A case of Canavan disease: the first biochemically proven case in a Japanese girl.
Canavan disease (CD) has only been diagnosed on autopsy or brain biopsy, however, specific biochemical markers, such as N-acetylaspartic acid (NAA) and aspartoacylase activity, have recently been described in CD. We report a case of CD having the above biochemical markers. High levels of NAA were found in her urine, serum and CSF. Fibroblasts did not exhibit aspartoacylase activity. Clinically, she presented progressive psychomotor retardation, cerebellar signs, pyramidal signs and relative megalencephaly. CT and MRI showed findings of leukodystrophy. The evoked potentials showed widespread involvement in the brainstem. Magnetic resonance spectra showed a high level of NAA in the white matter. In Japan, this case is the first of CD determined on the basis of biochemical markers.


Motivational interviewing and problem-solving therapy intervention for patients on antiretroviral therapy for HIV in Tshwane, South Africa: A randomized controlled trial to assess the impact on alcohol consumption.
Reduction of alcohol consumption is important for people undergoing treatment for HIV. We tested the efficacy of a brief intervention for reducing the average volume of alcohol consumed among patients on HIV antiretroviral therapy (ART). This study used a two-arm multi-centre randomized controlled trial with follow-up to 6 months. Recruitment occurred between May 2016 and October 2017 at six ART clinics at public hospitals in Tshwane, South Africa. Participants were people living with HIV, mean age 40.8 years [standard deviation (SD) = 9.07], 57.5% female, and on average 6.9 years (SD = 3.62) on ART. At baseline (BL), the mean number of drinks consumed over the past 30 days was 25.2 (SD = 38.3). Of 756 eligible patients, 623 were enrolled. Participants were randomly assigned to a motivational interviewing (MI)/problem-solving therapy (PST) intervention arm (four modules of MI and PST delivered over two sessions by interventionists) or a treatment as usual (TAU) comparison arm. People assessing outcomes were masked to group assignment. The primary outcome was the number of standard drinks (15 ml pure alcohol) consumed during the past 30 days assessed at 6-month follow-up (6MFU). Of the 305 participants randomized to MI/PST, 225 (74%) completed the intervention (all modules). At 6MFU, retention was 88% for the control and 83% for the intervention arm. In support of the hypothesis, an intention-to-treat-analysis for the primary outcome at 6MFU was -0.410 (95% confidence interval = -0.670 to -0.149) units lower on log scale in the intervention group than in the control group (P = 0.002), a 34% relative reduction in the number of drinks. Sensitivity analyses were undertaken for patients who had alcohol use disorders identification test (AUDIT) scores ≥ 8 at BL (n = 299). Findings were similar to those of the whole sample. In South Africa, a motivational interviewing/problem-solving therapy intervention significantly reduced drinking levels in HIV-infected patients on antiretroviral therapy at 6-month follow-up.


Application of C2 subfacetal screws for the management of atlantoaxial dislocation in patients with Klippel-Feil syndrome characterized by a narrow C2 pedicle and high-riding vertebral artery.
This study aims to investigate the clinical application and feasibility of C2 subfacetal screws in patients with Klippel-Feil syndrome (KFS), narrow C2 pedicles, and high-riding vertebral arteries (HRVAs). The clinical data of seven patients with KFS, atlantoaxial dislocation, narrow C2 pedicles, and HRVAs treated with C2 subfacetal screws were analyzed in this retrospective study. The internal height, isthmus height, and pedicle width of C2 vertebra were measured using preoperative computed tomography (CT). Subfacetal screws were inserted for 7 patients (12 sides). The position and length of the screws were observed using postoperative CT. Intraoperative dura mater and vertebral artery (VA) injuries were recorded. Bone fusion was observed using follow-up CT. The internal height was 10.5 ± 3.2 mm, the isthmus height was 3.7 ± 1.8 mm, the pedicle width was 3.0 ± 1.4 mm, and the screw length was 19.7 ± 1.5 mm. All patients had HRVAs and narrow pedicles. No injury to the dura mater and vertebral artery (VA) occurred in this group of patients. Bone fusion was achieved in all patients during follow-up. In patients with KFS, HRVA, and a narrow C2 pedicle, there is sufficient space below the C2 articular surface for screw insertion. When the pedicle is narrow and the C2 pedicle screw is not suitable for placement due to possible injury to the VA, subfacetal screws are a feasible alternative.


Oncogenic action of phospholipase A2 in prostate cancer.
Mortality from prostate cancer is a result of progression of cancer cells to become androgen-refractory and metastatic. Eicosanoid products of the cyclooxygenase (COX) and lipoxygenase (LOX) pathways are important mediators of the proliferation of prostate cancer cells in culture and regulate tumour vascularisation and metastasis in animal models. Pharmacological agents that block either COX or LOX products effectively reduce the size of prostate cancer xenografts. Recently, phospholipase A(2) (PLA(2)) enzymes, which regulate the provision of arachidonic acid to both COX- and LOX-derived eicosanoids, are found to also regulate the growth of prostate cancer cells and tumours, with one enzyme, secreted PLA(2)-IIA, being increased in prostate cancer tissues. Annexin A1 and A2, known inhibitors of cytosolic phospholipase A(2)-alpha activity, are absent in prostate cancer tissues. We propose that PLA(2) enzyme function is dysregulated by aberrant up regulation of secreted enzymes and downregulation of endogenous inhibitors of cytosolic phospholipase A(2) activity in prostate cancer and that this dysregulation contributes to the pathogenesis of prostate cancer. Thus, in addition to COX and LOX enzymes, PLA(2) enzymes represent important targets for the treatment of prostate cancer.


The Facial Artery as a Branch of the External Carotid Artery in Thomas Turner's (1793-1873) Treatise on the Arterial System (1825) and a Comparison with Modern Anatomy.
The aim of the present paper is to contribute to the understanding of the history of the anatomical study of the facial artery. The facial artery plays a fundamental role in the study of the anatomy of the face, and in maxillofacial and vascular surgery. The debate on the understating of this vessel is essential in the educational process, with special focus on the historical development of topographical and descriptive ideas about it. The comparison between the study of facial artery in the work of Thomas Turner (1793-1873) and modern anatomical concepts serves as an excellent educational paradigm. The documentary research method was used this short historical survey. CONCLUSION: Thomas Turner laid the scientific foundation for the accurate anatomical study of the facial artery.


The values of cerebrovascular pressure reactivity and brain tissue oxygen pressure reactivity in experimental anhepatic liver failure.
We investigated in a porcine model of anhepatic acute liver failure (ALF), the value of two parameters describing cerebrovascular autoregulatory capacity, pressure reactivity index (PRx) and brain tissue oxygen pressure reactivity (ORx), regarding their power to predict the development of intracranial hypertension. In six pigs, hepatectomy was performed. Only one animal was sham operated. All animals received neuromonitoring including arterial blood pressure, intracranial pressure (ICP), and brain tissue partial oxygen pressure (P(br)O(2)). The average time of neuromonitoring was 31.0 h. Cerebral perfusion pressures (CPP), cerebrovascular pressure reactivity index (PRx) and brain tissue oxygen reactivity index (ORx) were calculated. Perioperative disturbance of AR improved within 4 h after surgery. From 6 to 16 h post hepatectomy, ICP did slowly increase by 4 mmHg from baseline; CPP remained stable around 40 mmHg. PRx and ORx, however, indicated in this period a progressive loss of AR, reflected in a decrease of P(br)O(2) despite unchanged CPP. Beyond 16 h, ICP rose quickly. At CPP levels below 35 mmHg, P(br)O(2) fell to ischemic levels. The loss of cerebrovascular autoregulatory capacity, indicated by a rise of PRx and ORx precedes the final crisis of uncontrollable intracranial hypertension in this animal model by hours. During this phase cerebral blood flow, as reflected in tissue oxygenation, deteriorates despite unchanged CPP. Monitoring of AR during ALF therefore seems to carry the power to identify a risk for development of critical CBF and intracranial hypertension.


Stressful incidents, stress and coping strategies in the pre-registration house officer year.
Previous studies have drawn attention to the stresses experienced by doctors in their first year. To gain a deeper understanding of the causes of stress in newly qualified doctors, how they cope, and what interventions might make the year less traumatic. Postal questionnaire. This study focused on an open question asking about a stressful incident, the coping strategy used to deal with it, stressors in general and current levels of stress using the General Health Questionnaire. 336 hospitals throughout the United Kingdom. A cohort of doctors followed from the time of their application to medical school, studied towards the end of their pre-registration year (n=2456). The response rate to the questionnaire was 58.4%. The incidents were categorised into the major groups Responsibility (33.6%), Interpersonal (29.7%), Overwork (17.0%), Death and disease (13.0%), and Self (6.7%). GHQ revealed psychological morbidity in 31% of respondents. Stress levels were highest in those reporting an incident about Responsibility or Self, lowest in those describing Death or disease. Stressors in general and preferred coping strategies differed between the groups. The incidents suggested the following interventions to reduce stress: better supervision in the first few weeks in post, at night, and for medical problems on surgical wards; more attention to avoiding sleep deprivation; more time for discussion with colleagues at work; more personal time with friends and family. The choice of incident described was influenced by the personal characteristics of the respondent.


Interaction of oxicam NSAIDs with DMPC vesicles: differential partitioning of drugs.
Small unilamellar vesicles (SUVs) formed by the dimyristoylphosphatidylcholine (DMPC), a phospholipid; serve as a membrane mimetic system that can be used to study the effect of absence of net surface charges on drug-membrane interaction. The targets of non-steroidal anti-inflammatory drugs (NSAIDs) are cyclooxygenases, which are membrane active enzymes. Hence, to approach their targets NSAIDs have to pass different bio-membranes. Different membrane parameters are expected to guide the first level of interaction of these drugs before they are presented to their targets. Our earlier studies have demonstrated the crucial role of surface charges of membrane mimetic systems like micelles and mixed micelles on the interaction of oxicam NSAIDs. In order to see whether net surface charges of membranes are essential for the interaction of oxicam NSAIDs, we have studied the incorporation of two oxicam NSAIDs, viz., piroxicam and meloxicam in DMPC vesicles using the intrinsic fluorescence properties of the drugs. To see whether different prototropic forms of the drugs can interact with DMPC vesicles, studies were carried out under different pH conditions. Transmission electron microscopy (TEM) was used to characterize the SUVs those were formed at different pH values. Steady state fluorescence anisotropy measurements show that both forms of the two drugs, viz., global neutral and anion can be incorporated into the DMPC vesicles. Partition coefficient (KP) between DMPC and the aqueous buffer used has been calculated in all cases from fluorescent intensity measurements. The KP values for the neutral and anionic forms of piroxicam are 219.0 and 25.8, respectively, and that for meloxicam are 896.7 and 110.2, respectively. From the KP values it is evident that irrespective of the nature of the prototropic forms, meloxicam has a higher KP value than piroxicam. This correlates with the previously calculated log KP values between n-octanol and aqueous phase, which demonstrates that in absence of net surface charges of DMPC vesicles the hydrophobic interaction is the principal driving force for incorporation. Our results imply that for bio-membranes having no net surface charges hydrophobic effect plays a principal role to guide these NSAIDs to their targets.


