovascular causes and 14.2% non-cardiovascular causes. The 30-day and 1-year rehospitalization rates were significantly higher in patients with lower systolic blood pressure (SBP, P < 0.001 and P = 0.002), diastolic blood pressure (DBP, P < 0.001 and P = 0.017), sodium (P < 0.001 and P = 0.029) and estimated glomerular filtration rate (eGFR, P < 0.001 and P = 0.002) and higher urea (P < 0.001 for both), serum creatinine (P < 0.001 and P = 0.003), and uric acid (P < 0.001 for both), respectively. Risk of hospitalization within 1 year varied significantly by ethnicity and was relatively higher in Indian (28.3%), followed by Malay (24.4%) and Chinese (21.9%; P = 0.008). In-hospital mortality within 1-year post-index date was higher in patients with lower weight (P = 0.002), body mass index (P = 0.009), SBP (P < 0.001), DBP (P < 0.001), sodium (P < 0.001), eGFR (P < 0.001) and higher heart rate (P = 0.039), urea (P < 0.001), serum potassium (P = 0.038), serum creatinine (P < 0.001), and uric acid (P < 0.001). In-hospital mortality within 1-year post-index date was also higher in patients with severe or end-stage chronic kidney disease (CKD) compared with mild/moderate CKD (P < 0.001) and in patients with HF with reduced ejection fraction (HFrEF) compared with those with mid-range or preserved ejection fraction (P < 0.001). The most commonly prescribed HF medications at discharge were loop diuretics (89.2%), β-blockers (68.5%), mineralocorticoid receptor antagonists (56.2%), angiotensin-converting enzyme inhibitors (31.5%), and angiotensin receptor blockers (20.8%). This study provides a greater understanding of the characteristics, treatment patterns, and outcome of hospitalized HF patients in a leading referral centre in Malaysia and will aid the implementation of meaningful interventions to improve patient outcome for HF patients.


High-speed swept source optical coherence Doppler tomography for deep brain microvascular imaging.
Noninvasive microvascular imaging using optical coherence Doppler tomography (ODT) has shown great promise in brain studies; however, high-speed microcirculatory imaging in deep brain remains an open quest. A high-speed 1.3 μm swept-source ODT (SS-ODT) system is reported which was based on a 200 kHz vertical-cavity-surface-emitting laser. Phase errors induced by sweep-trigger desynchronization were effectively reduced by spectral phase encoding and instantaneous correlation among the A-scans. Phantom studies have revealed a significant reduction in phase noise, thus an enhancement of minimally detectable flow down to 268.2 μm/s. Further in vivo validation was performed, in which 3D cerebral-blood-flow (CBF) networks in mouse brain over a large field-of-view (FOV: 8.5 × 5 × 3.2 mm3) was scanned through thinned skull. Results showed that fast flows up to 3 cm/s in pial vessels and minute flows down to 0.3 mm/s in arterioles or venules were readily detectable at depths down to 3.2 mm. Moreover, the dynamic changes of the CBF networks elicited by acute cocaine such as heterogeneous responses in various vessel compartments and at different cortical layers as well as transient ischemic events were tracked, suggesting the potential of SS-ODT for brain functional imaging that requires high flow sensitivity and dynamic range, fast frame rate and a large FOV to cover different brain regions.


Central α-adrenoceptors contribute to mustard oil-induced central sensitization in the rat medullary dorsal horn.
Our previous studies have demonstrated that application of the inflammatory irritant mustard oil (MO) to the tooth pulp produces trigeminal central sensitization that includes increases in mechanoreceptive field size and responses to noxious stimuli and decrease in activation threshold in brainstem nociceptive neurons of trigeminal subnucleus caudalis (the medullary dorsal horn, MDH). The aim of the present study was to test if central noradrenergic processes are involved in the central sensitization of MDH neurons and if α1-adrenoceptors or α2-adrenoceptors or both are involved. In urethane/α-chloralose-anesthetized rats, the activity of extracellularly recorded and functionally identified single nociceptive neurons in the MDH was studied. Continuous intrathecal (i.t.) superfusion of the adrenergic modulator guanethidine and α-adrenoceptor blocker phentolamine or selective α1-adrenoceptor antagonist prazosin over the medulla strongly attenuated all three MO-induced parameters of central sensitization in the MDH nociceptive neurons, compared to phosphate-buffered saline (as vehicle control). In contrast, i.t. superfusion of the selective α2-adrenoceptor antagonist yohimbine had little effect on the mechanoreceptive field expansion and the decreased mechanical activation threshold, and indeed facilitated responses to noxious stimuli of sensitized nociceptive neurons. Superfusion of each of the four chemicals alone did not affect baseline nociceptive neuronal properties. These findings provide the first documentation of the involvement of central noradrenergic processes in MDH in the development of the central sensitization, and that α1- and α2-adrenoceptors may be differentially involved.


Development potential of bovine oocytes matured in vitro or in vivo.
Bovine oocytes matured in vivo or in vitro were evaluated after sperm-oocyte incubation for frequency of sperm penetration, frequency of male pronuclei formation, and embryonic development. The frequency of sperm penetration was not different for in vitro matured oocytes (216/295, 73%) vs. in vivo matured oocytes (119/176, 70%). However, formation of male pronuclei was reduced (p less than 0.05) for oocytes matured in vitro (149/216, 69%) vs. in vivo (104/119, 88%). Early embryonic development was evaluated 48 h after the onset of sperm-egg incubations. In vitro matured and fertilized oocytes failed to develop to the 2-cell stage (3/88, 3%), whereas oocytes matured in vivo showed normal development (23/56, 40%) to the 2- and 4-cell stage. Development to the blastocyst stage was evaluated after 5 days in ovine oviducts (in vivo). Morulae and blastocysts were obtained only after in vitro fertilization from oocytes that were in vivo-matured (recovered from oviduct, 14/56, 25%; recovered from follicle, 36/80, 45%). Oocytes that were matured in vitro and fertilized in vitro failed to develop to morulae (0/33) in vivo.


Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity.
Tumours often engage the lymphatic system in order to invade and metastasize. The tumour-draining lymph node may be an immune-privileged site that protects the tumour from host immunity, and lymph flow that drains tumours is often increased, enhancing communication between the tumour and the sentinel node. In addition to increasing the transport of tumour antigens and regulatory cytokines to the lymph node, increased lymph flow in the tumour margin causes mechanical stress-induced changes in stromal cells that stiffen the matrix and alter the immune microenvironment of the tumour. We propose that synergies between lymphatic drainage and flow-induced mechanotransduction in the stroma promote tumour immune escape by appropriating lymphatic mechanisms of peripheral tolerance.


Mycn regulates intestinal development through ribosomal biogenesis in a zebrafish model of Feingold syndrome 1.
Feingold syndrome type 1, caused by loss-of-function of MYCN, is characterized by varied phenotypes including esophageal and duodenal atresia. However, no adequate model exists for studying the syndrome's pathological or molecular mechanisms, nor is there a treatment strategy. Here, we developed a zebrafish Feingold syndrome type 1 model with nonfunctional mycn, which had severe intestinal atresia. Single-cell RNA-seq identified a subcluster of intestinal cells that were highly sensitive to Mycn, and impaired cell proliferation decreased the overall number of intestinal cells in the mycn mutant fish. Bulk RNA-seq and metabolomic analysis showed that expression of ribosomal genes was down-regulated and that amino acid metabolism was abnormal. Northern blot and ribosomal profiling analysis showed abnormal rRNA processing and decreases in free 40S, 60S, and 80S ribosome particles, which led to impaired translation in the mutant. Besides, both Ribo-seq and western blot analysis showed that mTOR pathway was impaired in mycn mutant, and blocking mTOR pathway by rapamycin treatment can mimic the intestinal defect, and both L-leucine and Rheb, which can elevate translation via activating TOR pathway, could rescue the intestinal phenotype of mycn mutant. In summary, by this zebrafish Feingold syndrome type 1 model, we found that disturbance of ribosomal biogenesis and blockage of protein synthesis during development are primary causes of the intestinal defect in Feingold syndrome type 1. Importantly, our work suggests that leucine supplementation may be a feasible and easy treatment option for this disease.


