Therapeutic treatment with the anti-inflammatory drug candidate MW151 may partially reduce memory impairment and normalizes hippocampal metabolic markers in a mouse model of comorbid amyloid and vascular pathology.
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, but therapeutic options are lacking. Despite long being able to effectively treat the ill-effects of pathology present in various rodent models of AD, translation of these strategies to the clinic has so far been disappointing. One potential contributor to this situation is the fact that the vast majority of AD patients have other dementia-contributing comorbid pathologies, the most common of which are vascular in nature. This situation is modeled relatively infrequently in basic AD research, and almost never in preclinical studies. As part of our efforts to develop small molecule, anti-inflammatory therapeutics for neurological injury and disease, we have recently been exploring potentially promising treatments in preclinical multi-morbidity contexts. In the present study, we generated a mouse model of mixed amyloid and hyperhomocysteinemia (HHcy) pathology in which to test the efficacy of one of our anti-inflammatory compounds, MW151. HHcy can cause cerebrovascular damage and is an independent risk factor for both AD dementia and vascular contributions to cognitive impairment and dementia. We found that MW151 was able to partially rescue hippocampal-dependent spatial memory and learning deficits in this comorbidity context, and further, that the benefit is associated with a normalization of hippocampal metabolites detectable via magnetic resonance spectroscopy. These findings provide evidence that MW151 in particular, and potentially anti-inflammatory treatment more generally, may be beneficial in AD patients with comorbid vascular pathology.


Lymphoma Recognition in Histology Image of Gastric Mucosal Biopsy with Prototype Learning.
Lymphomas are a group of malignant tumors developed from lymphocytes, which may occur in many organs. Therefore, accurately distinguishing lymphoma from solid tumors is of great clinical significance. Due to the strong ability of graph structure to capture the topology of the micro-environment of cells, graph convolutional networks (GCNs) have been widely used in pathological image processing. Nevertheless, the softmax classification layer of the graph convolutional models cannot drive learned representations compact enough to distinguish some types of lymphomas and solid tumors with strong morphological analogies on H&E-stained images. To alleviate this problem, a prototype learning based model is proposed, namely graph convolutional prototype network (GCPNet). Specifically, the method follows the patch-to-slide architecture first to perform patch-level classification and obtain image-level results by fusing patch-level predictions. The classification model is assembled with a graph convolutional feature extractor and prototype-based classification layer to build more robust feature representations for classification. For model training, a dynamic prototype loss is proposed to give the model different optimization priorities at different stages of training. Besides, a prototype reassignment operation is designed to prevent the model from getting stuck in local minima during optimization. Experiments are conducted on a dataset of 183 Whole slide images (WSI) of gastric mucosa biopsy. The proposed method achieved superior performance than existing methods.Clinical relevance- The work proposed a new deep learning framework tailored to lymphoma recognition on pathological image of gastric mucosal biopsy to differentiate lymphoma, adenocarcinoma and inflammation.


Intrauterine device insertions: which variables matter?
Many factors are suspected to influence the intrauterine device (IUD) insertion process. This study sought to examine the effects of a few key variables on IUD insertion tolerability, complications and follow-up issues. A retrospective chart review was undertaken of all IUD insertions over an 11-month period at an urban Canadian women's clinic. Linear regression analysis of 354 insertions assessed the effects of parity, age, local anaesthesia and other variables on insertion pain. Chi square (χ(2)) and analysis of variance statistics were employed to evaluate differences in insertion complications by parity and age. A χ(2) test was performed to compare follow-up expulsion or removal rates by parity. Statistically significant differences were found, with nulliparous women and those who received local anaesthesia reporting more insertion pain. Age, IUD type and recent abortion status did not affect insertion pain. Nulliparous women did not experience significantly more insertion difficulty or complications, nor did they have higher rates of expulsion or removal at follow-up. These findings suggest that the practice of providing cervical anaesthesia at IUD insertion may cause slightly more pain, without any obvious additional benefit. The difference in insertion pain by parity, although statistically significant, is small enough to be of questionable clinical importance. Overall, these findings add to the growing body of evidence for IUDs being safe and well-tolerated in nulliparous women.


An ultra-high timing resolution pulse generator with spur suppression and correction of errors based on real-time computation.
In this paper, a novel ultra-high timing resolution pulse generator is proposed. It is based on the waveform real-time computation method. Through real-time computing and filtering of the waveform samples, a pulse with a 0.1 ps timing resolution pulse could be generated at a 2.5 GSPS sampling rate. Based on the waveform real-time computation method, jitters are injected into the waveform time parameter to break the harmonic components caused by non-integer multiples of the sampling rate and waveform frequency. Waveform spurs are further suppressed using this approach. The pulse error correction is achieved by designing digital filters that complement the waveform distortion features. The complementary digital filters are then combined as Farrow filter coefficients by polynomial fitting. Based on the real-time computation method, pulse width modulation, frequency modulation, and amplitude modulation are easy to realize. The implemented pulse generator has four channels, whose minimum pulse width, edge time, frequency range, and amplitude range are 4, 2.5 ns, 1 μHz-120 MHz, and 50 mVpp-5 Vpp, respectively. All timing resolution and timing accuracy of pulse width, edge time, pulse period, and channel delay are 0.1 and 50 ps, respectively. Timing parameters can be changed continuously without glitches.