Volatile/semi-volatile metabolites profiling in living vegetables via a novel covalent triazine framework based solid-phase microextraction fiber coupled with GC-QTOF-MS.
An in vivo solid-phase microextraction (SPME) fiber with high-coverage capture capacity of plant endogenous substances based on the porous covalent triazine framework (CTF) material was developed. The CTF fiber coupled with gas chromatographic quadrupole time-of-flight mass spectrometer (GC-QTOF-MS) analysis was used for monitoring untargeted endogenous metabolites in living Chinese cabbage plants (Brassica campestris L. ssp. chinensis Makino (var. communis Tsen et Lee)). A total of 100 endogenous substances were identified, mainly including aldehydes, ketones, acids, alcohols, phenols, alkanes, alkenes, esters, isorhodanates, nitriles, as well as indole and its derivatives. Using the in vivo metabolites analysis method, Chinese cabbage plants at different growing stages demonstrated significantly statistical differences in plant metabolism. In addition, metabolic dysregulation of Chinese cabbage plants under fipronil pesticide contamination was observed. To summarize, the proposed approach provides a feasible method to capture metabolic information in living vegetables and for risk assessment of pesticide use during agricultural production.


Suppression of DRR1 results in the accumulation of insoluble ubiquitinated proteins, which impairs drought stress tolerance.
Drought stress has detrimental effects on plants. Although the abscisic acid (ABA)-mediated drought response is well established, defensive mechanisms to cope with dehydration-induced proteotoxicity have been rarely studied. DRR1 was identified as an Arabidopsis drought-induced gene encoding an ER-localized RING-type E3 Ub ligase. Suppression of DRR1 markedly reduced tolerance to drought and proteotoxic stress without altering ABA-mediated germination and stomatal movement. Proteotoxicity- and dehydration-induced insoluble ubiquitinated protein accumulation was more obvious in DRR1 loss-of-function plants than in wild-type plants. These results suggest that DRR1 is involved in an ABA-independent drought stress response possibly through the mitigation of dehydration-induced proteotoxic stress.


Bacterial ABC transporters of iron containing compounds.
Iron acquisition is an essential aspect of cell physiology for most bacteria. Although much is known about how bacteria initially recognize the various iron sources they can encounter, whether siderophore, heme, host iron/heme binding proteins, much less is known about how the iron containing compounds (Fe2+, Fe3+, Fe3+-siderophore complex or heme) are transported across the cytoplasmic membrane. This last transport step is powered by specific ABC (ATP-Binding-Cassette) transporters, made up of a substrate binding protein (SBP) that delivers its cargo to the TMD (TransMembrane Domain) of the ABC transporter triggering the entry of the substrate inside the cytoplasm upon catalytic activity of the ABC module. This review focuses on structural aspects of the functioning of such ABC transporters with the most part devoted to the substrate binding proteins.


Comparative evaluation of classical intrafascial-supracervical hysterectomy (CISH) with transuterine mucosal resection as performed by pelviscopy and laparotomy--our first 200 cases.
A novel way of performing endoscopic intrafascial supracervical hysterectomy is presented. By using the endoscopic approach for dissection as well as uterine extraction using the serrated-edged macro-morcellator, we avoid giving the patient a colpotomy incision and its inherent post-operative discomfort. A further modification involves nearly complete excision (95%) of uterocervical mucosa using a calibrated resection tool, thus eliminating the possible subsequent development of cervical stump neoplasia. Sparing of the cardinal ligament insertion provides support to the cervical stump. Hemorrhage and genitourinary complications are prevented by avoiding dissection of the parametrium at the level of endocervix. Comparison of data of the pelviscopic CISH procedure with the laparotomy approach in our preliminary series (n = 190) confirms our claims as to its safety. Data on long-term postoperative evaluation are ongoing, but the initial reports deny any postoperative discomfort. Larger randomized studies are required to prove its value compared with the existing techniques. We believe that with its multitude of benefits, the classic intrafascial serrated-edged macro-morcellated (SEMM) hysterectomy (= CISH) may emerge as an attractive alternative to conventional hysterectomy.


Effects of Sound on the Behavior of Wild, Unrestrained Fish Schools.
To assess and manage the impact of man-made sounds on fish, we need information on how behavior is affected. Here, wild unrestrained pelagic fish schools were observed under quiet conditions using sonar. Fish were exposed to synthetic piling sounds at different levels using custom-built sound projectors, and behavioral changes were examined. In some cases, the depth of schools changed after noise playback; full dispersal of schools was also evident. The methods we developed for examining the behavior of unrestrained fish to sound exposure have proved successful and may allow further testing of the relationship between responsiveness and sound level.


Alterations in the structure, function, and chemistry of C fibers following local application of vinblastine to the sciatic nerve of the rat.
Vinblastine, a transport blocker, was applied locally to the sciatic nerve in rats. It was found to be a powerful neurotoxin with a dose-dependent action, destroying all afferents at doses of 5 X 10(-4)M, primarily C fibers at intermediate doses of 2.5 X 10(-4)M, and only at a critically low dose of 10(-4)M was a degeneration-free axon transport blockade, lasting for 4 to 5 days, produced. Such transport block failed to alter thermal responsiveness of the rats as measured behaviorally, by the flexor reflex, or by dorsal horn cell responses. It did, however, significantly reduce both the chemical sensitivity of the C afferents and their ability to produce neurogenic edema. This began 24 hr after treatment and lasted 4 to 5 days. Therefore, it is likely that these functions are dependent on the continuous transport of some compound to the axon terminals from the cell body. This low concentration of local vinblastine treatment also resulted in depletion of fluoride-resistant acid phosphatase from C fiber terminals in the dorsal horn of the spinal cord. Transmission from C fibers to second-order neurons in the spinal cord, however, was totally unaffected. Substance P levels in the spinal terminals was largely unaffected, although in 1 of 5 cases there was depletion. It appears, therefore, that some, but not all, retrograde changes in sensory neurons following peripheral nerve damage can be mimicked by blockade of axon transport. The effects following vinblastine treatment are compared to other peripheral nerve manipulations, such as cut, crush, and application of local capsaicin.


Machine learning methods for low-cost pollen monitoring - Model optimisation and interpretability.
Pollen is a major issue globally, causing as much as 40 % of the population to suffer from hay fever and other allergic conditions. Current techniques for monitoring pollen are either laborious and slow, or expensive, thus alternative methods are needed to provide timely and more localised information on airborne pollen concentrations. We have demonstrated previously that low-cost Optical Particle Counter (OPC) sensors can be used to estimate pollen concentrations when machine learning methods are used to process the data and learn the relationships between OPC output data and conventionally measured pollen concentrations. This study demonstrates how methodical hyperparameter tuning can be employed to significantly improve model performance. We present the results of a range of models based on tuned hyperparameter configurations trained to predict Poaceae (Barnhart), Quercus (L.), Betula (L.), Pinus (L.) and total pollen concentrations. The results achieved here are a significant improvement on results we previously reported: the average R2 scores for the total pollen models have at least doubled compared to using previous parameter settings. Furthermore, we employ the explainable Artificial Intelligence (XAI) technique, SHAP, to interpret the models and understand how each of the input features (i.e. particle sizes) affect the estimated output concentration for each pollen type. In particular, we found that Quercus pollen has a strong positive correlation with particles of optical diameter 1.7-2.3 μm, which distinguishes it from other pollen types such as Poaceae and may suggest that type-specific subpollen particles are present in this size range. There is much further work to be done, especially in training and testing models on data obtained across different environments to evaluate the extent of generalisability. Nevertheless, this work demonstrates the potential this method can offer for low-cost monitoring of pollen and the valuable insight we can gain from what the model has learned.


Perception and Reality: Why a Wholly Empirical Paradigm is Needed to Understand Vision.
A central puzzle in vision science is how perceptions that are routinely at odds with physical measurements of real world properties can arise from neural responses that nonetheless lead to effective behaviors. Here we argue that the solution depends on: (1) rejecting the assumption that the goal of vision is to recover, however imperfectly, properties of the world; and (2) replacing it with a paradigm in which perceptions reflect biological utility based on past experience rather than objective features of the environment. Present evidence is consistent with the conclusion that conceiving vision in wholly empirical terms provides a plausible way to understand what we see and why.


Evaluation of bactericidal efficacy of silver ions on Escherichia coli for drinking water disinfection.
The purpose of this study is the development of a suitable process for the disinfection of drinking water by evaluating bactericidal efficacy of silver ions from silver electrodes. A prototype of a silver ioniser with silver electrodes and control unit has been fabricated. Silver ions from silver electrodes in water samples were estimated with an atomic absorption spectrophotometer. A fresh culture of Escherichia coli (1.75 × 10(3) c.f.u./ml) was exposed to 1, 2, 5, 10 and 20 ppb of silver ions in 100 ml of autoclaved tap water for 60 min. The effect of different pH and temperatures on bactericidal efficacy was observed at constant silver ion concentration (5 ppb) and contact time of 30 min. The maximum bactericidal activity (100%) was observed at 20 ppb of silver ion concentration indicating total disinfection after 20 min while minimum bactericidal activity (25%) was observed after 10 min at 01 ppb of silver ions. Likewise, 100% bactericidal activity was noticed with 2, 5 and 10 ppb of silver ions after 60, 50 and 40 min, respectively. Bactericidal activity at pH 5, 6, 7, 8 and 9 was observed at 79.9%, 79.8%, 80.5%, 100% and 100%, respectively, whereas it was 80.4%, 88.3%, 100%, 100% and 100% at 10°C, 20°C, 30°C, 40°C and 50°C, respectively. The findings of this study revealed that very low concentrations of silver ions at pH 8-9 and temperature >20°C have bactericidal efficacy for total disinfection of drinking water. Silver ionisation is suitable for water disinfection and an appropriate alternative to chlorination which forms carcinogenic disinfection by-products.