Effect of the estrogen antagonist, tamoxifen, on development of glomerulosclerosis in the Cohen diabetic rat.
Long-term administration of the estrogen antagonist, tamoxifen, to female, Cohen diabetic rats caused a significant decrease in the incidence of glomerulosclerosis, 12.5% as compared with 58.3% in control, untreated, diabetic female rats. This change in incidence was correlated with a corresponding decrease in plasma estradiol and cholesterol levels, but not with changes in oral glucose tolerance or insulin response. A similar correlation between decreased incidence of glomerulosclerosis and a decrease in plasma estradiol was previously noted in ovariectomized animals.


Steroid structure and function:I. Conformational transmission in 17alpha-acetoxy progesterone.
The molecular conformation of 17alpha-acetoxy progesterone has been determined crystallographically and is compared with that of progesterone. The 17alpha-acetate substituent restricts the flexibility of the progesterone side chain, strains bond lengths in the C- and D-rings, and has long range effects on the A-ring conformation. The A-ring adopts a perfect sofa conformation similar to that observed in one conformational isomer of progesterone. Consequently this progesterone isomer is proposed to be that best suited to binding in the rabbit and human uterus.


Pachymetry and Elevation Back Map Changes in Keratoconus Patients After Crosslinking Procedure.
The crosslinking (CXL) procedure using the standard Dresden protocol is established as the gold standard for the treatment of progressive keratoconus. The aim of this paper is to correlate the pachymetry and elevation back map (EBM) changes in the period from 3 to12 months of keratoconus patients after the CXL procedure. M. Forty-four eyes of 34 patients with keratoconus were analyzed after performed standard Dresden protocol CXL procedure. All of them underwent complete preoperative examination with a follow up of 12 months with a focus on pachymetry and EBM changes performed by Oculus Pentacam (Scheimpflug technology) analysis. Pachymetry changed significantly in 12 months post cross-linking, especially in the first 6 months after which it slightly increased. Differences in EBM preoperatively and 12 months postoperatively were not statistically significant. Corneal pachymetry in keratoconus patients decreases after the CXL procedure. Differences in pachymetry preoperatively and 3, 6 and 12 months postoperatively were statistically significant, but the value of corneal thickness increased from the third month to 12 months post-op. Differences in EBM preoperatively and 12 months postoperatively were not still statistically significant, which is good, because the increase in elevation, as one of the signs of progression of the keratoconus - did not occur.


Simvastatin induces cell death in a mouse cerebellar slice culture (CSC) model of developmental myelination.
Statins (inhibitors of HMG-CoA reductase) have shown promise in treating multiple sclerosis (MS). However, their effect on oligodendrocyte remyelination of demyelinated axons has not been clarified. Since developmental myelination shares many features with the remyelination process, we investigated the effect of lipophilic simvastatin on developmental myelination in organotypic cerebellar slice cultures (CSC). In this study, we first characterized developmental myelination in CSC from postnatal day (P)5 and P10 mice that express enhanced green fluorescence protein (eGFP) in oligodendrocyte-lineage cells. We then examined the effect of simvastatin on three developmental myelination stages: early myelination (P5 CSC, 2DIV), late myelination (P10 CSC, 2DIV) and full myelination (P10 CSC, 10DIV). We found that treatment with simvastatin (0.1 microM) for 6 days decreased the survival of Purkinje cells and oligodendrocytes drastically during the early myelination stage, while moderately during the late and full myelination stages. Oligodendrocytes are more resistant than Purkinje cells. The toxic effect of simvastatin could be rescued by the product of HMG-CoA reductase mevalonate but not low-density lipoprotein (LDL). Additionally, this toxic effect is independent of isoprenylation since farnesyl pyrophosphate (Fpp) but not geranylgeranyl pyrophosphate (GGpp) provided partial rescue. Our findings therefore suggest that inhibition of cholesterol synthesis is detrimental to neuronal tissue.


Surgical treatment of undifferentiated soft tissue sarcoma in a young 17-year-old woman: A case report.
This case report describes the clinical case of a 17-year-old woman with an undifferentiated soft tissue sarcoma in the left supratrocanteric area. The young woman came for observation at our plastic surgery hospital with a large vascular mass visible on her left side which also made walking difficult. Our patient reports the onset of the mass about two months earlier and its growth very quickly. In this case report, we will analyze the demolitive and reconstructive surgical procedures in order to guarantee our patient radical surgery and the possibility of continuing radiotherapy and any specific chemotherapy to avoid the risk of relapse and metastasis over time.


Comparison of the Ahmed glaucoma valve with the Baerveldt glaucoma implant: a meta-analysis.
This study aims to compare the efficacy and safety of the Ahmed glaucoma valve (AGV) with the Baerveldt glaucoma implant (BGI) in glaucoma patients. Databases were searched to identify studies that met pre-stated inclusion criteria, involving randomized controlled clinical trials (RCTs) and non-randomized controlled clinical trials. Treatment effect was analyzed using a random-effect model. Ten controlled clinical trials (1048 eyes) were analyzed, involving two RCTs and eight retrospective comparative studies. Short-term results (6-18 months) and long-term results (>18 months) were analyzed separately. There was no significant difference in the success rate for short-term follow-up between the AGV and BGI groups (5 studies, 714 eyes, odds ratio [OR]: 0.97; 95 % confidence interval [CI]: 0.56, 1.66; P = 0.90). For long-term pooled results (7 studies, 835 eyes), the success rate of AGVs was lower than that of BGIs (OR: 0.73; 95 % CI: 0.54, 0.99, P = 0.04), However, subgroup and sensitivity analyses did not show a significant difference in the success rate between the two groups (P ≥0.05). The AGV group had a higher mean intraocular pressure than the BGI group in short-term (6 studies, 685 eyes, weighted mean difference [WMD]: 2.12 mmHg; 95 % CI: 0.72-3.52; P <0.05) and long-term pooled results (7 studies, 659 eyes, WMD: 1.85 mmHg; 95 % CI: 0.43, 3.28; P = 0.01). The BGI group required fewer glaucoma medications after implantation than the AGV group in two follow-up periods (all P <0.05). The AGV was found to be associated with a significantly lower frequency of total complications (8 studies, 971 eyes, OR: 0.67; 95 % CI: 0.50-0.90; P = 0.007) and severe complications (8 studies, 971 eyes, OR: 0.57; 95 % CI: 0.36-0.91; P = 0.02) than the BGI. The study showed no significant difference in success rate between the two groups. The BGI was more effective for control of intraocular pressure and required fewer medications than the AGV, but the AGV had lower incidence of total and severe complications than the BGI.


Antibody-induced lysis of isolated rat epididymal adipocytes and complement activation in vivo.
To identify human monoclonal antibodies selectively binding to human adipocytes and to evaluate their ability to induce lysis of isolated rat adipocytes in vitro and to reduce rat complement levels in vivo. Using phage display technology, human monoclonal antibodies binding to human adipocyte plasma membranes were identified. Three antibodies (Fat 13, Fat 37, and Fat 41) were selected based on their additional cross-reaction with rat adipocytes and reformatted as a rat chimeric IgG2bs. The ability of these antibodies, both singly and in combination, to induce lysis of rat epididymal adipocytes in vitro and the reduction of serum complement levels in vivo in the rat was evaluated. All antibodies caused similar time- and dose-dependent lysis of isolated rat adipocytes. Calculated mean EC(50) values (maximum percentage of lysis in parentheses) were 0.680 microg/mL (63.2%), 0.546 microg/mL (72.4%), and 0.391 microg/mL (73.7%) for Fat 13, Fat 37, and Fat 41, respectively. Combinations were no more effective than individual antibodies in inducing lysis. Anti-adipocyte antibodies (both singly and in combination) were also similarly effective in vivo. In rats, doses of monoclonal antibody up to 10 mg/kg intraperitoneal generally caused almost complete depletion of serum complement up to 24 hours after dosing recovering to baseline values by day 5. Individual and combinations of monoclonal anti-adipocyte antibodies produced a complement-dependent and concentration-dependent activity to lyse adipocytes in vitro and in vivo as measured by a dramatic depletion in serum complement.