Postnatal development of the renin-angiotensin system in rats.
The purpose of this investigation was to correlate the development of the various enzyme activities associated with the renin-angiotensin system with age-related differences in the steady-state concentrations of angiotensin I (AI) and II (AII). Angiotensin was quantified by radioimmunoassay. Plasma renin activity and concentration increased between birth and 3 wk of age, and declined thereafter to adult values. Renal renin content, on the other hand, increased throughout the first 6 wk of postnatal life. The concentration of AII in plasma also increased following birth; however, maximum concentrations were not attained until 5 wk of age. In contrast, plasma AI did not increase between 3 and 6 wk of age. These data suggest that the steady-state concentration of AII in neonatal rat plasma may be partially limited by the low plasma renin substrate concentration. The increase in AII between 3 and 6 wk of age may reflect the increasing converting enzyme activity.


Preventing LVAD implantation by early short-term mechanical support and prolonged inodilator therapy : A case series with acute refractory cardiogenic shock treated with veno-arterial extracorporeal membrane oxygenation and optimised medical strategy.
Cardiogenic shock continues to be a life-threatening condition carrying a high mortality and morbidity, where the prognosis remains poor despite intensive modern treatment modalities. In recent years, mainly technical improvements have led to a more widespread use of short- and long-term mechanical circulatory support, such as veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and left ventricular assist devices (LVADs). Currently, LVADs are indispensable as 'bridge' to cardiac recovery, heart transplantation (HTX), and/or as destination therapy Importantly, both LVADs and HTX put a vast burden on financial resources, besides significant short- and long-term risks of morbidity and mortality. These considerations underscore the importance of optimal timing and appropriate patient selection for LVAD therapy, avoiding as much as possible an unfortunate and costly clinical path. In this report, we present a series of three cases with acute refractory cardiogenic shock ('crash and burn', INTERMACS profile 1) successfully treated by ECMO and early optimal medical therapy preventing a certain path towards LVAD and/or HTX, for which they were initially referred. This conservative approach in INTERMACS profile one patients warrants very early introduction of adequate medical heart failure therapy under the umbrella of a combination of short-term mechanical circulatory and inotropic support by phosphodiesterase inhibitors. Therefore, this novel combined medical-mechanical approach could have important clinical implications for this extremely challenging patient category, as it may avoid an unnecessary and costly clinical path towards LVAD and/or heart transplantation.


Age-related effects on markers of inflammation and cartilage metabolism in response to an intra-articular lipopolysaccharide challenge in horses.
Eighteen Quarter Horses were used in a randomized complete design for a 28-d experiment to evaluate age-related effects on inflammation and cartilage turnover after induction of a single inflammatory insult using lipopolysaccharide (LPS). Horses were grouped by age as yearlings (3 males and 3 females), 2 to 3 yr olds (2/3 yr old; 2 males and 4 females), and skeletally mature 5 to 8 yr olds (mature; 2 males and 4 females). On d 0, all horses were individually housed and fed diets that met or exceeded requirements. On d 14, horses were challenged with an intra-articular injection of LPS. Radial carpal joints were randomly assigned to receive 0.5 ng LPS solution obtained from O55:B5 or 0.8 mL sterile lactated Ringer's solution as a contralateral control. Synovial fluid was collected prior to LPS injection at h 0 before injection and at 6, 12, 24, 168, and 336 h after injection. Samples were analyzed using commercial ELISA kits for PGE, collagenase cleavage neoepitope (C2C), and carboxypropeptide of type II collagen (CPII). Heart rate (HR), respiratory rate (RR), and rectal temperature (RT) were monitored over the initial 24 h and carpal circumference and surface temperature were also recorded, with additional measurements at 168 and 336 h. Data were analyzed using PROC MIXED of SAS. Values for RT, HR, and RR were within the normal range for each age group. Heart rate and RT were influenced by age ( < 0.01), whereas RR was unaffected ( ≤ 0.21). Joint circumference was not influenced by age of horse ( = 0.84), but circumference and surface temperature increased ( < 0.01) over time across all age groups. Synovial PGE concentrations tended ( = 0.09) to be influenced by age, with yearlings having lower ( = 0.03) concentrations than mature horses. Concentrations of synovial C2C were affected by age of horse, with yearlings and 2/3 yr olds having lower ( < 0.01) concentrations than mature horses. Similarly, synovial CPII was influenced by age, with yearlings and 2/3 yr olds having lower ( ≤ 0.02) concentrations than mature horses. Ratios of anabolic CPII to catabolic C2C varied by age, with mature and 2/3-yr-old horses having greater ( < 0.01) values compared with yearlings. These results indicate that inflammation and the corresponding cartilage turnover in response to LPS administration vary with age.