Trends in fatty acid intakes of 10-year-old children, 1973 to 1982.
Diets of four groups of 10-year-old children (no. = 871, 30% black, 70% white) were examined over 10 years with 24-hour dietary recalls to study temporal trends in cholesterol, fat, and fatty acid intakes in a community. Boys had higher intakes per day and per kilogram body weight than girls for all nutrients (p less than .0001), but there were no sex differences in nutrients per 1,000 kcal. The only racial difference detected was a higher myristic acid intake in whites (p less than .02). There was a 16% decline in dietary cholesterol intake between 1978 and 1982. Three shifts in fatty acid intake increased the P:S ratio from 0.29 in 1973 to 0.45 in 1978: (a) a 5% decline in oleic acid, coupled with a 5% rise in linoleic acid; (b) a quadrupling of linolenic acid; and (c) less stearic and more myristic acid, with palmitic acid unchanged. Total fat intake provided 38% of the calories in each survey, but the changes in proportions of fatty acids paralleled trends in food consumption patterns and nutrient sources. Despite the changes, few children met prudent diet recommendations, and serum total cholesterol and very-low-density-lipoprotein cholesterol levels did not change over time.


Optimizing the Timeliness of Surgical Therapy in Patients with Breast Cancer Undergoing Immediate Breast Reconstruction.
In breast cancer, coordination of surgical therapy with immediate breast reconstruction (IBR) has been found to significantly delay surgical therapy, which in turn can have an adverse effect on patient survival. The objective of this study was to investigate factors that impact the timeliness of surgical therapy in this setting, which may help to optimize the care of patients with breast cancer. Patients with breast cancer undergoing surgical therapy for breast cancer and immediate reconstruction were reviewed. Patients were divided into two groups: those who underwent surgery ≤ 30 days (group A) and > 30 days (group B) after diagnosis. Multivariate statistical analysis of demographic, disease, surgical, and process of care factors was performed. A total of 348 cases met inclusion criteria, of which 255 (73.2%) were in group A and 93 (26.7%) were in group B. No significant differences were identified in clinical stage, oncologic procedure, or type of reconstruction. On multivariate analysis, an increased likelihood of undergoing surgery ≤ 30 days of diagnosis was observed, with shorter time intervals between surgical oncologist and plastic surgeon consultations [odds ratio (OR) 1.3; 95% confidence interval (CI) 1.1-1.6, p = 0.011]. The number of operating days in common between the surgical oncologist and plastic surgeon nor having the same clinic day impacted timeliness. Patients may undergo both breast conservation surgery and mastectomy with all major types of immediate reconstruction in a timely manner. Early initiation of plastic surgery referrals and surgeon flexibility to work outside the parameters of institutional schedules may help facilitate the timeliness of surgery.


Feasibility of using hyperpolarized [1-13C]lactate as a substrate for in vivo metabolic 13C MRSI studies.
The development of dynamic nuclear polarization in solution has enabled in vivo 13C MR studies at high signal-to-noise ratio following injection of prepolarized 13C substrates. While prior studies have demonstrated the ability to observe metabolism following injection of hyperpolarized 13C pyruvate, the goal of this study was to develop and test a new hyperpolarized agent for investigating in vivo metabolism, [1-13C]lactate. A preparation for prepolarized 13C lactate and the requisite dissolution media were developed to investigate the feasibility for in vivo 13C MRS/MRSI studies following injection of this hyperpolarized agent. This study demonstrated, for the first time, not only the ability to detect hyperpolarized [1-13C]lactate in vivo but also the metabolic products 13C pyruvate, 13C alanine and 13C bicarbonate following injection in normal rats. The use of 13C lactate as a substrate provided the opportunity to study the conversion of lactate to pyruvate in vivo and to detect the secondary conversions to alanine and bicarbonate through pyruvate. This study also demonstrated the potential value of this hyperpolarized agent to investigate in vivo lactate uptake and metabolism in preclinical animal models.


[Comparative histofluorescent study of cardiac sympathetic nerves and adrenal catecholamines in rats under immobilization stress and administered a toxic dose of noradrenaline].
Changes in the adrenergic nerves of the rat heart and dynamics of adrenal catecholamines during immobilization stress and administration of a toxic dose of noradrenaline were found to be of the same type in general. They were manifested by a decrease of the number of fluorescent nerve terminals in the cardiac ventricles and an increase of catecholamine content in the adrenal glands 24 hours after the beginning of the experiment.


Brief report: STING expressed in tumor and non-tumor compartments has distinct roles in regulating anti-tumor immunity.
Type I interferon-mediated activation of immune cells can facilitate the generation of productive tumor antigen-specific T cell responses in solid tumors. The cGAS/STING DNA sensing pathway is a critical upstream mediator of type I interferon production and is an important regulator of anti-tumor immunity. Numerous STING pathway agonists are now being tested in clinical trials, but the effectiveness of this approach is not yet clear and a better understanding of the relative importance of this pathway in various tumor settings is needed. We have evaluated syngeneic tumor models with different baseline inflammatory states to determine the contributions of STING activity in both tumor and non-tumor cellular compartments to anti-tumor immune responses. We find that productive anti-tumor immune responses in the poorly immunogenic B16F10 model show a strong dependence on STING expression in non-tumor cells. In the immunogenic MC38 model, constitutive STING activation in tumor cells can partially bypass the requirement for STING-dependent activity from immune cells. Our findings reveal multiple, context-dependent roles for STING activity in the regulation of anti-tumor immunity and the response to immunotherapy. In preclinical models where STING is basally active, checkpoint inhibition is more likely to have a therapeutic effect and removal of STING signaling from either the tumor or the non-tumor compartment has a minimal effect. Removal of STING signaling in both, however, diminishes the efficacy derived from checkpoint therapy. Further work is needed to understand the heterogeneity of STING signaling in patients, both in tumor cells and the tumor microenvironment, and the best means of harnessing this pathway to generate anti-tumor immunity and improve therapeutic outcomes.


Do dental research journals publish only positive results? A retrospective assessment of publication bias.
The study aimed to determine the presence of publication bias in the top five dental journals with high impact factor published during 2007-2016. The journals included are Journal of Clinical Periodontology, Dental Materials, Clinical Oral Implant Research (COIR), Journal of Endodontics, and Journal of Dental Research (JDR). The content of these journals was hand searched by two authors for scouring the proportion of positive or negative results. Articles showing two outcomes (primary and secondary) were registered depending on the primary result. The present study revealed higher percentage of statistically significant results in the published dental literature. Of five journals, JDR has shown fewer tendencies toward publication of nonsignificant results, whereas COIR has evidenced the highest publication of nonsignificant results. The journals with higher impact factor showed significantly different acceptance rate for research with positive results. However, year-wise publication (2007-2016) did not depict any significant difference. In dental research journals, articles with positive results are finding a better way in getting published compared to articles with negative results.


A convolutional neural network STIFMap reveals associations between stromal stiffness and EMT in breast cancer.
Intratumor heterogeneity associates with poor patient outcome. Stromal stiffening also accompanies cancer. Whether cancers demonstrate stiffness heterogeneity, and if this is linked to tumor cell heterogeneity remains unclear. We developed a method to measure the stiffness heterogeneity in human breast tumors that quantifies the stromal stiffness each cell experiences and permits visual registration with biomarkers of tumor progression. We present Spatially Transformed Inferential Force Map (STIFMap) which exploits computer vision to precisely automate atomic force microscopy (AFM) indentation combined with a trained convolutional neural network to predict stromal elasticity with micron-resolution using collagen morphological features and ground truth AFM data. We registered high-elasticity regions within human breast tumors colocalizing with markers of mechanical activation and an epithelial-to-mesenchymal transition (EMT). The findings highlight the utility of STIFMap to assess mechanical heterogeneity of human tumors across length scales from single cells to whole tissues and implicates stromal stiffness in tumor cell heterogeneity.


Pharmaceutical properties, biodistribution, and imaging characteristics of manganese-mesoporphyrin. A potential hepatobiliary contrast agent for magnetic resonance imaging.
Manganese (III) mesoporphyrin (Mn-mesoporphyrin) was investigated for its pharmaceutical properties and magnetic resonance imaging characteristics as a potential hepatobiliary contrast agent. Solubility, partition coefficient, plasma binding, proton relaxation enhancement, biodistribution, biliary excretion, liver extraction ratio, and liver enhancement were measured in various in-vitro and in-vivo systems. Mn-mesoporphyrin was soluble and stable at moderate alkaline pH in phosphate buffer. The octanol/water coefficient was 25.98, and the compound was highly protein bound. R1 for water and plasma were 1.94 and 2.35 L/mmol sec, respectively. R1 in liver was calculated to be 15.72 L/mmol sec. Biodistribution studies in rats and mice confirmed hepatotrophic properties and biliary excretion was 65% over 24 hours. First pass liver uptake was 15%. Magnetic resonance imaging studies showed persistent liver enhancement at 0.05 mmol/kg. Mn-mesoporphyrin is a lipophilic compound that shows potential as a hepatobiliary magnetic resonance contrast agent.


A quantitative continuous enzyme assay of intramolecularly quenched fluorogenic phospholipase substrates for molecular imaging.
There has been recent growth in the development of activatable near-infrared (NIR) fluorescent probes for molecular imaging, generally designed by placing fluorochromes on a cleavable substrate in close proximity to one another, such that they self-quench, but fluoresce on separation via enzymatic cleavage of the substrate. Although these probes offer excellent contrast, the detection of enzyme activity has largely only been described qualitatively. In order to assess the effectiveness of a probe, it is useful to have a quantitative measure, such as the enzyme-substrate kinetic parameters. We have developed an assay to determine kinetic parameters and applied it to an intramolecularly quenched molecule, Pyro-PtdEtn-BHQ, a NIR fluorescent probe specific to phosphatidylcholine-specific phospholipase C. The development of this assay includes corrections for intermolecular quenching, calibration, optimization of reaction mixtures, and determination of kinetic and inhibition parameters. This assay can easily be extended to analyze and compare the efficiency of other fluorescent activatable phospholipase probes as suitable molecular imaging agents.