A simple model of COVID-19 explains disease severity and the effect of treatments.
Considerable effort has been made to better understand why some people suffer from severe COVID-19 while others remain asymptomatic. This has led to important clinical findings; people with severe COVID-19 generally experience persistently high levels of inflammation, slower viral load decay, display a dysregulated type-I interferon response, have less active natural killer cells and increased levels of neutrophil extracellular traps. How these findings are connected to the pathogenesis of COVID-19 remains unclear. We propose a mathematical model that sheds light on this issue by focusing on cells that trigger inflammation through molecular patterns: infected cells carrying pathogen-associated molecular patterns (PAMPs) and damaged cells producing damage-associated molecular patterns (DAMPs). The former signals the presence of pathogens while the latter signals danger such as hypoxia or lack of nutrients. Analyses show that SARS-CoV-2 infections can lead to a self-perpetuating feedback loop between DAMP expressing cells and inflammation, identifying the inability to quickly clear PAMPs and DAMPs as the main contributor to hyperinflammation. The model explains clinical findings and reveal conditions that can increase the likelihood of desired clinical outcome from treatment administration. In particular, the analysis suggest that antivirals need to be administered early during infection to have an impact on disease severity. The simplicity of the model and its high level of consistency with clinical findings motivate its use for the formulation of new treatment strategies.


Genetic positioning of centromeres through half-tetrad analysis in gynogenetic diploid families of the Zhikong scallop (Chlamys farreri).
Centromere mapping is a powerful tool for improving linkage maps, investigating crossover events, and understanding chiasma interference during meiosis. Ninety microsatellite markers selected across all linkage groups (LGs) from a previous Chlamys farreri genetic map were studied in three artificially induced meiogynogenetic families for centromere mapping by half-tetrad analysis. Inheritance analyses showed that all 90 microsatellite loci conformed to Mendelian inheritance in the control crosses, while 4.4 % of the microsatellite loci showed segregation departures from an expected 1:1 ratio of two homozygote classes in meiogynogenetic progeny. The second division segregation frequency (y) of the microsatellites ranged from 0.033 to 0.778 with a mean of 0.332, confirming the occurrence of partial chiasma interference in this species. Heterogeneity of y is observed in one of 42 cases in which markers were typed in more than one family, suggesting variation in gene-centromere recombination among families. Centromere location was mostly in accordance with the C. farreri karyotype, but differences in marker order between linkage and centromere maps occurred. Overall, this study makes the genetic linkage map a more complete and informative tool for genomic studies and it will also facilitate future research of the structure and function of the scallop centromeres.


Postpartum Depression and Early Predictors of Lower Maternal Confidence at 12 to 15 Months after Delivery.
The objective of the present study is to assess the association of early postpartum depression and maternal confidence with low maternal confidence at 12-15 months after delivery. Prospective study performed from 2013 to 2015 with 358 postpartum women who had participated in a cluster trial to treat their depression during pregnancy. At 6-8 months after birth, we reviewed socio-demographics, obstetric data and Postpartum Depression (PPD) with the Patient Health Questionnaire-9. Maternal Confidence (MC) was assessed at 6-8 and 12-15 months after birth with the Maternal Confidence Questionnaire. Low and High MC was defined using 50% percentile. The crude and adjusted Odds Ratios (OR) with the 95% Confidence Interval (CI) were calculated using Poisson regression with robust variance. Multivariate models estimated the ORs between postpartum depression and LMC at 12-15 months adjusted for socio-demographic variables, maternal characteristics and previous LMC. Statistical analysis was performed with STATA12 and the significance level was considered equal or lower than 5%. Among a sample of women who were depressed during pregnancy, 19% had probably moderate to severe depression, at the beginning of the child' second year of life. Low maternal confidence was associated with previous low maternal confidence (OR = 1.71; 95% CI 1.33:2.20, p = <0.001) and vaginal delivery but not with previous PPD. Based on our findings, detection and treatment of women presenting confidence problems at the first months after delivery may prevent later mother self-efficacy problems.


Clinical outcomes and prognostic factors in patients with stage II-III breast cancer treated with neoadjuvant chemotherapy followed by surgery and postmastectomy radiation therapy in the modern treatment era.
There are no randomized studies on the indication for postmastectomy radiation therapy (PMRT) in patients who receive neoadjuvant chemotherapy (NAC) followed by a mastectomy. The aim of this study was to determine clinical outcomes and identify reliable prognostic factors in patients with locally advanced breast cancer treated with NAC followed by a mastectomy and PMRT. We retrospectively evaluated the relationship between clinicopathological factors and outcomes in 351 patients with stage II or III breast cancer who underwent NAC followed by radical mastectomy and PMRT between March 2005 and December 2013. The median follow-up duration was 81 months (Range, 12-156 months). For all patients, the 5-year locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates were 91.3 %, 69.8 %, and 83.4 %, respectively. On multivariate analysis, estrogen-receptor positivity, and complete response of cancer in axillary nodes (ypN0) were significant prognostic factors for better LRFS, while lympho-vascular invasion and clinical stage IIIC were independent prognostic factors for worse LRFS. The number of axillary node metastasesafter surgery was an independent prognostic factor of DMFS and OS. Patients with hormone receptor- and human epidermal growth factor receptor 2 positivity had significantly better 5-year LRFS rates. We identified several prognostic factors in our study. In particular, the number of axillary node metastases is significantly related to OS.


Studies on the digestion of carbohydrates in the camel (Camelus dromedarius).
Camels with cannulas in the small intestine were used to study the "digestive-absorptive" capacities of the small intestine. Solutions of different carbohydrates were infused through the cannulas and the responses in blood glucose levels were measured. Monosaccharides were readily absorbed from the camel small intestine. The pattern of disaccharide absorption indicated that there was high lactase activity and low maltase and sucrase activity, in the camel small intestinal mucosa.


Clinical features of 32 new Japanese cases with autoimmune haemorrha-philia due to anti-factor XIII antibodies.
Autoimmune haemophilia-like disease (or haemorrha-philia) due to anti-factor XIII (FXIII; F13 to avoid confusion with FVIII or FXII) antibodies (termed AH13) is a severe bleeding disorder. Although AH13 is thought to be rare, 'the number of its diagnosed patients' has recently increased in Japan. However, its prevalence remains unknown. To improve understanding of this disease, we examined and diagnosed 32 'new' Japanese patients with AH13. The presence of antibodies against F13-A subunit and/or F13-B subunit was confirmed by using a dot blot test and enzyme-linked immunosorbent assays. Most of our patients had autoantibodies against the F13-A subunit (88%). A predominance of men (59%) was observed. The mean age and residual F13 activity of our AH13 cohort were 71.7 years and 10.5% of normal, respectively, and 53% of cases were idiopathic. Autoimmune disorders and malignancies were the leading underlying disease (both 16%). Intramuscular and subcutaneous bleeding were the leading symptoms (both 72%). Most of our patients were treated with F13 concentrates (72%) to arrest bleeding and with prednisolone (81%) to eradicate anti-F13 autoantibodies. Cyclophosphamide and rituximab (both 25%) were also administered. The mortality of AH13 was high (22%), and haemorrhage was the major cause of death (71%). Moreover, 13% of our AH13 patients were diagnosed after haemorrhagic death. Physicians/haematologists must raise the awareness of AH13 as a life-threatening disease. This report represents the only experience of a nationwide survey, and may contribute to a diagnosis on potentially overlooked non-Japanese AH13 patients in other countries in the world.