Duchenne muscular dystrophy gene expression in normal and diseased human muscle.
A probe for the 5' end of the Duchenne muscular dystrophy (DMD) gene was used to study expression of the gene in normal human muscle, myogenic cell cultures, and muscle from patients with DMD. Expression was found in RNA from normal fetal muscle, adult cardiac and skeletal muscle, and cultured muscle after myoblast fusion. In DMD muscle, expression of this portion of the gene was also revealed by in situ RNA hybridization, particularly in regenerating muscle fibers.


Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons.
Transactivating DNA-binding protein-43 (TDP-43) deposits represent a typical finding in almost all ALS patients, more than half of FTLD patients and patients with several other neurodegenerative disorders. It appears that perturbation of nucleo-cytoplasmic transport is an important event in these conditions but the mechanistic role and the fate of TDP-43 during neuronal degeneration remain elusive. We have developed an experimental system for visualising the perturbed nucleocytoplasmic transport of neuronal TDP-43 at the single-cell level in vivo using zebrafish spinal cord. This approach enabled us to image TDP-43-expressing motor neurons before and after experimental initiation of cell death. We report the formation of mobile TDP-43 deposits within degenerating motor neurons, which are normally phagocytosed by microglia. However, when microglial cells were depleted, injury-induced motor neuron degeneration follows a characteristic process that includes TDP-43 redistribution into the cytoplasm, axon and extracellular space. This is the first demonstration of perturbed TDP-43 nucleocytoplasmic transport in vivo, and suggests that impairment in microglial phagocytosis of dying neurons may contribute towards the formation of pathological TDP-43 presentations in ALS and FTLD.


The Pyk2 FERM domain as a target to inhibit glioma migration.
The invasion of malignant glioma cells into the surrounding normal brain precludes effective clinical treatment. In this report, we investigated the role of the NH(2)-terminal FERM domain in the regulation of the promigratory function of Pyk2. We report that the substitution of residues that constitute a small cleft on the surface of the F3 module of the FERM domain do not significantly alter Pyk2 expression but result in the loss of Pyk2 phosphorylation. A monoclonal antibody, designated 12A10, specifically targeting the Pyk2 FERM domain was generated and recognizes an epitope located on the beta5C-alpha1C surface of the F3 module of the FERM domain. Amino acid substitutions in the F3 module that resulted in the loss of Pyk2 phosphorylation also inhibited the binding of 12A10, suggesting that the 12A10 epitope overlaps a site that plays a role in Pyk2 activity. Conjugation of 12A10 to a membrane transport peptide led to intracellular accumulation and inhibition of glioma cell migration in a concentration-dependent manner. A single chain Fv fragment of 12A10 was stable when expressed in the intracellular environment, interacted directly with Pyk2, reduced Pyk2 phosphorylation, and inhibited glioma cell migration in vitro. Stable intracellular expression of the 12A10 scFv significantly extended survival in a glioma xenograft model. Together, these data substantiate a central role for the FERM domain in regulation of Pyk2 activity and identify the F3 module as a novel target to inhibit Pyk2 activity and inhibit glioma progression.


Methyl jasmonate, yeast extract and sucrose stimulate phenolic acids accumulation in Eryngium planum L. shoot cultures.
Eryngium planum L. has been reported as a medicinal plant used in traditional medicine in Europe. The tissue cultures may be an alternative source of the biomass rich in desired bioactive compounds. The purpose of this study was to investigate the influence of the biotechnological techniques on the selected phenolic acids accumulation in the agitated shoot cultures of E. planum. Qualitative and quantitative analyses of those compounds in 50% aqueous - methanolic extracts from the biomass were conducted by applying the HPLC method. Methyl jasmonate (MeJA), yeast extract (YE) and sucrose (Suc) stimulated accumulation of the phenolic acids: rosmarinic (RA), chlorogenic (CGA) and caffeic (CA) in in vitro shoot cultures. Cultivation of shoots in liquid MS media supplemented with 1.0 mg L(-1) 6-benzyladenine and 0.1 mg L(-1) indole-3-acetic acid in the presence of 100 µM MeJA for 48h was an optimum condition of elicitation and resulted in approximately 4.5-fold increased content of RA + CGA + CA in plant material compared to the control (19.795 mg g(-1) DW, 4.36 mg g(-1) DW, respectively). The results provide the first evidence that the selected phenolic acids can be synthesized in elicited shoot cultures of flat sea holly in higher amount than in untreated shoots.