Clinical characteristics and risk factors of infection in patients with systemic lupus erythematosus: A systematic review and meta-analysis of observational studies.
Infection is one of the major causes of morbidity and mortality in systemic lupus erythematosus (SLE) patients. We conducted a systematic review and meta-analysis to investigate the clinical characteristics and risk factors of infection in SLE by comparing demographic factors, laboratory data, clinical features, and therapeutic factors between infection and non-infection SLE patients. PubMed, Embase, and Cochrane databases were searched systematically without restricting the language or year (up to September 2019) by using MeSH terms and keywords pertaining to SLE and infection. Three independent reviewers selected all observational studies based on the established inclusion criteria. Odds ratio (OR) and standardized mean difference (SMD) along with 95% confidence intervals (CI) were used and the analyses were carried out by using a random/fixed-effects model. When necessary, different subgroup and sensitivity analyses were conducted. Study quality was assessed by the modified version (nine-star scoring system) of the Newcastle-Ottawa Scale (NOS) and publication bias was evaluated by funnel plots, and Egger's and Begg's tests. In total, we included 39 studies (3709 infection SLE patients and 10526 non-infection SLE patients) based on the inclusion criteria. Compared with the SLE patients without infection, we found that infected SLE patients had a significantly higher incidence rate of the following: 1) lymphopenia (OR = 2.738 95%CI (1.017-7.376), P = 0.046, I2 = 81.4%), 2) thrombocytopenia (OR = 1.61 95%CI (1.4-1.85), P<0.001, I2 = 0%), 3) anemia (OR = 2.294 95%CI (1.402-3.755), P = 0.001, I2 = 83.0%), 4) hypoproteinemia (OR = 2.336 95%CI (1.408-3.876), P = 0.001, I2 = 84.2%), 5) C3 consumed (OR = 1.890 95%CI (1.190-3.002), P = 0.007, I2 = 77.4%), 6) diabetes mellitus (OR = 3.890 95%CI (2.450-6.160), P < 0.001, I2 = 0%), 7) elevated creatinine (OR = 1.954 95%CI (1.646-2.320), P < 0.001, I2 = 0.0%), 8) renal involvement (OR = 2.692 95%CI (2.000-3.623), P < 0.001, I2 = 76.0%), 9) serositis (OR = 3.877 95%CI (0.995-15.110), P = 0.051, I2 = 79.1%), and 10) use of steroid immunosuppressants (OR = 3.116 95%CI (1.959-4.957), P < 0.001, I2 = 77.9%). Furthermore, infected SLE patients had a significantly higher mean dose of prednisone (SMD = 2.088 95%CI (1.196-2.981), P < 0.001, I2 = 97.8%). In addition, SLE patients with infection showed a significantly lower incidence of antimalarial drug use (OR = 0.634 95%CI (0.451-0.892), P = 0.009, I2 = 56.0%). Infected SLE patients had a significantly higher level of 1) 24-h urinary protein (SMD = 0.560 95%CI (0.300-0.810), P < 0.001, I2 = 0%), 2) CRP (SMD = 0.437 95%CI (0.184-0.691), P = 0.001, I2 = 68.6%), and 3) SLE Collaborating Clinics damage index (SDI) (SMD = 0.451 95%CI (0.238-0.664), P < 0.001, I2 = 0.0%), along with a significantly lower level of albumin (SMD = -0.400 95%CI (-0.610--0.200), P < 0.001, I2 = 0.0%). After adjustment for false discovery rate (FDR), lymphopenia and serositis were no longer associated with the occurrence of infection; however, the remaining factors were still associated with infection in SLE. According to the nine-star scoring system of NOS, 71.79% of the studies were considered as high methodological quality (low risk of bias). No significant publication bias, except for renal involvement, was detected from funnel plots or Egger's and Begg's test, while this publication bias of renal involvement did not impact the pooled estimates. We identified many factors including thrombocytopenia, anemia, hypoproteinemia, hypocomplementemia, hypoalbuminemia, higher level of CRP, higher SDI score, renal involvement and diabetes mellitus that were associated with infection in SLE patients. In addition, glucocorticoids (especially high-dose) and immunosuppressants (e.g. cyclophosphamide) rendered SLE patients more susceptible to infection, while antimalarial drug administration (hydroxychloroquine) was a protective factor against infection in SLE patients. SLE patients with the above clinical characteristics and risk factors might be at high risk from infection, which might contribute to the early identification of infection in SLE patients for better prognosis.


Timing control of gait: a study of essential tremor patients vs. age-matched controls.
Essential tremor (ET) is a common movement disorder characterized by kinetic, postural and intention tremors. Mounting evidence suggests an underlying dysfunction of the cerebellum or cerebellar system. While few recent studies report impairments in timing control of finger movements in ET, timing control of gait has not been examined to date. We compared timing control of gait in ET patients vs. controls, and further assessed the association of these timing impairments with tremor severity among the ET patients. One-hundred-fifty-five ET patients and 60 age-matched controls underwent a comprehensive neurological assessment and gait analysis, which included walking at a criterion step frequency (cadence) with a metronome (timing production) and walking at a criterion step frequency after the metronome was turned off (timing reproduction). Outcomes of interest for both conditions were timing accuracy (measured by cadence error) and timing precision (measured by cadence variability). We also assessed cadence and step time across conditions. Cadence was lower in ET patients than controls (p < 0.03), whereas step time was similar for ET patients and controls. Accuracy (cadence error) and precision (cadence variability) were not different in ET patients compared with controls. Cranial tremor score was significantly associated with cadence (timing production condition, p = 0.003 and timing reproduction condition, p = 0.0001) and cadence error (timing production condition, p = 0.01). Kinetic tremor and intention tremor scores were not associated with gait measures. ET patients do not demonstrate impairments in timing control of gait as compared with matched controls. Prior work shows that patients with cerebellar dysfunction demonstrate selective impairments in timing of discrete movements (such as finger tapping) but not continuous movements (such as circle drawing). Taken together, these results support the hypothesis that the cerebellum may be important for timing control of discrete rather than continuous movements.


[Modern imaging technology for childhood urinary tract infection].
Imaging in childhood urinary tract infection (UTI) is still a matter of debate. There are established guidelines, however new knowledge and the changed medical environment have enhanced this ongoing discussion. These new insights have impacted therapy and consequently the imaging algorithm. Modern imaging methods -- particularly MRI and modern ultrasound (US) -- are less invasive with a lower radiation burden. Additionally, it has been shown that VUR is a poor predictor for renal scarring out, which affects long-term results. Furthermore, the majority of UT malformations is depicted by prenatal US. The most crucial aspect of improving long-term outcome appears to be the early and reliable depiction of UTI and effective treatment to prevent renal scarring. This review tries to present this new knowledge and to discuss the potential of modern imaging. Recent changes in imaging algorithms are highlighted and an outcome-oriented algorithm that addresses these recent developments is proposed, without lightly abandoning established standards. It consists of an orienting US and -- for depiction of renal involvement -- amplitude coded color Doppler sonography or renal static scintigraphy (considered the gold standard, particularly for evaluating scars); in future MRI may play a role. Based on this concept, only patients with renal damage as well as patients with complex urinary tract malformations or intractable recurrent UTI may have to undergo VCUG.


Fibrosing mediastinitis in a child with Mendelian susceptibility to mycobacterial disease possibly due to Bacillus Calmette-Guérin.
Mendelian susceptibility to mycobacterial disease (MSMD) is an uncommon disorder with increased susceptibility to less virulent mycobacteria including bacillus Calmette-Guérin (BCG). Fibrosing mediastinitis (FM) is also a rare condition defined by excessive fibrotic reactions in the mediastinum. So far, some infectious organisms and autoimmune diseases have been introduced as possible etiologies of FM. However, no study has ever discussed the possible association of BCG infection and FM. In this study, we report a 3-year-old female presenting with persistent fever, weakness, and bloody diarrhea in addition to mediastinal lymphadenopathy, hepatosplenomegaly, and pleural and pericardial effusion. Further examinations established a diagnosis of MSMD based on her clinical condition, immunologic data, positive tests for mycobacterial species, positive family history, and genetic study (IL12RB1 gene, c.G1193C, p.W398S). A year and a half later, she was referred with submandibular lymphadenitis and underwent immunologic work-up which revealed high inflammatory indices, a slight reduction in numbers of CD3 + and CD4 + cells as well as elevated CD16/56 + cell count and hyperimmunoglobulinemia. Purified protein derivative (PPD), QuantiFERON, and gastric washing test were all negative. Her chest computed tomography (CT) scan revealed suspicious para-aortic soft tissue and her echocardiography was indicative of strictures in superior vena cava and pulmonary veins. She further underwent chest CT angiography which confirmed FM development. Meanwhile, she has been treated with anti-mycobacterial agents and subcutaneous IFN-γ. In summary, we described a novel case of MSMD in a child presenting with granulomatous FM possibly following BCG infection. This is the first report introducing aberrant BCG infection as the underlying cause of FM. This result could assist physicians in identifying early-onset FM in suspicious cases with MSMD. However, more studies are required to support this matter.


No differences between group versus individual treatment of childhood anxiety disorders in a randomised clinical trial.
The present study compares an individual versus a group format in the delivery of manualised cognitive-behavioural therapy (FRIENDS) for children with anxiety disorders. Clinically referred children (aged 8 to 12) diagnosed with Separation Anxiety Disorder (n = 52), Generalised Anxiety Disorder (n = 37), Social Phobia (n = 22) or Specific Phobia (n = 16) were randomly assigned to individual (n = 65) or group (n = 62) treatment. Analyses were conducted separately for the intent-to-treat sample and the sample of children who completed treatment. Analyses included chi-square comparisons and regression analyses with treatment format as a predictor. Forty-eight percent of the children in the individual versus 41% in the group treatment were free of any anxiety disorder at post-treatment; 62% versus 54% were free of their primary anxiety disorder. Regression analyses showed no significant difference in outcome between individual and group treatment. Children improved in both conditions. Choice between treatments could be based on pragmatic considerations such as therapeutic resources, referral rates, and the preference of the parents and the child.


Replication of the Scandinavian Simvastatin Survival Study using a primary care medical record database prompted exploration of a new method to address unmeasured confounding.
To examine whether identifiable study characteristics and/or analytic methods used determine observational study validity, as assessed by replicating randomized controlled trials using observational data. A cohort from the United Kingdom General Practice Research Database (GPRD) was used to replicate the Scandinavian Simvastatin Survival Study RCT, which investigated statin treatment of hypercholesterolemic subjects with coronary heart disease. All aspects of the RCT except randomization were replicated to the extent possible in the GPRD study, which included 2,871 Unexposed and 1,280 statin-treated Exposed subjects. Overall mortality [adjusted hazard ratio 0.71 (0.53-0.96)] and myocardial infarction [adjusted HR 0.79 (0.61-1.02)] decreased in the GPRD study similar to the RCT. Coronary revascularization increased two-fold in the GPRD study, whereas it decreased significantly in the RCT [0.63 (0.54-0.74)]. This latter disparity prompted use of a new methodology to adjust for unmeasured confounding, which yielded an adjusted HR [1.0 (0.75-1.33)] more comparable to the RCT. This study provides additional evidence that a replicated GPRD observational study can yield results reasonably similar to a RCT. More important, it provides preliminary evidence suggesting that a new analytic methodology may adjust for unmeasured confounding, the major limitation to research using observational data.