Does caffeine prevent hypoxaemic episodes in premature infants? A randomized controlled trial.
Fifty spontaneously breathing, preterm infants 48 h old, of 32 weeks' gestation or less, were assigned randomly to receive caffeine citrate (loading dose 20 mg/kg, maintenance dose 10 mg/kg per day) or a placebo (NaCl 0.9%). The study hypothesis was that caffeine reduces the proportion of infants with recurrent hypoxaemic episodes (decrease in transcutaneous PO2 of 20% within 20 s) from 50% to 25%. Transcutaneous oxygen tension (tcPO2) and heart rate were recorded continuously for 50 h and analysed by computer. The two groups were similar in gestational age, birth weight, delivery mode, sex distribution, and Apgar scores. The mean serum concentration (+/- SD) of caffeine 2 h after the second maintenance dose was 96.0 (+/- 34.5) mumol/l in the group receiving caffeine and 9.3 (+/- 12.8) mumol/l in the group receiving a placebo. The mean proportion of infants with more than six hypoxaemic episodes per 12 h in the caffeine groups was higher (57%) than in the control group (51%). The mean proportion of infants with more than six episodes of bradycardia per 12 h was not statistically different in the caffeine group (79%) from the control group (86%). Our results suggest that prophylactic caffeine has little if any effect on the risk of developing hypoxaemic episodes and bradycardia in small preterm infants and the supposed 50% reduction which was considered clinically important at the start of the trial can be rejected with confidence.


Whole body heat stress increases motor cortical excitability and skill acquisition in humans.
Vigorous systemic exercise stimulates a cascade of molecular and cellular processes that enhance central nervous system (CNS) plasticity and performance. The influence of heat stress on CNS performance and learning is novel. We designed two experiments to determine whether passive heat stress (1) facilitated motor cortex excitability and (2) improved motor task acquisition compared to no heat stress. Motor evoked potentials (MEPs) from the first dorsal interosseus (FDI) were collected before and after 30 min of heat stress at 73 °C. A second cohort of subjects performed a motor learning task using the FDI either following heat or the no heat condition. Heat stress increased heart rate to 65% of age-predicted maximum. After heat, mean resting MEP amplitude increased 48% (p<0.05). MEP stimulus-response amplitudes did not differ according to stimulus intensity. In the second experiment, heat stress caused a significant decrease in absolute and variable error (p<0.05) during a novel movement task using the FDI. Passive environmental heat stress (1) increases motor cortical excitability, and (2) enhances performance in a motor skill acquisition task. Controlled heat stress may prime the CNS to enhance motor skill acquisition during rehabilitation.


Impact of levosimendan on efficacy and renal function in acute heart failure according to renal function: A perspective, multi-center, real-world registry.
Acute heart failure (AHF) is associated with high mortality. Levosimendan, an inodilator, has proved to increase cardiac output and exert renoprotective effect in AHF. Our aim was to investigate the efficacy and renoprotective effects of levosimendan in patients with AHF and different renal function. This is a prospective, observational, multi-center registry. Patients admitted with AHF between June 2020 and May 2022 and treated with levosimendan during the hospital stay were included. Baseline characteristics, laboratory tests, electrocardiogram (ECG), chest X-ray, echocardiography, and treatment were collected. A 5-point Likert scale was used to document patients' baseline dyspnea. The estimated glomerular filtration rate (eGFR) was calculated by means of the Modification of Diet in Renal Disease equation. After levosimendan infusion, patients underwent assessment of degree of dyspnea, and levels of brain-type natriuretic peptide (BNP) /N-terminal pro-BNP (NT-pro BNP), and eGFR repeatedly. Among 789 AHF patients who received levosimendan treatment in this study, 33.0 % were female, mean age was 64.9 ± 16.8 years, and mean eGFR was 72.6 ± 32.5 ml/min/m2. The mean score of dyspnea was 3.0 ± 1.0 using 5-point Likert scale before levosimendan infusion. Dyspnea improved in 68.7% patients at 6h after infusion of levosimendan, and in 79.5% at 24 h. Lower eGFR was associated with lower efficacy rate after 6h infusion (71.7, 70.7, 65.2, and 66.0%, respectively) and after 24 h infusion (80.5, 81.4, 76.2, and 77.8%, respectively). The levels of BNP or NT-pro BNP were also decreased after levosimendan treatment, and in each eGFR category. Levels of eGFR increased from baseline (72.6 ± 32.5 ml/min/m2) to 12-24h (73.8 ± 33.5 ml/min/m2) and 24-72h (75.0 ± 33.4 ml/min/m2) after starting treatment (p < 0.001). However, the eGFR levels increased only in patients with eGFR lower than 90.0 ml/min/m2. In AHF patients who received levosimendan, degree of dyspnea and levels of BNP or NT-pro BNP were significantly improved, especially in patients with higher eGFR levels. However, levosimendan infusion increase eGFR only in AHF patients with renal dysfunction.


The U-shaped association of altitudes with prevalence of hypertension among residents in Tibet, China.
We aimed to evaluate the association of altitudes with the prevalence of hypertension among residents aged 15 years and above in Tibet, China. Data for 11,407 Tibetan residents from the National Health Services Survey in 2013 were analyzed. Association between altitudes and prevalence of physician-diagnosed hypertension was assessed by two logistic regression models as follows: (i) a base model adjusted for age and gender, and (ii) a full model additionally adjusted for body mass index, education, marital status, area of residence, distance to the nearest medical institute, smoking, drinking, and exercise. Nonlinear relationship between altitudes and prevalence of hypertension was explored by restricted cubic spline analyses. Sensitivity analyses were conducted by restricting to residents of rural and/or nomadic areas. The prevalence of hypertension was estimated to be 37.6%. We found a U-shaped association between altitudes and prevalence of physician-diagnosed hypertension with a turning point at around 3800 m (12,467 ft). For residents living above 3800 m, a 1000 m increase in altitudes was associated with 2.05 (95% confidence interval [CI]: 1.62-2.61) times higher odds of having physician-diagnosed hypertension, after adjusting for age and gender. When further controlling for all covariates, the odds ratio (OR) dropped to 1.87 (95% CI: 1.46-2.41). For residents living below 3800 m, a 1000 m increase was associated with 0.29 (95% CI: 0.19-0.44) times less likelihood of having physician-diagnosed hypertension in the full model. Sensitivity analyses among residents in rural and/or nomadic areas showed similar associations. To conclude, altitudes were in a U-shaped association with prevalence of hypertension.


Antifertility profile of the aqueous extract of Moringa oleifera roots.
An aqueous extract of Moringa oleifera roots was investigated for its estrogenic, anti-estrogenic, progestational and antiprogestational activities. Oral administration of extract progressively increased the uterine wet weight of bilaterally ovariectomized rats. This estrogenic activity was supported by stimulation of uterine histo-architecture. When the extract was given conjointly with estradiol dipropionate (EDP), there was a successive reduction in the uterine wet weight when compared to the gain with EDP alone and uterine histological structures were also inhibited. In the deciduoma test, the highest dose of 600 mg/kg interfered with the formation of deciduoma in 50% of the rats, showing some antiprogestational activity. Doses up to 600 mg/kg of the extract orally failed to induce a decidual response in the traumatized uterus of ovariectomized rats. The antifertility effect of the extract appears to be due to multiple attributes.


Live-cell imaging of septins and cell polarity proteins in the growing dikaryotic vegetative hypha of the model mushroom Coprinopsis cinerea.
The developmental biology underlying the morphogenesis of mushrooms remains poorly understood despite the essential role of fungi in the terrestrial environment and global carbon cycle. The mushroom Coprinopsis cinerea is a leading model system for the molecular and cellular basis of fungal morphogenesis. The dikaryotic vegetative hyphae of this fungus grow by tip growth with clamp cell formation, conjugate nuclear division, septation, subapical peg formation, and fusion of the clamp cell to the peg. Studying these processes provides many opportunities to gain insights into fungal cell morphogenesis. Here, we report the dynamics of five septins, as well as the regulators CcCla4, CcSpa2, and F-actin, visualized by tagging with fluorescent proteins, EGFP, PA-GFP or mCherry, in the growing dikaryotic vegetative hyphae. We also observed the nuclei using tagged Sumo proteins and histone H1. The five septins colocalized at the hyphal tip in the shape of a dome with a hole (DwH). CcSpa2-EGFP signals were observed in the hole, while CcCla4 signals were observed as the fluctuating dome at the hyphal tip. Before septation, CcCla4-EGFP was also occasionally recruited transiently around the future septum site. Fluorescent protein-tagged septins and F-actin together formed a contractile ring at the septum site. These distinct specialized growth machineries at different sites of dikaryotic vegetative hyphae provide a foundation to explore the differentiation program of various types of cells required for fruiting body formation.