Finite Element-Based Personalized Simulation of Duodenal Hydrogel Spacer: Spacer Location Dependent Duodenal Sparing and a Decision Support System for Spacer-Enabled Pancreatic Cancer Radiation Therapy.
Pancreatic cancer is the fourth leading cause of cancer-related death, with a very low 5-year overall survival rate (OS). Radiation therapy (RT) together with dose escalation significantly increases the OS at 2 and 3 years. However, dose escalation is very limited due to the proximity of the duodenum. Hydrogel spacers are an effective way to reduce duodenal toxicity, but the complexity of the anatomy and the procedure makes the success and effectiveness of the spacer procedure highly uncertain. To provide a preoperative simulation of hydrogel spacers, we presented a patient-specific spacer simulator algorithm and used it to create a decision support system (DSS) to provide a preoperative optimal spacer location to maximize the spacer benefits. Our study was divided into three phases. In the validation phase, we evaluated the patient-specific spacer simulator algorithm (FEMOSSA) for the duodenal spacer using the dice similarity coefficient (DSC), overlap volume histogram (OVH), and radial nearest neighbor distance (RNND). For the simulation phase, we simulated four virtual spacer scenarios based on the location of the spacer in para-duodenal space. Next, stereotactic body radiation therapy (SBRT) plans were designed and dosimetrically analyzed. Finally, in the prediction phase, using the result of the simulation phase, we created a Bayesian DSS to predict the optimal spacer location and biological effective dose (BED). A realistic simulation of the spacer was achieved, reflected in a statistically significant increase in average target and duodenal DSC for the simulated spacer. Moreover, the small difference in average mean and 5th-percentile RNNDs (0.5 and 2.1 mm) and OVH thresholds (average of less than 0.75 mm) showed that the simulation attained similar separation as the real spacer. We found a spacer-location-independent decrease in duodenal V20Gy, a highly spacer-location-dependent change in V33Gy, and a strong correlation between L1cc and V33Gy. Finally, the Bayesian DSS predicted the change in BED with a root mean squared error of 3.6 Gys. A duodenal spacer simulator platform was developed and used to systematically study the dosimetric effect of spacer location. Further, L1cc is an informative anatomical feedback to guide the DSS to indicate the spacer efficacy, optimum location, and expected improvement.


Supercritical fluid chromatography.
Chromatographic separations with a supercritical fluid as the mobile phase were suggested more than 20 years ago. Availability of commercial hardware makes this technique more widely usable today. Many separations by this method are now carried out with supercritical carbon dioxide as the mobile phase and packed liquid-chromatography columns as the stationary phase. Although carbon dioxide has many practical advantages, including its near-ambient critical temperature and minimal interference with spectrometric detection, the use of other supercritical fluids or addition of modifiers to carbon dioxide may extend the applications of this technique. Some mixtures that are difficult to analyze by other chromatographic methods may be susceptible to separation by supercritical fluid chromatography. Mixtures that have been separated with supercritical carbon dioxide include resin acids with the empirical formula C20H30O2 and ubiquinones from bacterial cell wall extracts of Legionella pneumophila.


Safety, Performance, and Efficacy of Cardiac Contractility Modulation Delivered by the 2-Lead Optimizer Smart System: The FIX-HF-5C2 Study.
Prior studies of cardiac contractility modulation (CCM) employed a 3-lead Optimizer system. A new 2-lead system eliminated the need for an atrial lead. This study tested the safety and effectiveness of this 2-lead system compared with the 3-lead system. Patients with New York Heart Association III/IVa symptoms despite medical therapy, left ventricular ejection fraction 25% to 45%, and not eligible for cardiac resynchronization therapy could participate. All subjects received an Optimizer 2-lead implant. The primary end point was the estimated difference in the change of peak VO2 from baseline to 24 weeks between FIX-HF-5C2 (2-lead system) subjects relative to control subjects from the prior FIX-HF-5C (3-lead system) study. Changes in New York Heart Association were a secondary end point. The primary safety end point was a comparison of device-related adverse events between FIX-HF-5C2 and FIX-HF-5C subjects. Sixty subjects, 88% male, 66±9 years old with left ventricular ejection fraction 34±6% were included. Baseline characteristics were similar between FIX-HF-5C and FIX-HF-5C2 subjects except that 15% of FIX-HF-5C2 subjects had permanent atrial fibrillation versus 0% in FIX-HF-5C. CCM delivery did not differ significantly between 2- and 3-lead systems (19 892±3472 versus 19 583±4998 CCM signals/day, CI of difference [-1228 to 1847]). The change of peak VO2 from baseline to 24 weeks was 1.72 (95% Bayesian credible interval, 1.02-2.42) mL/kg per minute greater in the 2-lead device group versus controls. 83.1% of 2-lead subjects compared with 42.7% of controls experienced ≥1 class New York Heart Association improvement (P<0.001). There were decreased Optimizer-related adverse events with the 2-lead system compared with the 3-lead system (0% versus 8%; P=0.03). The 2-lead system effectively delivers comparable amount of CCM signals (including in subjects with atrial fibrillation) as the 3-lead system, is equally safe and improves peak VO2 and New York Heart Association. Device-related adverse effects are less with the 2-lead system. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03339310.


Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.
Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma. We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0-1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing. Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5-19·0) in the nivolumab group and 8·0 months (4·6-15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2-13·3 vs 8·4 months, 7·2-9·9; hazard ratio for death 0·77, 95% CI 0·62-0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease). Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients. ONO Pharmaceutical Company and Bristol-Myers Squibb.