Super-resolved time-frequency measurements of coupled phonon dynamics in a 2D quantum material.
Methods to probe and understand the dynamic response of materials following impulsive excitation are important for many fields, from materials and energy sciences to chemical and neuroscience. To design more efficient nano, energy, and quantum devices, new methods are needed to uncover the dominant excitations and reaction pathways. In this work, we implement a newly-developed superlet transform-a super-resolution time-frequency analytical method-to analyze and extract phonon dynamics in a laser-excited two-dimensional (2D) quantum material. This quasi-2D system, 1T-TaSe2, supports both equilibrium and metastable light-induced charge density wave (CDW) phases mediated by strongly coupled phonons. We compare the effectiveness of the superlet transform to standard time-frequency techniques. We find that the superlet transform is superior in both time and frequency resolution, and use it to observe and validate novel physics. In particular, we show fluence-dependent changes in the coupled dynamics of three phonon modes that are similar in frequency, including the CDW amplitude mode, that clearly demonstrate a change in the dominant charge-phonon couplings. More interestingly, the frequencies of the three phonon modes, including the strongly-coupled CDW amplitude mode, remain time- and fluence-independent, which is unusual compared to previously investigated materials. Our study opens a new avenue for capturing the coherent evolution and couplings of strongly-coupled materials and quantum systems.


Interaction with caveolin-1 modulates G protein coupling of mouse β3-adrenoceptor.
Caveolins act as scaffold proteins in multiprotein complexes and have been implicated in signaling by G protein-coupled receptors. Studies using knock-out mice suggest that β(3)-adrenoceptor (β(3)-AR) signaling is dependent on caveolin-1; however, it is not known whether caveolin-1 is associated with the β(3)-AR or solely with downstream signaling proteins. We have addressed this question by examining the impact of membrane rafts and caveolin-1 on the differential signaling of mouse β(3a)- and β(3b)-AR isoforms that diverge at the distal C terminus. Only the β(3b)-AR promotes pertussis toxin (PTX)-sensitive cAMP accumulation. When cells expressing the β(3a)-AR were treated with filipin III to disrupt membrane rafts or transfected with caveolin-1 siRNA, the cyclic AMP response to the β(3)-AR agonist CL316243 became PTX-sensitive, suggesting Gα(i/o) coupling. The β(3a)-AR C terminus, SP(384)PLNRF(389)DGY(392)EGARPF(398)PT, resembles a caveolin interaction motif. Mutant β(3a)-ARs (F389A/Y392A/F398A or P384S/F389A) promoted PTX-sensitive cAMP responses, and in situ proximity assays demonstrated an association between caveolin-1 and the wild type β(3a)-AR but not the mutant receptors. In membrane preparations, the β(3b)-AR activated Gα(o) and mediated PTX-sensitive cAMP responses, whereas the β(3a)-AR did not activate Gα(i/o) proteins. The endogenous β(3a)-AR displayed Gα(i/o) coupling in brown adipocytes from caveolin-1 knock-out mice or in wild type adipocytes treated with filipin III. Our studies indicate that interaction of the β(3a)-AR with caveolin inhibits coupling to Gα(i/o) proteins and suggest that signaling is modulated by a raft-enriched complex containing the β(3a)-AR, caveolin-1, Gα(s), and adenylyl cyclase.


Species coexistence, intransitivity, and topological variation in competitive tournaments.
Competitive intransitivity occurs when species' competitive abilities cannot be listed in a strict hierarchy, but rather form competitive loops, as in the game 'Rock-Paper-Scissors'. Indices are useful for summarizing intransitivity in communities; however, as with most indices, a great deal of information is compressed into single number. So while recent ecological theory, experiments, and natural history observations demonstrate that competitive intransitivity can promote species coexistence, the consequence of variation in the 'topology' of competitive interactions that is not accounted for by intransitivity indices is much less well understood. We use a continuous analytical model and two complementary discrete lattice models (one spatially explicit, the other aspatial) to demonstrate that such variation does indeed greatly affect species coexistence. Specifically, we show that although intransitivity indices are good at capturing broad patterns of coexistence, communities with different levels of intransitivity can have equal coexistence, and communities with equal intransitivity can have different coexistence, due to underlying variation in competitive network topology.


A new enzymatic approach for estimating total and direct bilirubin.
We designed an enzymatic assay for total (TBil) and direct bilirubin (DBil), the principle of which involves measuring the decrease in absorbance at 450 nm produced by bilirubin oxidase from Myrothecium verrucaria. Since TBil and DBil are oxidized at pH 7.2 and 3.7, respectively, the degree of bilirubin oxidation is measurable in each case. An analysis of bilirubin by high-performance liquid chromatography, before and after the enzymatic reaction with bilirubin oxidase, verified the specificity of the enzyme. The results obtained using this method varied linearly with TBil and DBil concentrations up to at least 250 mg/L and 150 mg/L, respectively. Reducing substances, commonly used anticoagulants and hemoglobin showed no apparent interference. The degree of day-to-day precision (CV) for TBil and DBil ranged from 1.2% (206.2 mg/L) to 10.6% (3.5 mg/L) and from 1.8% (84.3 mg/L) to 12.4% (2.1 mg/L), respectively. Values measured using this new method correlated well with those obtained by Malloy-Evelyn's method and the slide method employing the Kodak Ektachem analyzer.


The inhibition of HIF-2α on the ATM/Chk-2 pathway is involved in the promotion effect of arsenite on benzo(a)pyrene-induced cell transformation.
Both arsenite and benzo(a)pyrene (BaP) are known human carcinogens. Studies on the mode-of-action of arsenite indicate that it can also act as co-carcinogen or as a cancer promoter, and that it can facilitate progression of cancers. Some studies on development of lung cancers have suggested a synergism between arsenite exposure and cigarette smoking. The mechanism of action for such an effect, however, remains obscure. In the present study, we investigated the effects of HIF-2α on arsenite- and BaP-induced cell malignant transformation as well as on signal transduction pathways in human bronchial epithelial (HBE) cells. The results show that arsenite accelerates the neoplastic transformation and migration of cells and enhances chromosomal aberrations induced by BaP. HIF-2α is involved in blocking the effects of arsenite in activating the ATM/Chk-2 pathway and in repair of DNA damage induced by BaP. Moreover, blocking of HIF-2α prevents the effects of arsenite on the neoplastic transformation, cell migration, and chromosomal aberrations caused by BaP. These results indicate that the repressive effect of HIF-2α on the ATM/Chk-2 pathway leads to genomic instability, which is involved in arsenite-accelerated, BaP-induced malignant transformation of HBE cells.


Assessment of Health Information Technology Interventions in Evidence-Based Medicine: A Systematic Review by Adopting a Methodological Evaluation Framework.
The application of Health Information Technologies (HITs) can be an effective way to advance medical research and health services provision. The two-fold objective of this work is to: (i) identify and review state-of-the-art HITs that facilitate the aims of evidence-based medicine and (ii) propose a methodology for HIT assessment. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Furthermore, we consolidated existing knowledge in the field and proposed a Synthesis Framework for the Assessment of Health Information Technology (SF/HIT) in order to evaluate the joint use of Randomized Controlled Trials (RCTs) along with HITs in the field of evidence-based medicine. 55 articles met the inclusion criteria and refer to 51 (RCTs) published between 2008 and 2016. Significant improvements in healthcare through the use of HITs were observed in the findings of 31 out of 51 trials-60.8%. We also confirmed that RCTs are valuable tools for assessing the effectiveness, acceptability, safety, privacy, appropriateness, satisfaction, performance, usefulness and adherence. To improve health service delivery, RCTs apply and exhibit formalization by providing measurable outputs. Towards this direction, we propose the SF/HIT as a framework which may help researchers to carry out appropriate evaluations and extend their studies.


Effect of the transverse ligament rupture on the biomechanics of the cervical spine under a compressive loading.
In order to diagnosis a transverse ligament rupture in the cervical spine, clinicians normally measure the atlas-dens interval by using CT scan images. However, the impact of this tear on the head and neck complex biomechanics is not widely studied. The transverse ligament plays a very important role in stabilizing the joint and its alteration may have a substantial effect on the whole head and neck complex. A finite element model consisting of bony structures along with cartilage, intervertebral discs and all ligaments was developed based on CT and MRI images. The effect of head weights (compressive load) of 30 N to 57 N was investigated in the cases of intact and ruptured transverse ligament joints. The model was validated based on experimental studies investigating the response of the cervical spine under the extension-flexion moment. The predictions indicate a significant alteration of the kinematics and load distribution at the facet joints of the cervical spine with a transverse ligament tear. The vertebrae flexion, the contact force at the facets joints and the atlas-dens interval increase with the rupture of the transverse ligament and are dependent to the head weight. A transverse ligament tear increases the flexion angle of the head and the vertebrae as well as the atlas-dens interval. The atlas-dens interval reaches a critical value when the compressive loading exceeds 40 N. Supporting the head after an injury should be considered to avoid compression of the spinal cord and permanent neurologic damage.


Surfacing Filipino student nurses' perspectives of comfort and comforting viewed through metaphorical lens.
Comfort has been an integral component of nursing interventions. It is also supposed that the degree to which comfort is evidenced in nursing performance depends in great measure on the way forthcoming nurses perceive the said construct during their educational training. This study purports to describe student nurses' outlook of the words "comfort" and "comforting", through conscious doodling, and at the same time to find out instances of similarity or striking distinctions in students' perception on the said terms. A sample of 163 freshmen and 116 senior students were provided with a 2-part questionnaire. The first part used a robotfoto to determine the student subject's cartographic sketch. In the second part, a sheet of paper was given to each respondent who was asked to sketch a particular object, event or thought with which he associates the words, comfort and comforting. Moreover, a brief explanation of their illustrations was also called for. Metaphor representations were drawn up and analyzed and clustered according to their similarities in meaning, representation and the number of times the sketches were utilized by the respondents in order to comprehend how they interpret their sketches. Interestingly, this study yielded four major aspects that reflected the respondent's perception on the words "comfort" and "comforting", namely; physiologic, socio-environmental, psycho-spiritual and emotional. Results of this qualitative study did not show any marked difference in the interpretation of the construct under investigation on the comparison of the student's perception of the terms "comfort" and "comforting".