Living in towers as risk factor of pollen allergy.
The effects of fluctuations in pollen counts have important implications for health services. Little research on the clinical implications of the vertical distribution of pollen in allergy symptoms has been carried out. We have investigated the allergic symptoms of a population of 17 171 patients coming from our health area (Valladolid, Spain) and living in the city and villages. We compared the prevalence of sensitization to different pollens: Graminae, trees and shrub in relation with the floor of the building where they were living. Relative risk of pollen sensitization (confidence index, CI 95%) was higher in patients who were living at high floors than in those patients who were living in lower floors or at street level, independently of rural or urban conditions The chi-square showed a lineal trend in this relationship in the case of sensitization to grass pollen: chi(2): 1794, P > 0.00001 On the basis of our local investigations, natural pollen sensitization appears to increase with height where the patient lives. This paper reports clinical results on the influence of vertical pollen distribution in pollen allergy.


Intraocular lens power calculations after refractive surgery: consensus-K technique.
To describe a new strategy for intraocular lens (IOL) power calculations after laser in situ keratomileusis (LASIK), determine the accuracy of the method, and compare the results with those of previously described techniques. Emory Eye Center, Atlanta, Georgia, USA. This retrospective comparative series compared eyes having cataract extraction after laser in situ keratomileusis (LASIK) and eyes having cataract extraction without previous surgery (control group) from January 1997 to December 2005. In the LASIK group, 2 strategies were used to determine the appropriate corneal curvature (K) value for IOL calculation: (1) the nonconsensus method and (2) the consensus-K technique. Postoperative outcomes were compared and included refraction, deviation from target refraction, and deviation from the ideal K or ideal IOL value for several techniques. There were 43 LASIK eyes (14 nonconsensus and 29 consensus K) and 50 control eyes. The mean absolute deviation from target refraction in the nonconsensus group (1.47 diopters [D]) was significantly higher than that in the consensus-K group (0.52 D) (P = .02) or control group (0.44 D) (P = .01); the mean was not statistically different between the consensus-K group and the control group (P = .5). Compared with values with the consensus-K technique, the absolute deviation from back-calculated K values was significantly higher (P<.05) with all other K-generating methods tested except the classic refractive history method (0.56 D versus 0.65 D) (P = .4). When compared with the IOL value generated using the consensus-K technique, the absolute deviation from back-calculated IOL values was significantly higher for all other methods (P<.05). The consensus-K technique generated refractive outcomes similar to those in the control group and was better than with all other K- or IOL-generating techniques except the classic refractive history method. The consensus method showed less variability and higher predictability than all other methods tested.


Expression of selected genes isolated from whole blood, liver and obex in lambs with experimental classical scrapie and healthy controls, showing a systemic innate immune response at the clinical end-stage.
Incubation period, disease progression, pathology and clinical presentation of classical scrapie in sheep are highly dependent on PRNP genotype, time and route of inoculation and prion strain. Our experimental model with pre-colostrum inoculation of homozygous VRQ lambs has shown to be an effective model with extensive PrPSc dissemination in lymphatic tissue and a short incubation period with severe clinical disease. Serum protein analysis has shown an elevation of acute phase proteins in the clinical stages of this experimental model, and here, we investigate changes in gene expression in whole blood, liver and brain. The animals in the scrapie group showed severe signs of illness 22 weeks post inoculation necessitating euthanasia at 23 weeks post inoculation. This severe clinical presentation was accompanied by changes in expression of several genes. The following genes were differentially expressed in whole blood: TLR2, TLR4, C3, IL1B, LF and SAA, in liver tissue, the following genes differentially expressed: TNF-α, SAA, HP, CP, AAT, TTR and TF, and in the brain tissue, the following genes were differentially expressed: HP, CP, ALB and TTR. We report a strong and evident transcriptional innate immune response in the terminal stage of classical scrapie in these animals. The PRNP genotype and time of inoculation are believed to contribute to the clinical presentation, including the extensive dissemination of PrPSc throughout the lymphatic tissue.


The use of hybrid H-2 genes for localizing the positions of polymorphic determinants recognized by antibodies and by cytotoxic T cells.
Hybrid H-2 genes have been constructed in which the DNA sequences encoding the C2 domains were exchanged between the H-2Ld and H-2Dd genes in order to determine the positions of polymorphic sites of mouse class I antigen. DNA-mediated gene transfer allowed the expression of hybrid H-2 genes in mouse fibroblasts. Binding studies with monoclonal anti-H-2 antibodies against the transformed cells revealed that some serologic determinants were mapped to the C2 domain, while the majority mapped to the N and/or C1 domains. In contrast, uncloned anti-Ld and anti-Dd cytotoxic T lymphocytes predominantly recognized N and/or C1 but not C2 domains. Additionally, all three H-2-restricted hapten-specific cytotoxic T-cell populations (TNP, FITC, and AED) showed predominant detection of N and/or C1 domains.


HLA-A*2402-restricted HIV-1-specific cytotoxic T lymphocytes and escape mutation after ART with structured treatment interruptions.
Although a limited duration of immune activation of structured treatment interruptions (STIs) has been reported, the immune escape mechanism during STIs remains obscure. We therefore investigated the role of three immunodominant cytotoxic T lymphocyte (epitopes) in 12 HLA-A*2402-positive patients participating longitudinally during the clinical study of early antiretroviral treatment (ART) with five series of structured treatment interruptions (STIs). The frequency of HLA-A*2402-restricted CTLs varied widely and a sustained CTL response was rarely noted. However, a Y-to-F substitution at the second position in an immunodominant CTL epitope Nef138-10 (Nef138-2F), which was previously demonstrated as escape mutation, was frequently detected in seven patients primarily and emerged in the remaining five patients thereafter, and the existence of escape mutations was correlated with high pVL levels early in the clinical course. These findings suggest that escape mutation in the immunodominant CTL epitope may be one of the mechanisms to limit HIV-1-specific immune control in STIs.


Factors influencing length of stay and mortality after first and second hip fractures: an event modeling analysis.
The aim of this study was to investigate factors influencing length of stay and mortality in first and second hip fractures. This was a retrospective study with data analysis. The study was conducted at a level 1 trauma center. Six hundred and seventy-two patients treated for hip fractures (OTA 31-A, 31-B, 32-A1.1) over 30 months were split into 2 groups. 1FG: Six hundred and ten patients (90.8%) suffered a fracture for the first time. 2FG: Sixty-two patients (9.2%) had previously sustained contralateral fractures. Dynamic hip screws or cephalomedullary nails (31-A fractures); cephalomedullary nails (32-A1.1); dynamic hip screws or cannulated screws (undisplaced 31-B fractures); and hemiarthroplasty (displaced 31-B fractures) were used. Postoperative lengths of stay on trauma ward (LOS-T) on the rehabilitation unit (LOS-R) and in hospital (LOS-H) were calculated. Dates of death were recorded. Event analysis and structural equation modeling were used to assess the impact of second fractures, fracture types, age, gender, and ASA grades on these. : The 2 groups were comparable in gender distribution, ASA grades, fracture types, LOS, and mortality at 120 days. 2FG patients were older than 1FG (mean 83.3 vs 80.2 years) with a higher proportion being discharged to institutional care (35.5% vs 18.5%). Event modeling analysis showed that LOS-T was dependent on ASA grade, whereas mortality was dependent on ASA grade, age, and gender. Second fractures were not related to the risks of increased LOS-T, LOS-R, and mortality. Second fractures per se do not increase the risk of longer postoperative stay or higher mortality. Any observed effect on these outcomes in second fractures represents the influence of increasing age. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