Molecular identification of enteroviruses including two new types (EV-98 and EV-107) isolated from Japanese travellers from Asian countries.
Of 58 enterovirus strains isolated from Japanese travellers returning from Asian countries, eight were non-serotypable with existing antisera. By sequencing a part of the VP1 region, six of these strains were typed as echovirus 9, enterovirus (EV)-73, EV-79 or EV-97. The nucleotide identity of the VP1 region of isolate T92-1499 to all enterovirus prototypes was <70 %. The VP1 sequence of isolate TN94-0349 was closely related to coxsackievirus (CV)-A9 (73.3 % nucleotide identity), but the virus could not be neutralized with a serum raised against the prototype CV-A9 strain. On the basis of complete molecular comparisons, T92-1499 and TN94-0349 were identified as EV-98 and EV-107, respectively, by the ICTV Picornavirus Study Group. Serum neutralization tests of Japanese individuals revealed a seroprevalence rate of 11 % for EV-73, and even lower seroprevalence rates, 1.0-3.8 %, were found for the other new enteroviruses, suggesting that prior circulation of these viruses in Japan was unlikely.


DIC in Pregnancy - Pathophysiology, Clinical Characteristics, Diagnostic Scores, and Treatments.
Obstetrical hemorrhage and especially DIC (disseminated intravascular coagulation) is a leading cause for maternal mortality across the globe, often secondary to underlying maternal and/or fetal complications including placental abruption, amniotic fluid embolism, HELLP syndrome (hemolysis, elevated liver enzymes and low platelets), retained stillbirth and acute fatty liver of pregnancy. Various obstetrical disorders can present with DIC as a complication; thus, increased awareness is key to diagnosing the condition. DIC patients can present to clinicians who may not be experienced in a variety of aspects of thrombosis and hemostasis. Hence, DIC diagnosis is often only entertained when the patient already developed uncontrollable bleeding or multi-organ failure, all of which represent unsalvageable scenarios. Beyond the clinical presentations, the main issue with DIC diagnosis is in relation to coagulation test abnormalities. It is widely believed that in DIC, patients will have prolonged prothrombin time (PT) and partial thromboplastin time (PTT), thrombocytopenia, low fibrinogen, and raised D-dimers. Diagnosis of DIC can be elusive during pregnancy and requires vigilance and knowledge of the physiologic changes during pregnancy. It can be facilitated by using a pregnancy specific DIC score including three components: 1) fibrinogen concentrations; 2) the PT difference - relating to the difference in PT result between the patient's plasma and the laboratory control; and 3) platelet count. At a cutoff of ≥26 points, the pregnancy specific DIC score has 88% sensitivity, 96% specificity, a positive likelihood ratio (LR) of 22, and a negative LR of 0.125. Management of DIC during pregnancy requires a prompt attention to the underlying condition leading to this complication, including the delivery of the patient, and correction of the hemostatic problem that can be guided by point of care testing adjusted for pregnancy.


[Information sources and prescribing in the Lisbon region].
Quality in prescribing and rational use of drugs requires that physicians are kept up to date with developments in the medical literature and have knowledge of newly available drugs. This study aimed to examine, quantitatively, the sources of drug information that are used by physicians and to verify if there are differences according to work setting, namely health centers and hospitals. Cross-sectional descriptive analysis based on the application of a self-administered anonymous questionnaire developed specifically for the study. The 71 physician respondents were drawn from one public hospital (60.9%) and three public health centers (39.1%) in the Lisbon region. Respondents were asked to rate information sources in terms of their importance for prescribing and to report their use of these sources both in their general drug adoption procedures, in the adoption of one of a number of target 'new' drugs and in the evaluation of the therapeutic, pharmacological and economic value of drugs. Commercial sources were cited more frequently than professional or official sources of information in the process of adopting new drugs for prescribing. In evaluating the therapeutic and economic value of a new drug, doctors used primarily studies disseminated by the pharmaceutical industry. Official sources of information were only used widely in case of uncertainties in the dose and dose regime of drugs. The use of sources of information varied with physician's characteristics and with the place of work, with primary care doctors revealing more frequent use of commercial sources. Doctors working in hospitals and health centers use commercial sources above all others. There are, however, some differences according to work setting. In combining scientific information with interpersonal communication, the pharmaceutical industry appears to have a more effective strategy for communicating information to doctors. Health authorities should take this knowledge on board when drawing up strategies for improving the quality of prescribing, thereby assuring that the best quality information is used in clinical practice.


Unregulated alternative medicine.
Unconventional (i.e. alternative, traditional, or complementary) treatments are used by many individuals for a variety of symptoms and disorders. Reports on fraudulent products used for unconventional treatments are not uncommon. These include herbal remedies offered as "natural" while containing non-labeled synthetic pharmacological ingredients or even toxic agents, patients not being informed of active ingredients, products containing no active substances, or unqualified individuals or "clinics" delivering dangerous advice or treatment. Reports on tainted topical products remain rare due to the high analytical demands necessary to detect minimal traces of unknown ingredients, the fact that patients often use medications from different sources, and patient over-reliance on the effectiveness of folk remedies or advertised claims. The patients' assumption of receiving a safe and effective therapy by "natural" products has shown to be unreliable. The authors urge that quality standards for "natural" and pharmaceutical products should be the same and that only qualified professionals should deliver treatment and medical advice.