Steroidal lactones as inhibitors of 17beta-hydroxysteroid dehydrogenase type 5: chemical synthesis, enzyme inhibitory activity, and assessment of estrogenic and androgenic activities.
Androgens are well known to play a predominant role in prostate cancer and other androgen-dependent diseases. To decrease the level of androgen testosterone in the prostate, we are interested in developing inhibitors of 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD5). This enzyme expressed in the prostate is one of the two enzymes able to convert 4-androstene-3,17-dione into testosterone. From a screening study, it was found that a series of steroid derivatives bearing a lactone on D-ring demonstrated potent inhibition of 17beta-HSD5 over-expressed in HEK-293 cells. The results of enzymatic assays using intact cells indicated that a C18-steroid (estradiol or 3-deoxyestradiol) backbone and a spiro-delta-lactone (six-member ring) are important for a strong inhibitory activity. Moreover, the presence of a dimethyl group at the alpha-position of the lactone carbonyl increases the selectivity of the inhibitor toward 17beta-HSD5. Compound 26, a 3-deoxyestradiol derivative with a dimethylated spiro-delta-lactone at position 17, possesses the most potent inhibitory activity for 17beta-HSD5 (IC(50)=2.9 nM). It showed no binding affinity for estrogen, androgen, progestin and glucocorticoid receptors (ER, AR, PR and GR). A weak proliferative effect was, however, observed on ZR-75-1 (ER+) cells in culture at high concentration (1 microM), but not at 0.03 microM. Interestingly, no significant proliferative effect was detected on Shionogi (AR+) cells in culture in the presence of 0.1 and 1 microM of lactone 26.


Relationships between three beliefs as barriers to symptom management and quality of life in older breast cancer survivors.
To describe relationships among perceived barriers to symptom management and quality of life and to test the mediating role of perceived communication difficulties on the relationships between other perceived barriers to symptom management and quality of life in older adult breast cancer survivors. Cross-sectional descriptive-correlational design using baseline data from a randomized, controlled trial that tested the efficacy and durability of the individualized representational intervention in reducing symptom distress and improving quality of life in older adult breast cancer survivors. The community, an oncology clinic, and a state tumor registry. 190 older adult breast cancer survivors (X age = 70.4 years) who were an average of 3.3 years after breast cancer diagnosis. Path analysis using Mplus, version 5.1. Negative beliefs about symptom management (Symptom Management Beliefs Questionnaire [SMBQ]), perceived negative attitudes from healthcare providers (Communication Attitudes [CommA]), perceived communication difficulties (CommD), and quality of life. Significant direct effects of SMBQ and CommA on CommD were found after controlling for age, number of health problems, and number of symptoms. CommD was a significant mediator of the effects of CommA on quality of life after controlling for the covariates. SMBQ had significant total effects on quality of life after adjusting for the covariates but was not mediated by CommD. Patient-provider communication is an important factor in the quality of life of older adult breast cancer survivors. Developing and testing nursing interventions focusing on enhancing both positive beliefs about symptom management and effective communication in old age is suggested. Older adults and healthcare providers must overcome stereotyped beliefs about aging that may affect self-care and health outcomes for this population. Older adults must be allowed to express their views and emotions about aging.


Effects of lateral opening wedge and medial closing wedge distal femoral osteotomies on axial load stability.
The stability of the current distal femoral osteotomy is insufficient for early weight bearing and bone healing. The purpose of this study was to test the stability of medial closing wedge- (MCW-) and lateral opening wedge-distal femoral osteotomies (LOW-DFO), which have improved with the recent advances in technology. We used composite bone models with MCW-DFO, improved with biplanar osteotomy technique and a Tomofix™ MDF plate, or LOW-DFO improved with biplanar osteotomy technique, a Tomofix™ LDF plate, and a β-TCP bone substitute, BONISH® graft. A cyclic axial loading test was employed to evaluate the strain on a plate and hinge point. The breaking axial load was measured. Tensile strain on the plate produced by cyclic axial loading was significantly lower for LOW-DFO (2.0 ± 0.8 MPa) than for MCW-DFO (3.9 ± 1.6 MPa, P < .05). Compressive strain on the hinge point produced by cyclic axial loading was lower for LOW-DFO (6.6 ± 2.9 MPa) than for MCW-DFO (7.7 ± 4.6 MPa,). The maximum breaking axial load was significantly higher for LOW-DFO (5511 ± 945 N) than for MCW-DFO (4303 ± 518 N, P < .05). LOW-DFO improved with recent advanced technology was superior to MCW-DFO improved with advanced technology in both cyclic axial loading test and breaking axial load test. This suggests that LOW-DFO facilitates earlier weight bearing and bone healing than does MCW-DFO.


Pulmonary artery hypertension in childhood: The transforming growth factor-β superfamily-related genes.
Pulmonary artery hypertension (PAH) is very rare in childhood, and it can be divided into heritable, idiopathic drug- and toxin-induced and other disease (connective tissue disease, human immunodeficiency virus infection, portal hypertension, congenital heart disease, or schistosomiasis)-associated types. PAH could not be interpreted solely by pathophysiological theories. The impact of the transforming growth factor-β superfamily-related genes on the development of PAH in children remains to be clarified. Pertinent literature on the transforming growth factor-β superfamily-related genes in relation to PAH in children published after the year 2000 was reviewed and analyzed. Bone morphogenetic protein receptor type II gene mutation promotes cell division or prevents cell death, resulting in an overgrowth of cells in small arteries throughout the lungs. About 20% of individuals with a bone morphogenetic protein receptor type II gene mutation develop symptomatic PAH. In heritable PAH, bone morphogenetic protein receptor type II mutations may be absent; while mutations of other genes, such as type I receptor activin receptor-like kinase 1 and the type III receptor endoglin (both associated with hereditary hemorrhagic telangiectasia), caveolin-1 and KCNK3, the gene encoding potassium channel subfamily K, member 3, can be detected, instead. Gene mutations, environmental changes and acquired adjustment, etc. may explain the development of PAH. The researches on PAH rat model and familial PAH members may facilitate the elucidations of the mechanisms and further provide theories for prophylaxis and treatment of PAH.


Orbital decompression in Graves' orbitopathy: efficacy and safety.
Vision-threatening compressive optic neuropathy occurs in a minority of patients with Graves' orbitopathy. Surgical orbital decompression, systemic glucocorticoids and orbital irradiation are treatment options. Orbital decompression is being performed on an increasing number of patients for other indications such as corneal exposure and disfiguring proptosis. To examine the outcomes of surgical orbital decompression for Graves' orbitopathy by one surgeon. An analysis of a retrospective case series of 88 consecutive patients (151 orbits) who underwent orbital decompression for Graves' orbitopathy between April 1991 and November 2002. The indication for surgery was compressive optic neuropathy for 57 orbits; 94 orbits had an indication other than optic neuropathy. Of those with optic neuropathy, 94% had improvement or maintenance of visual acuity and 93% had improvement in colour vision after decompression. The overall mean reduction in proptosis was 4.7 mm. Of all patients, 30% had new or worsened diplopia postdecompression. Patients with optic neuropathy were more likely to develop new or worsened diplopia than those without optic neuropathy. Orbital decompression is a safe procedure and effective in improving vision in compressive optic neuropathy. It is effective in reducing proptosis, therefore improving exposure keratopathy and cosmesis. However, new or worsened diplopia is a significant postoperative complication, and subsequent strabismus surgery might be required. This is an important consideration, especially for patients undergoing surgery for non-optic neuropathy indications.


Signal alterations of glutamate-weighted chemical exchange saturation transfer MRI in lysophosphatidylcholine-induced demyelination in the rat brain.
To compare in vivo glutamate-weighted chemical exchange saturation transfer (GluCEST-weighted) signal changes between in a rat model of demyelinated multiple sclerosis and control groups. Using a pre-clinical 7 T magnetic resonance imaging (MRI) system, CEST imaging was applied to a toxin (lysophosphatidylcholine; LPC) induced rat (MSLPC) and control (CTRL) groups to compare in vivo glutamate signal changes. The GluCEST-weighted signals were analyzed based on the magnetization transfer ratio asymmetry approach at 3.0 ppm on the region-of-interests (ROIs) in the corpus callosum and hippocampus at each hemispheric region. GluCEST-weighted signals were significantly changed between the CTRL and MSLPC groups, while higher glutamate signals were indicated in the MSLPC than the CTRL group ([MSLPC / CTRL]; hippocampus: [6.159 ± 0.790 / 4.336 ± 0.446] and corpus callosum: [-3.545 ± 0.945 / -6.038 ± 0.620], all p = 0.001). Our results show increased GluCEST-weighted signals in the LPC-induced demyelination rat brain compared with control. GluCEST-weighted imaging could be a useful tool for defining a biomarker to estimate the glutamate-related metabolism in MS.


Circulating Furin-Cleaved Proprotein Convertase Subtilisin/Kexin Type 9 Concentration Predicts Future Coronary Events in Japanese Subjects.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates as mature and furin-cleaved forms, which differ in their properties to degrade low-density lipoprotein (LDL) receptors. In this study, we sought to investigate whether PCSK9 subtypes associate with atherosclerotic cardiovascular events. We investigated 1,436 statin-naive Japanese subjects without any cardiovascular disease in the Suita Study, an epidemiologic Japanese cohort study. Total, mature, and furin-cleaved PCSK9 levels were measured by means of enzyme-linked immunosorbent assay. The occurrence of coronary and stroke events were compared in subjects stratified by PCSK9 level tertile. Total, mature, and furin-cleaved PCSK9 levels were associated with non-high-density lipoprotein cholesterol (all P < 0.001) and systolic blood pressure (P = 0.001, P = 0.004, and P < 0.001, respectively). Furthermore, only furin-cleaved PCSK9 level was correlated to high-sensitivity C-reactive protein (hs-CRP) (P < 0.001). During the 13.6-year observational period, furin-cleaved PCSK9 level predicted a greater likelihood of experiencing coronary events (tertile 2: hazard ratio [HR]: 2.84 [95% confidence interval [CI]: 1.21-6.65; P = 0.01]; tertile 3: HR: 2.81 [95% CI: 1.17-6.74; P = 0.02]), but not stroke (tertile 2: HR: 1.31 [95% CI: 0.72-2.40; P = 0.36]; tertile 3: HR: 1.27 [95% CI: 0.68-2.38; P = 0.44]). Total and mature PCSK9 levels were not associated with coronary events (total PCSK9: tertile 2: HR: 1.35 [95% CI: 0.68-2.68; P = 0.39]; tertile 3: HR: 1.13 [95% CI: 0.54-2.34; P = 0.73]; mature PCSK9: tertile 2: HR: 1.02 [95% CI: 0.52-2.02; P = 0.93]; tertile 3: HR: 0.96 [95% CI: 0.47-1.95; P = 0.92]) and stroke events (total PCSK9: tertile 2: HR: 0.90 [95% CI: 0.50-1.61; P = 0.72]; tertile 3: HR: 0.99 [95% CI:0.54-1.80; P = 0.97]; mature PCSK9: tertile 2: HR: 0.86 [95% CI: 0.47-1.57; P = 0.63]; tertile 3: HR: 1.11 [95% CI: 0.61-1.99; P = 0.72]), respectively. Furin-cleaved but not total and mature PCSK9 was associated with both LDL cholesterol and hs-CRP and predicted future coronary events in the primary prevention settings. Our findings provide pathophysiological insights into the properties of PCSK9 subtypes in association with coronary events.