Secondhand Tobacco Smoke and Functional Impairments in Older Adults Living in the Community.
There has been no comprehensive examination of the potential association of SHS with broad functional limitation assessment in older adults, where functional limitations are burdensome and challenging. We examined 2258 community-dwelling non-smoking older adults from the Seniors-Enrica-2-cohort. At baseline (2017) and follow-up (2019) grip strength was measured with a Jamar dynamometer, lower-extremity performance with the Short Physical Performance Battery (SPPB), overall physical function using the physical component summary (PCS) of the Spanish version of the SF-12, frailty with a Deficits Accumulation Index (DAI), and mobility limitations with the Rosow-Breslau scale. Baseline exposure to SHS was assessed by serum cotinine, and past exposure was self-reported. Cross-sectional analyses were performed using linear and logistic regression models, whereas functional performance changes were examined using repeated measures models with robust SE estimates. Overall, the median (IQR) serum cotinine concentration was 0.079 (0.035-0.175) ng/ml, with 20 participants presenting concentrations ≥3 ng/ml. Compared to the unexposed, fully-adjusted models showed that the highest exposure group (≥0.239 ng/ml) presented lower grip strength (mean difference: -1.05 kg; 95% CI = -1.80, -0.31) and higher DAI scores (1.52; 95% CI = 0.38, 2.66) at baseline. Similarly, in models of self-reported past exposure, never-smokers who had lived with ≥2 smokers or been exposed to higher SHS cumulative doses showed lower baseline SPPB values, higher DAI scores, and higher prevalence of mobility limitations. In prospective analyses, those in the highest quartile of baseline cotinine presented harmful SPPB [-0.24 (-0.46, -0.02)] and DAI [1.28 (0.00, 2.55)] changes, and higher risk of mobility limitations [hazard ratio: 1.64; 95% CI = 1.01, 2.68] than the unexposed. SHS exposure over the life-course and during old age may accelerate functional decline. This manuscript provides a comprehensive examination of the relationship between secondhand smoke exposure and a broad range of functional limitations in older adults. Results show that: (i) non-smokers who had been exposed to higher cumulative doses of SHS in adulthood show worse physical function than non-exposed. (ii) Exposure to SHS during old age, as measured with cotinine concentrations, is associated with accelerated short-term functional declines. (iii) The effects of SHS are stronger among older adults with chronic morbidities. (iv) Results suggest that more efforts are needed to protect older adults from passive smoking, especially to those with chronic conditions because of their potential greater vulnerability to the effects of SHS.


Lin28A Reduced Sevoflurane-Induced Nerve Injury and Cognitive Dysfunction by Inhibiting Tau Acetylation and Phosphorylation via Activating SIRT1 in Elderly Rats.
Sevoflurane (Sev) might cause neurotoxicity in elderly rats. However, the role of Lin28A in Sev-induced neurotoxicity remains unclear in elderly rats. In this study, elderly rats were used to construct an Sev-induced nerve injury model. Learning and memory abilities were assessed by Morris water maze (MWM) trainings; pathological alterations in hippocampal region were assessed by HE staining; neuronal apoptosis was assessed by TUNEL; related protein expression was analyzed by immunofluorescence, immunohistochemistry, and Western blotting. Results of this study showed that Sev treatment caused nerve injury and cognitive dysfunction in elderly rats, with increased neuronal apoptosis and decreased Lin28A levels. Pathological impairment and learning and memory abilities of elderly rats were significantly improved after forced overexpression of Lin28A using AAV, accompanied by decreased expression of CD68, Iba-1, and GFAP. TUNEL analysis showed that Lin28A overexpression significantly reversed Sev-induced neuronal apoptosis. Further mechanistic analysis showed that Lin28A significantly promoted SIRT1 expression, which further reversed Sev-induced Tau acetylation at lysine 280 and 686 and Tau hyperphosphorylation, thereby alleviating nerve injury and cognitive dysfunction in elderly rats. The introduction of SIRT1 inhibitor EX527 further confirmed the involvement of SIRT1 in the regulation of Lin28A in elderly rats. In conclusion, our findings demonstrated that Lin28A reduced sevoflurane-induced nerve injury and cognitive dysfunction by inhibiting Tau acetylation and phosphorylation via activating SIRT1 in elderly rats.


Oral sialic acid supplementation in NANS-CDG: Results of a single center, open-label, observational pilot study.
NANS-CDG is a congenital disorder of glycosylation (CDG) caused by biallelic variants in NANS, encoding an essential enzyme in de novo sialic acid synthesis. It presents with intellectual developmental disorder (IDD), skeletal dysplasia, neurologic impairment, and gastrointestinal dysfunction. Some patients suffer progressive intellectual neurologic deterioration (PIND), emphasizing the need for a therapy. In a previous study, sialic acid supplementation in knockout nansa zebrafish partially rescued skeletal abnormalities. Here, we performed the first in-human pre- and postnatal sialic-acid study in NANS-CDG. In this open-label observational study, 5 patients with NANS-CDG (range 0-28 years) were treated with oral sialic acid for 15 months. The primary outcome was safety. Secondary outcomes were psychomotor/cognitive testing, height and weight, seizure control, bone health, gastrointestinal symptoms, and biochemical and hematological parameters. Sialic acid was well tolerated. In postnatally treated patients, there was no significant improvement. For the prenatally treated patient, psychomotor and neurologic development was better than two other genotypically identical patients (one treated postnatally, one untreated). The effect of sialic acid treatment may depend on the timing, with prenatal treatment potentially benefiting neurodevelopmental outcomes. Evidence is limited, however, and longer-term follow-up in a larger number of prenatally treated patients is required.


Comparison of SNP tagging methods using empirical data: association study of 713 SNPs on chromosome 12q14.3-12q24.21 for asthma and total serum IgE in an African Caribbean population.
Few comparison studies have been performed on single nucleotide polymorphism (SNP) tagging methods to examine their consistency and effectiveness in terms of inferences about association with disease. We applied several SNP tagging methods to SNPs on chromosome 12q (n=713) and compared the utility of these methods to detect association for asthma and serum IgE levels among a sample of African Caribbean families from Barbados selected through asthmatic probands. We found that a high level of information regarding association is retained in Clayton's htSNP, Stram's TagSNP, and de Bakker's Tagger. We also found a high degree of consistency between TagSNP and Tagger. Using this set of 713 SNPs on chromosome 12q, our study provides insight towards analytic strategies for future studies of complex traits.


On the causes of gene-body methylation variation in Arabidopsis thaliana.
Gene-body methylation (gbM) refers to sparse CG methylation of coding regions, which is especially prominent in evolutionarily conserved house-keeping genes. It is found in both plants and animals, but is directly and stably (epigenetically) inherited over multiple generations in the former. Studies in Arabidopsis thaliana have demonstrated that plants originating from different parts of the world exhibit genome-wide differences in gbM, which could reflect direct selection on gbM, but which could also reflect an epigenetic memory of ancestral genetic and/or environmental factors. Here we look for evidence of such factors in F2 plants resulting from a cross between a southern Swedish line with low gbM and a northern Swedish line with high gbM, grown at two different temperatures. Using bisulfite-sequencing data with nucleotide-level resolution on hundreds of individuals, we confirm that CG sites are either methylated (nearly 100% methylation across sampled cells) or unmethylated (approximately 0% methylation across sampled cells), and show that the higher level of gbM in the northern line is due to more sites being methylated. Furthermore, methylation variants almost always show Mendelian segregation, consistent with their being directly and stably inherited through meiosis. To explore how the differences between the parental lines could have arisen, we focused on somatic deviations from the inherited state, distinguishing between gains (relative to the inherited 0% methylation) and losses (relative to the inherited 100% methylation) at each site in the F2 generation. We demonstrate that deviations predominantly affect sites that differ between the parental lines, consistent with these sites being more mutable. Gains and losses behave very differently in terms of the genomic distribution, and are influenced by the local chromatin state. We find clear evidence for different trans-acting genetic polymorphism affecting gains and losses, with those affecting gains showing strong environmental interactions (G×E). Direct effects of the environment were minimal. In conclusion, we show that genetic and environmental factors can change gbM at a cellular level, and hypothesize that these factors can also lead to transgenerational differences between individuals via the inclusion of such changes in the zygote. If true, this could explain genographic pattern of gbM with selection, and would cast doubt on estimates of epimutation rates from inbred lines in constant environments.