Peripheral artery disease diagnosis based on deep learning-enabled analysis of non-invasive arterial pulse waveforms.
This paper intends to investigate the feasibility of peripheral artery disease (PAD) diagnosis based on the analysis of non-invasive arterial pulse waveforms. We generated realistic synthetic arterial blood pressure (BP) and pulse volume recording (PVR) waveform signals pertaining to PAD present at the abdominal aorta with a wide range of severity levels using a mathematical model that simulates arterial blood circulation and arterial BP-PVR relationships. We developed a deep learning (DL)-enabled algorithm that can diagnose PAD by analyzing brachial and tibial PVR waveforms, and evaluated its efficacy in comparison with the same DL-enabled algorithm based on brachial and tibial arterial BP waveforms as well as the ankle-brachial index (ABI). The results suggested that it is possible to detect PAD based on DL-enabled PVR waveform analysis with adequate accuracy, and its detection efficacy is close to when arterial BP is used (positive and negative predictive values at 40 % abdominal aorta occlusion: 0.78 vs 0.89 and 0.85 vs 0.94; area under the ROC curve (AUC): 0.90 vs 0.97). On the other hand, its efficacy in estimating PAD severity level is not as good as when arterial BP is used (r value: 0.77 vs 0.93; Bland-Altman limits of agreement: -32%-+32 % vs -20%-+19 %). In addition, DL-enabled PVR waveform analysis significantly outperformed ABI in both detection and severity estimation. In sum, the findings from this paper suggest the potential of DL-enabled non-invasive arterial pulse waveform analysis as an affordable and non-invasive means for PAD diagnosis.


Structural implication of the induced immune response by Bacillus thuringiensis Cry proteins: role of the N-terminal region.
The potential role of the regions (carboxil and amino) of the Cry proteins in the ability of these proteins to elicit strong immune responses was investigated. Intraperitoneal immunization of mice with the homologous Cry1A protoxins (130-133 kDa), with the long C-terminal half gave rise mostly to similar, strong serum and mucosal IgG and IgM antibody response but a lower induction of these Ab by intranasal route. Remarkably, Cry3A protoxin, devoid of C-terminal half was able to induce a significant mucosal IgG, and IgM Ab as well as Cry1A protoxins, suggesting us that immunogenic abilities are not restricted to C-terminal half but N-terminal half itself could be involved. In fact, this assumption was strengthen by the strong immunogenic abilities of the Cry1A toxins, specially IgG and IgA Ab induced by both routes in different mucosal sites. These data indicate that immunogenic abilities of the Bt Cry proteins reside and depends of the N-terminal half.


Sirolimus versus calcineurin inhibitor-based immunosuppressive therapy in kidney transplantation: a 4-year follow-up.
Sirolimus is the one of new immunosuppressants that may be a substitute to traditional drugs such as cyclosporine. We present our investigation on sirolimus-based immunosuppression in kidney transplant recipients as compared with cyclosporine-based immunosuppression. We enrolled 100 patients in an open-labeled randomized clinical trial at Shahid Labbafinejad Medical Center. The patients were assigned to one of the immunosuppressive groups to receive either sirolimus or cyclosporine in combination with mycophenolate mofetil and steroids. All kidney transplant recipients were followed up by for serum creatinine and glomerular filtration rate for 4 years. There was no significant differences between the two groups regarding serum creatinine level and GFR until for years posttransplant; however, serum creatinine levels were significantly lower and the GFRs were higher in the sirolimus group after 3 and 4 years. The mean serum creatinine was 1.24 ± 0.28 mg/dL in the sirolimus group and 1.57 ± 0.33 mg/dL in the cyclosporine group at 4 years posttransplant (P = .02). Also, GFR was 79.8 ± 22.3 mL/min/1.73 m2 in the sirolimus group and 70.3 ± 23.6 mL/min/1.73 m2 in the cyclosporine group B (P = .04). Acute rejection was 1.7-fold higher in the cyclosporine group than in the sirolimus group. Our study demonstrated that sirolimus in the immunosuppressive regimen of kidney transplant recipients had better outcomes regarding graft and patient survival. The effectiveness of sirolimus for kidney allograft recipients should be further assessed to be implemented from the first day after transplantation.


Periodontal Stem Cells Synthesize Maresin Conjugate in Tissue Regeneration 3.
Periodontal disease is a significant public health problem worldwide. Excess unresolved chronic inflammation destroys the periodontal tissues that surround and support the teeth, and efforts to control inflammation by removal of bacterial deposits on the teeth have limited long-term impact. Likewise, procedures aimed at regeneration of the periodontal tissues have shown limited success. Recent advances in stem cell research have shown promising novel prospects for the use of periodontal ligament stem cells (PDLSCs) in tissue regeneration; however, control of inflammation remains a barrier. Human PDLSCs have been shown to release specialized proresolving lipid mediators (SPMs) that modulate the immune response and promote resolution of inflammation, tissue repair, and regeneration. Studies on stem cell biology in periodontology have also been limited by the lack of a good large animal model. Herein, we describe PDLSC biology of the Yorkshire pig (pPDLSCs). pPDLSCs were isolated and characterized. Using lipid mediator profiling, we demonstrate for the first time that pPDLSCs biosynthesize cysteinyl-containing SPMs (cys-SPMs), specifically, maresin conjugates in tissue regeneration 3 (MCTR3) and its authentication using liquid chromatography/tandem mass spectrometry. The exogenous addition of the n-3 precursor docosahexaenoic acid enhances MCTR3 biosynthesis. Using immunocytochemistry, we show that pPDLSCs express 4 of the SPM biosynthetic pathway enzymes necessary for SPM biosynthesis, including 5-lipoxygenase, 12-lipoxygenase, and 15-lipoxygenase-1. In addition, we identified and quantified the cytokine/chemokine profile of pPDLSCs using a 13-plex immunology multiplex assay and found that the pretreatment of pPDLSCs with MCTR3 in an inflammatory environment reduced the production of acute and chronic proinflammatory cytokines/chemokines. Together, these results suggest that enhancing resolution of inflammation pathways and mediators may be a possible key early event in predictable periodontal regeneration.