ADP-ribosylation as an intermediate step in inactivation of rifampin by a mycobacterial gene.
Mycobacterium smegmatis DSM43756 inactivates rifampin, and the inactivated antibiotic product recovered from culture medium was ribosylated on the 23-OH group. To study this process, the gene responsible for the inactivation was expressed at high levels by the lac promoter in Escherichia coli conferring resistance to >500 microg of antibiotic per ml. Cell homogenates generated a novel derivative designated RIP-TAs; in this study, we determined that RIP-TAs is 23-(O-ADP-ribosyl)rifampin. Our results indicated that RIP-TAs is an intermediate in the pathway leading to ribosylated rifampin and that the previously characterized gene encodes a mono(ADP-ribosyl)transferase which, however, shows no sequence similarity to other enzymes of this class.


Transcatheter Mitral Valve Therapy: Defining the Patient Who Will Benefit.
This report aims to define the clinical and anatomic variables key in determining patient suitability for transcatheter mitral valve therapies. Candidacy for transcatheter mitral valve repair requires weighing the clinical variables that may impact the ability to improve patient symptoms and prolong survival that include left ventricular ejection fraction, symptom severity, pulmonary hypertension, and magnitude of residual regurgitation or stenosis. Individualized selection of transcatheter repair or replacement based on patho-anatomy is being explored. The primary goal is achieving significant reduction in mitral regurgitation. Transcatheter mitral valve replacement requires rigorous anatomic screening using computed tomography and candidates should be able to take oral anticoagulation. Selection of patients for transcatheter mitral valve repair is complex and requires intimate knowledge of clinical variables and specific device limitations.


A case of acute myocardial infarction in paced rhythm. Utility of the Barcelona algorithm.
We describe the case of a 70-year-old man with a pacemaker implant who presented to us with atypical chest pain. His admission ECG did not satisfy the criteria for myocardial infarction according to standard Sgarbossa criteria, and Smith modified Sgarbossa criteria. However, we applied the recently developed Barcelona algorithm, which is used to diagnose acute myocardial infarction in the presence of intrinsic left bundle branch block.Electrocardiographic criteria for an acute myocardial infarction were met. Lead V6 displayed a low voltage QRS complex (3 mm) with 1 mm ST depression, satisfying the Barcelona criteria for acute myocardial infarction. He underwent primary angioplasty for critical in-stent restenosis of the left anterior descending coronary artery. This is the first case report, to the best of our knowledge, where Barcelona algorithm has been used to diagnose acute coronary syndrome in right-ventricular paced rhythm.


Hexose metabolism in pancreatic islets stimulation by D-glucose of [2-3H]glycerol detritiation.
1. In pancreatic islets, a rise in glucose concentration is known to increase the ratio between D-[6-14C]glucose oxidation and D-[5-3H]glucose utilization. The opposite situation was found to prevail in parotid cells. 2. In rat pancreatic islets, D-glucose caused a concentration-related stimulation of 3H2O production from [2-3H]glycerol, but failed to affect 3H2O production from [1(3)-3H]glycerol or 14CO2 production from [U-14C]glycerol. At the low concentration used in most of these experiments (i.e. 1.0 mM), glycerol failed to affect D-[U-14C]glucose oxidation. 3. These findings suggest that the preferential stimulation by D-glucose of mitochondrial oxidative events in pancreatic islets represents an unusual situation in secretory cells and involves an accelerated circulation in the glycerol phosphate shuttle.


Powder filling of electrospun material in vials: A proof-of-concept study.
The present paper reports the powder filling of milled electrospun materials in vials, which contained voriconazole and sulfobutylether-β-cyclodextrin. High-speed electrospinning was used for the production of the fibrous sample, which was divided into 6 parts. Each portion was milled using different milling methods and sizes of sieves to investigate whether the milling influences the powder and filling properties. Bulk and tapped density tests, laser diffraction and angle of repose measurements were applied to characterize the milled powders, while a vibratory feeder was used for the feeding experiments. The correlation between the material property descriptors and the feeding responses was investigated by multivariate data analysis. Based on the results, three samples were chosen for the vial filling, which was accomplished with 3400 mg electrospun material containing 200 mg voriconazole, representative of the commercial product. The feed rate was set to fit the 240 g/h production rate of the electrospinning and the relative standard deviation of three repeated vial filling was determined to see the accuracy of the process. This research shows that by applying a suitable milling method it is possible to process electrospun fibers to a powder, which can be filled into vials and used as reconstitution dosage forms.


Low-cost and Non-flammable Eutectic Electrolytes for Advanced Zn-I2 Batteries.
As a burgeoning electrolyte system, eutectic electrolytes based on ZnCl2 /Zn(CF3 SO3 )2 /Zn(TFSI)2 have been widely proposed in advanced Zn-I2 batteries; however, safety and cost concerns significantly limit their applications. Here, we report new-type ZnSO4 -based eutectic electrolytes that are both safe and cost-effective. Their universality is evident in various solvents of polyhydric alcohols, in which multiple -OH groups not only involve in Zn2+ solvation but also interact with water, resulting in the high stability of electrolytes. Taking propylene glycol-based hydrated eutectic electrolyte as an example, it features significant advantages in non-flammability and low price that is <1/200 cost of Zn(CF3 SO3 )2 /Zn(TFSI)2 -based eutectic electrolytes. Moreover, its effectiveness in confining the shuttle effects of I2 cathode and side reactions of Zn anodes is evidenced, resulting in Zn-I2 cells with high reversibility at 1 C and 91.4 % capacity remaining under 20 C. After scaling up to the pouch cell with a record mass loading of 33.3 mg cm-2 , super-high-capacity retention of 96.7 % is achieved after 500 cycles, which exceeds other aqueous counterparts. This work significantly broadens the eutectic electrolyte family for advanced Zn battery design.


Clinical predictors of incipient vertebral fractures and bone mineral density in kidney transplant patients.
Kidney transplant recipients are prone to metabolic bone diseases and consequent fractures. This study aimed to evaluate the incidence of incipient vertebral fractures, osteopenia, osteoporosis, and the clinical factors associated with incipient vertebral fractures in a group of kidney transplant patients. Two hundred sixty-four patients (F/M 124/140, 45.3 ± 13 years) who had undergone kidney transplantation in tertiary care centers were included. Vertebral fractures were assessed semiquantitatively using conventional thoracolumbar lateral radiography in 202 of the patients. Vertebral fractures were observed in 56.4% (n = 114) of the study group. The frequency of osteoporosis was 20.0% (53 of 264 patients), and osteopenia was 35.6% (94 of 264 patients). Bone mineral density (BMD) levels were in the normal range in 40.3% (n = 46) of the subjects with vertebral fractures. It was in the osteoporotic range in 20.1% (n = 23) and the osteopenic range in 40.3% (n = 46). Vertebral fractures were associated with age, duration of hemodialysis, BMI, and femoral neck Z score (R2 37.8%, p = 0.027). As incipient vertebral fractures can be observed in patients with normal BMD levels in kidney transplant recipients, conventional X-ray screening for vertebral fractures may be beneficial for a proper therapy decision of metabolic bone disease in kidney transplant recipients.


Mapping the genomic mosaic of two 'Afro-Bolivians' from the isolated Yungas valleys.
Unraveling the ancestry of 'Afro-American' communities is hampered by the complex demographic processes that took place during the Transatlantic Slave Trade (TAST) and the (post-)colonization periods. 'Afro-Bolivians' from the subtropical Yungas valleys constitute small and isolated communities that live surrounded by the predominant Native American community of Bolivia. By genotyping >580,000 SNPs in two 'Afro-Bolivians', and comparing these genomic profiles with data compiled from more than 57 African groups and other reference ancestral populations (n = 1,161 in total), we aimed to disentangle the complex admixture processes undergone by 'Afro-Bolivians'. The data indicate that these two genomes constitute a complex mosaic of ancestries that is approximately 80 % of recent African origin; the remaining ~20 % being European and Native American. West-Central Africa contributed most of the African ancestry to 'Afro-Bolivians', and this component is related to populations living along the Atlantic coast (i.e. Senegal, Ghana, Nigeria). Using tract length distribution of genomic segments attributable to distinct ancestries, we could date the time of admixture in about 400 years ago. This time coincides with the maximum importation of slaves to Bolivia to compensate the diminishing indigenous labor force needed for the development of the National Mint of Potosí. Overall, the data indicate that the genome of 'Afro-Bolivians' was shaped by a complex process of admixture occurring in America among individuals originating in different West-Central African populations; their genomic mosaics received additional contributions of Europeans and local Native Americans (e.g. Aymaras).


Lymphocyte sensitization in sheep inoculated with extracts of spontaneously occurring malignant lymphomas.
A macrophage migration inhibition test showed that the blood lymphocytes of 15 of 27 sheep inoculated in utero or at birth with disrupted cells from ovine malignant lymphomas responded in culture to antigens derived from three other lymphomas. A close association was seen between animals whose lymphocytes were antigen-sensitive and those which developed lymphocytosis. This association and the specificity of reaction between the various tumour antigens employed in the tests is interpreted as further evidence toward a viral aetiology in ovine malignant lymphoma.


Hsa_circRNA_0088036 acts as a ceRNA to promote bladder cancer progression by sponging miR-140-3p.
Circular RNAs (circRNAs) are a class of non-coding RNAs that play vital roles in cancer biology. However, the potential role of hsa_circRNA_0088036 in bladder cancer (BCa) remains unknown. Hsa_circRNA_0088036 was identified by microarray analysis and validated by quantitative real-time polymerase chain reaction. Functional assays were conducted to confirm the effects of hsa_circRNA_0088036 on the growth, migration, invasion, tumorigenesis, and metastasis of BCa cells. The luciferase reporter assay and RNA pull down assay were performed to investigate the interactions between hsa_circRNA_0088036, miR-140-3p, and forkhead box protein Q1 (FOXQ1). Upregulated expression of hsa_circRNA_0088036 in BCa tissues and cell lines was positively correlated with overall survival and clinicopathologic characteristics. Knockdown of hsa_circRNA_0088036 inhibited the growth, migration, and invasion of BCa cells both in vivo and in vitro. Mechanistically, hsa_circRNA_0088036 could directly interact with miR-140-3p and act as a miRNA sponge to modulate FOXQ1 expression. Knockdown of hsa_circRNA_0088036 inhibited the proliferation, migration, and metastasis of BCa cells via miR-140-3p/FOXQ1 signaling, suggesting that hsa_circRNA_0088036 is a potential biomarker and therapeutic target for BCa.