Sources of variance in baseline gene expression in the rodent liver.
The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization of variation due to individual, environmental, and technical factors. Analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in liver gene expression in the rodent. Here, studies which highlight contributions of different factors to gene expression variability in the rodent liver are discussed including a large meta-analysis of rat liver, which identified genes that vary in control animals in the absence of chemical treatment. Genes and their pathways that are the most and least variable were identified in a number of these studies. Life stage, fasting, sex, diet, circadian rhythm and liver lobe source can profoundly influence gene expression in the liver. Recognition of biological and technical factors that contribute to variability of background gene expression can help the investigator in the design of an experiment that maximizes sensitivity and reduces the influence of confounders that may lead to misinterpretation of genomic changes. The factors that contribute to variability in liver gene expression in rodents are likely analogous to those contributing to human interindividual variability in drug response and chemical toxicity. Identification of batteries of genes that are altered in a variety of background conditions could be used to predict responses to drugs and chemicals in appropriate models of the human liver.


The inverted U-shaped relationship between knowledge diversity of researchers and societal impact.
With the increasing importance of interdisciplinary research, some studies have focused on the role of reference diversity by analysing reference lists of published papers. However, the relationship between the knowledge diversity of collaborating team members and research performance has been overlooked. In this study, we measured knowledge diversity through the disciplinary attributes of collaborating authors and research performance (understood as societal impact) through altmetric data. The major findings are: (1) The relationship between interdisciplinary collaboration diversity and societal impact is not a simple linear one, showing an inverted U-shaped pattern; and (2) As the number of collaborative disciplines increases, the marginal effects diminish or even become outweighed by the costs, showing a predominance of negative influences. Hence, diversity in interdisciplinary collaboration does not always have a positive impact. Research collaborations need to take into account the cost issues associated with the diversity of member disciplines.


[Fusion in adolescent idiopathic scoliosis : Anterior, posterior or combined? One-stage or two-stage?].
Scoliosis is a complex, three-dimensional spinal deformity with various causes. Adolescent idiopathic scoliosis (AIS) is the most common form. Surgical treatment is indicated for curves greater than 45-50° meaured using the Cobb method. We can distinguish among posterior, anterior or combined surgical procedures. Today, the posterior, transpedicular approach has revolutionized scoliosis surgery. This review gives an overview of current surgical options in scoliosis treatment.


A test for blood in haematophagous insects and its application to apparent blood feeding in insectivorous Ceratopogonidae (Diptera).
A method is described to confirm the presence of blood in fixed haematophagous insects. It was used to establish that the dark gut contents of individuals of five genera of insectivorous midges (Ceratopogonidae) was not blood.


The molecular mechanism of microRNA-145 to suppress invasion-metastasis cascade in gastric cancer.
Invasion and metastasis are the major features of malignant tumors that are responsible for 90% of cancer-related deaths. Recently, microRNAs have been discovered to have a role in suppressing tumor metastasis. This study's aim was to clarify the roles of miR-145 in gastric carcinomas and its underlying molecular mechanism in regulating tumor metastasis. Here, we demonstrate a stepwise downregulation of miR-145 level in nontumorous gastric mucosa, primary gastric cancers and their secondary metastases. In vitro analysis of miR-145's ectopic expression and loss-of-function suggests that it suppresses gastric cancer cell migration and invasion. In vivo spontaneous metastasis and experimental metastasis assay further confirm its function in suppressing the invasion-metastasis cascade, including impairing local invasion and inhibiting hematogenous metastasis in gastric cancers. Furthermore, we identified a novel mechanism of miR-145 to suppress metastasis. N-cadherin (CDH2) was proved to be a direct target of miR-145, using luciferase assay and western blot. Re-expressing N-cadherin in miR-145-transfected cells reverses their migration and invasion defects. Although not a direct target of miR-145, matrix metallopeptidase 9 (MMP9), but not MMP2, was also significantly decreased in miR-145-expressing cells. We suggest that miR-145 suppresses tumor metastasis by inhibiting N-cadherin protein translation, and then indirectly downregulates its downstream effector MMP9.


Evaluation of jojoba oil as a low-energy fat. 1. A 4-week feeding study in rats.
The nutritional properties of jojoba oil (JO) were examined in a 4-wk feeding study of rats fed a diet with JO at dose levels of 2.2, 4.5 and 9%, supplemented with a conventional fat up to 18%. General health, survival and food intake were not adversely affected. Body-weight gains showed a dose-related decline, which amounted to 20% of the body weight in the high-dose group of both sexes. Clinical chemistry revealed significantly increased levels of various enzymes that were indicative of cell damage. Haematology showed a dose-related increase in white blood cells. On necropsy an apparent distension of the small intestine was found. Histopathological evaluation revealed marked intestinal changes characterized by massive vacuolization and lipid deposition in the enterocytes, accompanied by distension of the villi and an increased cell turnover of small intestinal cells. Faeces production and faeces lipid content were increased with increasing JO levels. The recovery of JO in the faeces also increased in a dose-related manner and was found to be correlated with the intestinal histopathological changes. The significant adverse clinical and histopathological effects observed in this study imply that JO cannot be considered as a promising alternative dietary fat with a low digestibility.


Decreased expression of methyl methansulfonate and ultraviolet-sensitive gene clone 81 (Mus81) is correlated with a poor prognosis in patients with hepatocellular carcinoma.
Recent work has demonstrated that methyl methansulfonate and ultraviolet-sensitive gene clone 81 (Mus81) is critical in the maintenance of chromosome stability and tumor suppression in mice. To investigate its role in human hepatocellular carcinoma (HCC), which currently is unknown, the authors examined the correlation between Mus81 expression and prognosis in patients with HCC. Reverse transcriptase-polymersase chain reaction and Western blot analyses were used to determine Mus81 expression levels in 41 paired HCC and paracarcinomatous liver tissue (PCLT) specimens. Immunohistochemistry analysis was also performed on 104 HCC specimens from patients with follow-up information. Both Mus81 messenger RNA and protein expression levels were decreased significantly in HCC specimens. Moreover, lower Mus81 expression levels were detected in nodular HCC (NHCC) than in solitary large HCC (SLHCC) specimens. Among 104 specimens of HCC, the positive rate of Mus81 was significantly lower than the rate in PCLT (P = .017), and the decreased Mus81expression was correlated significantly with high Edmondson-Steiner grade, multiple tumor nodes, and venous invasion. Patients with HCC who had low Mus81 expression had either poorer disease-free survival or poorer overall survival than patients who had with high Mus81 expression (P = .0027 and P = .0001, respectively). Multivariate Cox regression analysis revealed that low Mus81 expression was an independent prognostic factor for patients with HCC (risk ratio, 5.74; P = .012). Mus81 expression levels were decreased significantly in HCC specimens, and the decreased levels were correlated with a poor prognosis in patients with HCC, implicating Mus81 as a candidate prognostic marker in HCC.