A nationwide survey on Marinesco-Sjögren syndrome in Japan.
Marinesco-Sjögren syndrome (MSS) is an autosomal recessive multisystem disorder characterized by the tetralogy of cerebellar ataxia, congenital cataracts, intellectual disability, and progressive muscle weakness due to myopathy. MSS is extremely rare, and its clinical, pathological, and genetic features are not yet fully understood. We conducted a nationwide, questionnaire-based survey on MSS in Japan and carefully reviewed the medical records of 36 patients suspected of having this disease. In addition, pathological examinations of muscles, sequence and haplotype analysis in SIL1 were performed. The patients had been examined between the ages of 2 and 52 years. Delayed psychomotor development and cataracts from early childhood were observed in all patients, whereas no life-threatening events were observed. Mutations in SIL1 were identified in 24 of the 27 patients tested, and 43 of the 48 chromosomes possessed the SIL1 c.936dupG (p.Leu313fs) mutation. The haplotype analysis revealed that 31 of the 32 chromosomes (96.9%) with the c.936dupG mutation had the same haplotype. The results of haplotype analysis suggested the presence of a founder effect. The clinical features of patients without SIL1 mutations were indistinguishable from those with SIL1 mutations, suggesting the genetic heterogeneity of MSS.


Prospective association of TV viewing with acute phase reactants and coagulation markers: English Longitudinal Study of Ageing.
Inflammatory processes are putative mechanisms underlying the detrimental health effects of sedentary behaviour but no long-term prospective data are available. We examined the longitudinal association between TV viewing, physical activity and inflammatory markers over a 4-year follow-up period. Participants were 3612 men and women (mean age 64.1 ± 8.2 years) from the English Longitudinal Study of Ageing. Self-reported daily TV viewing was measured at baseline and 2 years follow up. Inflammatory markers (serum high-sensitivity C-reactive protein [CRP], white blood cell count [WBC], and fibrinogen) were measured at baseline (2008/09) and 4 years follow-up (2012/13). On average, participants viewed TV for 5.1 ± 4.0 h/d, and there was an increase of 1.9 h/wk TV viewing over 2 years. In linear models adjusted for covariates including physical activity, TV viewing was not associated with logeCRP at follow-up (B = 0.004, 95% CI, -0.001, 0.009, p = 0.09) but was associated with WBC (B = 0.018, 95% CI, 0.005, 0.031, p = 0.006), and fibrinogen (B = 0.004, 95% CI, 0.00, 0.008, p = 0.035). In contrast, physical activity was inversely associated with CRP (p = 0.047) and WBC (p = 0.026), but not fibrinogen (p = 0.22). An increase in TV viewing (of at least 1 h/d) was associated with higher concentrations of CRP (p = 0.015) and WBC (p = 0.05) at follow up after adjustment for covariates and baseline TV viewing. Physical activity and sedentary behaviour have contrasting associations with markers of low grade inflammation over 4 years of follow-up. These behaviours may be important in influencing the pro-inflammatory state seen with ageing.


A scheme for the identification of viridans streptococci.
A collection of strains representing all the currently recognised species of oral or viridans streptococci (Streptococcus sanguis, S. parasanguis, S. gordonii, S. oralis, S. mitis, S. salivarius, S. vestibularis, S. anginosus, S. constellatus, s. intermedius, S. mutans and S. sobrinus) were tested for the production of a range of glycosidase activities with 4-methylumbelliferyl-linked fluorogenic substrates, and for reactions in a range of conventional fermentation and hydrolytic tests. The resulting biochemical scheme, consisting of 14 tests, enabled the differentiation of all these species and distinguished three biotypes within S. sanguis. The scheme reported here represents an improvement over currently available schemes for the identification of viridans streptococci.


Laser raman spectroscopy--new probe of myosin substructure.
Laser Raman spectroscopy is used to probe the heterogeneous substructure of the large contractile protein myosin. Some peaks are assigned to specific chemical groups of the molecule; others, notably the conformationally sensitive amide III vibrations, provide information on the structurally distinct regions of the molecule. Deuteration of the NH groups is instrumental in the assignment of these vibrational modes. The relative intensities of bands typical of alpha-helical conformations (near 1265 and 1304 cm-1) and bands associated with nonhelical structure (near 1244 cm-1) are sensitive indicators of myosin substructure and represent potentially useful probes of conformational changes.