Inorganic and organic phosphate measurements in the nanomolar range.
A procedure, based on the complex formation of malachite green with phosphomolybdate under acidic conditions, to measure inorganic orthophosphate in the nanomolar range is described. The addition of polyvinyl alcohol is required to stabilize the dye-phosphomolybdate complex. The advantages of the assay are simplicity, stability of the reagents, and high sensitivity. Due to the high permissible acidity in the assay (0.9 N H2SO4), the method can be adapted easily to measure nanomolar amounts of phosphate, liberated from organic compounds like phosphoproteins and phospholipids after wet digestion.


Comparison of cardiac output determined by bioimpedance and bioreactance methods at rest and during exercise.
Bioreactance is a novel non-invasive method for cardiac output measurement that involves the analysis of blood flow-dependent changes in the phase shifts of electrical currents applied across the chest. The present study (1) compared resting and exercise cardiac outputs determined by bioreactance and bioimpedance methods and those estimated from measured oxygen consumption, (2) determined the relationship between cardiac output and oxygen consumption, and (3) assessed the agreement between the bioreactance and bioimpedance methods. Twelve healthy subjects (aged 30 ± 4 years) performed graded cardiopulmonary exercise test on a recumbent cycle ergometer on two occasions, 1 week apart. Cardiac output was monitored at rest, at 30, 50, 70, 90, 150 W and at peak exercise intensity by bioreactance and bioimpedance and expired gases collected. Resting cardiac output was not significantly different between the bioreactance and bioimpedance methods (6.2 ± 1.4 vs. 6.5 ± 1.4 l min(-1), P = 0.42). During exercise cardiac outputs were correlated with oxygen uptake for both bioreactance (r = 0.84, P < 0.01) and bioimpedance techniques (r = 0.82, P < 0.01). At peak exercise bioimpedance estimated significantly lower cardiac outputs than both bioreactance and theoretically calculated cardiac output (14.3 ± 2.6 vs. 17.5 ± 5.2 vs. 16.9 ± 4.9 l min(-1), P < 0.05). Bland-Altman analyses including data from rest and exercise demonstrated that the bioimpedance method reported ~1.5 l min(-1) lower cardiac output than bioreactance with lower and upper limits of agreement of -2.98 to 5.98 l min(-1). Bioimpedance and bioreactance methods provide different cardiac output estimates, particularly at high exercise intensity, and therefore the two methods cannot be used interchangeably. In contrast with bioimpedance, bioreactance cardiac outputs are similar to those estimated from measured oxygen consumption.


The peroneal muscular atrophy syndrome. Clinical genetic, electrophysiological and nerve biopsy studies. Part 3. Clinical, electrophysiological and pathological correlations.
This report analyses correlations between clinical, electrophysiological and pathological data derived from a series of families with peroneal muscular atrophy. It was found that the observed differences between families in median nerve forearm motor conduction velocity were unlikely to be due to differences in the age or severity of the cases. Similarly it it was unlikely that the pathological differences between cases were due to age or severity of the case. The conduction velocity in the Hypertrophic Neuropathy Group tended to increase slightly with age, while that in other cases tended to fall slightly. The conduction velocity and total myelinated fibre counts were inversely related to the degree of segmental demyelination. The Hypertrophic Neuropathy Group and the Intermediate Group of cases were found to behave differently in a number of correlative analyses, thus supporting the suggestion that they represent different disease entities.


Neuronal Nogo-A in New-born Retinal Ganglion Cells: Implication for the Formation of the Age-related Fiber Order in the Optic Tract.
Nogo-A is highly expressed in oligodendrocytes in the adult central nervous system (CNS). Recently it was found that Nogo-A is also expressed in some neuronal types during development. Here, we examined the expression pattern of Nogo-A in both the retina and optic tract (OT) of mouse embryos from E12 to E15. After perturbation of its function in the OT for 5 hr in the brain slice culture system using a Nogo-A specific antibody or antagonist of its receptor (NEP1-40), the optic nerve fibers and growth cones were traced with DiI. We showed that most Tuj-1 positive new-born neurons at E12 were Nogo-A positive. At E15, retinal neurons reduced the Nogo-A expression. It was worth noting that some projecting axons expressed Nogo-A along the retinofugal pathway. On the basis of their specific locations within the superficial half of the OT and the colocalization with GAP-43 (a marker for the newly born growth cones and axons), we concluded that those Nogo-A positive axons were the newly arrived retinal fibers. Blocking the function of Nogo-A with Nogo-A antibody or NEP1-40 resulted in the shift of DiI labeled axons and growth cones from the superficial half to the whole depth of the OT. These results indicate that Nogo-A in the newly born retinal ganglion cells (RGCs) and their axons are involved in sorting out the newly arrived axons to the subpial region of the OT. Anat Rec, 299:1027-1036, 2016. © 2016 Wiley Periodicals, Inc.


Long-standing bidirectional tachycardia in a patient with hypokalemic periodic paralysis.
Bidirectional tachycardia is an uncommon arrhythmia that usually occurs in aged persons with severe myocardial disease or digitalis intoxication, and carries a poor prognosis. This is a report of a young woman with familial hypokalemic periodic paralysis, who has a 13-year history of asymptomatic bidirectional tachycardia in the absence of organic heart disease or digitalis intoxication. Association of periodic paralysis and bidirectional tachycardia in this case and four previously reported cases suggests a strong relationship between this arrhythmia and potassium.


Profile of palbociclib in the treatment of metastatic breast cancer.
Breast cancer is the most common cancer diagnosed in women. Each year, thousands die either because of disease progression or failure of treatment. Breast cancer is classified into different subtypes based on the molecular expression of estrogen receptor (ER), progesterone receptor, and/or human epidermal growth factor receptor 2 (HER2). These receptors represent important therapeutic targets either through monoclonal antibodies or through small-molecule inhibitors directed toward them. However, up to 40% of patients develop either a primary or a secondary resistance to the current treatments. Therefore, there is an urgent need for investigating new targets in order to overcome the resistance and/or enhance the current therapies. Cell cycle is altered in many human cancers, especially in breast cancer. Cyclin-dependent kinases (CDKs), especially CDK4 and CDK6, play a pivotal role in cell cycle progression that makes them potential targets for new promising therapies. CDK inhibition has shown strong antitumor activities, ranging from cytostatic antiproliferative effects to synergistic effects in combination with other antitumor drugs. In order to overcome the drawbacks of the first-generation CDK inhibitors, recently, new CDK inhibitors have emerged that are more selective to CDK4 and CDK6 such as palbociclib, which is the most advanced CDK4/6 inhibitor in trials. In preclinical studies, palbociclib has shown a very promising antitumor activity, especially against ERα+ breast cancer subtype. Palbociclib has gained world attention, and US the Food and Drug Administration has accelerated its approval for first-line treatment in combination with letrozole for the first-line systematic treatment of postmenopausal women with ERα+/HER2- locally advanced or metastatic breast cancer. In this review, we discuss the potential role of CDK inhibition in breast cancer treatment, and focus on palbociclib progress from preclinical studies to clinical trials with mentioning the most recent ongoing as well as planned Phase II and Phase III trials of palbociclib in advanced breast cancer.


Differential tissue development compromising the growth rate and physiological performances of mussel.
Differences in the food acquisition rates and in the energetic costs of metabolism seem to affect the growth rate variability of mussels. The aim of this study was to analyze if the physiological performances responsible for such growth rate variability are accompanied by structural differences at tissue or cellular level in the main organs involved in energy acquisition (gill) and processing (digestive gland). Fast growers had higher cilia density and metabolic efficiency in their gill, and well-developed digestive tissue with barely no connective tissue or atrophy. Slow-growing mussels displayed stress signs that impede the proper acquisition, digestion and absorption of food: low cilia density, low mitochondrial capacity and high antioxidant activity levels in the gills, and high atrophy of the digestive gland. The data herein explains the growth rate variability of mussels, demonstrating that morphological and functional differences exist between fast and slow growers.


Health-related quality of life and medication adherence in elderly patients with epilepsy.
Considering the high prevalence of epilepsy in the elderly and the importance of maximising their quality of life (QoL), this study aimed to investigate the relationship between medication adherence and QoL, and the mediating effects of medication adherence on the association between serum antiepileptic drug (AED) level and seizure severity with QoL in elderly epileptics. In a longitudinal study, 766 elderly patients with epilepsy who were prescribed a minimum of one antiepileptic drug were selected by convenience sampling method. A Medication Adherence Report Scale (MARS-5) questionnaire was completed at the baseline. Seizure severity and QoL were assessed after six months using the Liverpool Seizure Severity Scale (LSSS) and the QoL in Epilepsy (QOLIE-31) questionnaires respectively. Serum level of AED was also measured at six-month follow-up. Medication adherence was significantly correlated with both seizure severity (β = -0.33, p < 0.0001) and serum AED level (β = 0.29, p < 0.0001) after adjusting for demographic and clinical characteristics. Neither QoL nor its sub-classes were correlated with seizure severity. In addition, a significant correlation was not observed between serum AED level and QoL. However, medication adherence was significantly correlated with QoL (β = 0.30, p < 0.0001). The mediating effects of medication adherence on the association between serum AED level (Z = 3.39, p < 0.001) and seizure severity (Z = -3.47, p < 0.001) with QoL were supported by the Sobel test. This study demonstrates that medication adherence has a beneficial impact on QoL in elderly epileptics. Therefore, adherence to treatment should be monitored to improve their QoL.


Three-stage surgery in the management of severe rigid angular kyphosis.
There are conflicting data regarding the management of rigid kyphosis. None of the currently known techniques can completely correct severe kyphosis without resulting in residual deformity. Seven patients with local kyphosis exceeding 60 degrees were operated on to achieve complete correction of the deformity. The surgery consisted of total spondylectomy of the deformed vertebra and simultaneous application of compression-distraction forces to this area. The operation included three stages: The initial stage includes resection of posterior spinal elements and temporary fixation. In the second stage, an anterior corpectomy is performed to conclude the resection, and simultaneous antero-posterior correction is obtained. The final stage includes another posterior procedure to achieve a precise correction and to correct any compensatory curves. All patients were operated on using this technique in a single session. The mean preoperative and postoperative kyphosis angles were 76.1 degrees (range, 65 degrees -92 degrees) and 6 degrees (range, 0 degrees -13 degrees), respectively. Complete bony fusion was achieved after a mean follow-up period of 38 months (range, 26-52 months) without any neurological sequelae or significant loss of correction.