Development and functions of natural killer cells.
Over the last decade, progress in molecular and cellular biology and gene targeting techniques has removed veils from the mysteries of natural killer (NK) cell development and function. NK cells are derived from hematopoietic stem cells, for which stem cell factor or Flt3 ligand is required in the early stage of differentiation to NK cell progenitors. Interleukin 15 then plays a crucial role for differentiation and/or maturation of NK progenitors into functional NK cells. Several members of the zinc finger, ETS, and interferon regulatory factor transcription factor families are also involved in the lineage commitment of hematopoietic stem or progenitors into NK cells. Animal models as well as patients deficient in NK cells have provided formal evidence that NK cells play an important role in vivo for innate immunity against tumors and viral infections and for linkage to adaptive immunity. Moreover, recent studies have revealed novel human NK cell subsets in peripheral blood that have the phenotypical characteristics CD3- CD16+ CD56+ and CD3- CD16- CD56bright, which are mainly involved in cytotoxicity and cytokine-mediated immunoregulation, respectively.


Hierarchical helical carbon nanotube fibre as a bone-integrating anterior cruciate ligament replacement.
High rates of ligament damage require replacements; however, current synthetic materials have issues with bone integration leading to implant failure. Here we introduce an artificial ligament that has the required mechanical properties and can integrate with the host bone and restore movement in animals. The ligament is assembled from aligned carbon nanotubes formed into hierarchical helical fibres bearing nanometre and micrometre channels. Osseointegration of the artificial ligament is observed in an anterior cruciate ligament replacement model where clinical polymer controls showed bone resorption. A higher pull-out force is found after a 13-week implantation in rabbit and ovine models, and animals can run and jump normally. The long-term safety of the artificial ligament is demonstrated, and the pathways involved in integration are studied.


Role and interpretation of total serum IgE measurements in the diagnosis of allergic airway disease in adults.
While total IgE measurements are often used in clinical practice, it is unclear how they should be interpreted for the diagnosis of allergic disorders. We studied whether total IgE may be used to rule out or predict sensitization and whether there are age or gender differences. ROC curves were assessed in subjects with asthma or allergy symptoms from a general population sample. We studied predictive values and likelihood ratios. At least one positive skin test (Phazet) or specific IgE measurement (CAP) served as reference. High negative predictive values, suitable to rule out sensitization, were not found. In younger subjects, high total IgE levels strongly increase the probability of sensitization. The relationship between monosensitization and total IgE was less strong, but meaningful positive likelihood ratios were found at higher levels of total IgE. The discriminating ability of total IgE was better in the age group 20-44 than 45-70 years and comparable in males and females. Total IgE is not useful to rule out sensitization to common inhalant allergens. High total IgE may indicate a high probability of sensitization and may be useful to decide whether further investigation is warranted in patients with negative specific allergy tests to a panel of common inhalant allergens.


Development of Skylab medical equipment and flight preparations.
The purpose of this report is to provide an introduction and overview of the Skylab medical program. Some of the more important medical systems and equipment provided for crew sustenance are described. The major inflight medical experiments are reviewed, and the test programs are discussed. The medical operations procedures and the techniques used to monitor crew health are reviewed to provide an understanding of the medical management of this complex mission.


ALS-causing P56S mutation and splicing variation on the hVAPB MSP domain transform its β-sandwich fold into lipid-interacting helical conformations.
P56S mutation on VAPB MSP domain causes a familial ALS, characteristic of severe aggregation both in vivo and in vitro. We previously showed that P56S rendered the MSP domain to be predominantly disordered in water. Unexpectedly, here we reveal that P56S-MSP transforms into a highly helical conformation in a membrane environment. This chameleon transformation is shared by a splicing variant VAPB-3 with a truncated MSP domain, which is also highly disordered and buffer insoluble as demonstrated here by NMR. Our discovery provides a mechanism for ALS-causing VAPB mutants/variants to gain novel functions such as to mediate ER structure before significant accumulation of aggregates occurs.


Surface restructuring, kinetic oscillations, and chaos in heterogeneous catalytic reactions.
We present comprehensive Monte Carlo simulations of isothermal kinetic oscillations and chaos in catalytic reactions accompanied by adsorbate-induced surface restructuring. Our analysis is based on the lattice-gas model describing surface restructuring in terms of the statistical theory of first-order phase transitions. As an example, we treat the kinetics of the NO-H2 reaction on the Pt(100) surface. A proposed reduced mechanism of this reaction includes NO adsorption, desorption, and decomposition occurring on the restructured patches of the surface (the decomposition products are rapidly removed from the surface via N2 desorption and H2O formation and desorption). Calculations are performed with a qualitatively realistic ratio between the rates of different elementary steps. In particular, NO diffusion is several orders of magnitude faster compared to the other steps. On the nm scale, the model predicts formation of restructured islands with atomically sharp boundaries. The shape of the islands is found to change dramatically with varying reaction conditions. Despite phase separation on the surface, the transition from almost harmonic oscillations (with relatively small separate islands) to chaos (with merging islands) is demonstrated to occur via the standard Feigenbaum scenario. Near the critical point, the dependence of the amplitude of oscillations on the governing parameter is shown to be close to that predicted for the Hopf supercritical bifurcation.


Natural and experimental transfer of anti-Pertussis antibodies confers resistance to experimental autoimmune encephalomyelitis.
Pregnant rats challenged with Bordetela Pertussis vaccine, with or without encephalitogenic antigen during pregnancy, transferred a resistance to induction of experimental autoimmune encephalomyelitis (EAE) to their offspring. Cross-fostering experiments showed that the protection against EAE is conferred during the lactation period through the transfer of anti pertussis antibodies in the milk. The degree of protection correlated with antibody levels. Passive transfer of these antibodies through intraperitoneal injection to naive adult rats also conferred the same degree of protection against EAE induction. It is suggested that such transfer of resistance and antibodies may serve as a model for the study of milk transmitted immunocompetent factors, as well as a model for the mechanisms involved in the resistance to EAE.


The cytoskeletal framework and poliovirus metabolism.
The cytoskeletal framework prepared by detergent lysis of suspension-grown HeLa cells is compared to the structure obtained from poliovirus-infected cells. This framework, which retains major features of cell morphology and carries the cellular polyribosomes as well as the major structural filaments, is profoundly reorganized following virus infection. This reorganization underlies, at least in part, the morphological changes termed the "cytoplasmic effect." These cytoskeletal changes appear related to the involvement of the framework with viral-specific metabolism. Extensive cytoskeleton alterations occur even when guanidine inhibits viral replication, and thus result from small amounts of early viral products. The normally spheroidal nucleus deforms, allowing a modified region of the cytoplasm to occupy a central position in the cell, and many membrane-enclosed vesicles peculiar to the infected cell are elaborated here. The skeleton preparation reveals that this region contains intermediate filaments arranged in a pattern unique to infected cells. Further changes occur when viral replication is permitted. The central region filaments become coated with darkly staining material which may be viral RNA. Numerous small particles appear on the filaments which resemble partially assembled virions. Mature virions, however, have no affinity for the cytoskeleton and appear to be free in the cytoplasm. Host cell messenger RNA, normally attached to the skeletal framework, is released in infected cells and is replaced by the viral-specific polyribosomes. The trabecular network which carries polyribosomes appears to be rearranged; the viral polyribosomes are located principally at the cell periphery and are excluded from the central region. The viral replication complex with its double-stranded RNA is also attached to the skeletal framework and may comprise the dark staining material coating the filaments of the central cell region.


Interfacial Engineering FeOOH/CoO Nanoneedle Array for Efficient Overall Water Splitting Driven by Solar Energy.
Interface engineering has been applied as an effective strategy to boost the electrocatalytic performance because of the strong coupling and synergistic effects between individual components. Here, we engineered vertically aligned FeOOH/CoO nanoneedle array with a synergistic interface between FeOOH and CoO on Ni foam (NF) by a simple impregnation method. The synthesized FeOOH/CoO exhibits outstanding electrocatalytic activity and stability for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) in an alkaline medium. For the overall water splitting, the bifunctional FeOOH/CoO nanoneedle catalyst requires only a cell voltage of 1.58 V to achieve a current density of 10 mA cm-2 , which is much lower than that required for IrO2 //Pt/C (1.68 V). The FeOOH/CoO catalyst has been successfully applied for solar cell-driven water electrolysis, revealing its great potential for commercial hydrogen production and solar energy storage.