GATA6 predicts prognosis and hepatic metastasis of colorectal cancer.
Liver metastasis is a major cause of mortality for colorectal cancer (CRC). However, the underlying mechanisms remain largely unknown. GATA binding protein 6 (GATA6), a zinc-finger transcription factor, is expressed in the colorectal epithelium. We investigated the clinical significance of GATA6 and its role in invasion and metastasis in CRC. Expression of GATA6 in 89 cancerous, 35 adjacent normal and 39 liver metastatic samples from 89 CRC patients undergoing surgical resection was detected by immunohistochemical (IHC) methods. The effect of GATA6 on invasion and metastasis was assessed in CRC cells by shRNA lentivirus or expressed-plasmid transfection. We found that GATA6 expression was significantly higher in liver metastatic tissues compared with adjacent normal tissues. Aberrant GATA6 expression in CRC was associated with liver metastasis. Kaplan-Meier analysis showed GATA6 expression correlated with poor overall survival (OS) in CRC. The cell invasion and migration of established CRC cell lines were decreased by GATA6 knockdown and enhanced by GATA6 overexpression in vitro. Thus, aberrant expression of GATA6 correlates with poor prognosis and liver metastasis in CRC.


Feature selection and classification for microarray data analysis: evolutionary methods for identifying predictive genes.
In the clinical context, samples assayed by microarray are often classified by cell line or tumour type and it is of interest to discover a set of genes that can be used as class predictors. The leukemia dataset of Golub et al. 1 and the NCI60 dataset of Ross et al. 2 present multiclass classification problems where three tumour types and nine cell lines respectively must be identified. We apply an evolutionary algorithm to identify the near-optimal set of predictive genes that classify the data. We also examine the initial gene selection step whereby the most informative genes are selected from the genes assayed. In the absence of feature selection, classification accuracy on the training data is typically good, but not replicated on the testing data. Gene selection using the RankGene software 3 is shown to significantly improve performance on the testing data. Further, we show that the choice of feature selection criteria can have a significant effect on accuracy. The evolutionary algorithm is shown to perform stably across the space of possible parameter settings - indicating the robustness of the approach. We assess performance using a low variance estimation technique, and present an analysis of the genes most often selected as predictors. The computational methods we have developed perform robustly and accurately, and yield results in accord with clinical knowledge: A Z-score analysis of the genes most frequently selected identifies genes known to discriminate AML and Pre-T ALL leukemia. This study also confirms that significantly different sets of genes are found to be most discriminatory as the sample classes are refined.


Pulsed infrared radiation excites cultured neonatal spiral and vestibular ganglion neurons by modulating mitochondrial calcium cycling.
Cochlear implants are currently the most effective solution for profound sensorineural hearing loss, and vestibular prostheses are under development to treat bilateral vestibulopathies. Electrical current spread in these neuroprostheses limits channel independence and, in some cases, may impair their performance. In comparison, optical stimuli that are spatially confined may result in a significant functional improvement. Pulsed infrared radiation (IR) has previously been shown to elicit responses in neurons. This study analyzes the response of neonatal rat spiral and vestibular ganglion neurons in vitro to IR (wavelength = 1,863 nm) using Ca(2+) imaging. Both types of neurons responded consistently with robust intracellular Ca(2+) ([Ca(2+)]i) transients that matched the low-frequency IR pulses applied (4 ms, 0.25-1 pps). Radiant exposures of ∼637 mJ/cm(2) resulted in continual neuronal activation. Temperature or [Ca(2+)] variations in the media did not alter the IR-evoked transients, ruling out extracellular Ca(2+) involvement or primary mediation by thermal effects on the plasma membrane. While blockage of Na(+), K(+), and Ca(2+) plasma membrane channels did not alter the IR-evoked response, blocking of mitochondrial Ca(2+) cycling with CGP-37157 or ruthenium red reversibly inhibited the IR-evoked [Ca(2+)]i transients. Additionally, the magnitude of the IR-evoked transients was dependent on ryanodine and cyclopiazonic acid-dependent Ca(2+) release. These results suggest that IR modulation of intracellular calcium cycling contributes to stimulation of spiral and vestibular ganglion neurons. As a whole, the results suggest selective excitation of neurons in the IR beam path and the potential of IR stimulation in future auditory and vestibular prostheses.


Treatment of sickle cell anemia with hydroxyurea and erythropoietin.
Hydroxyurea increases the production of fetal hemoglobin (hemoglobin F) in patients with sickle cell anemia and therefore has the potential for alleviating both the hemolytic and vaso-occlusive manifestations of the disease. There is preliminary evidence that recombinant human erythropoietin may also increase hemoglobin F production. We treated five patients with sickle cell disease with escalating doses of intravenous erythropoietin for eight weeks. Three of these patients were subsequently treated with daily doses of oral hydroxyurea. After the optimal dose was determined, erythropoietin was then given along with hydroxyurea for four weeks. Treatment with erythropoietin, either alone or in combination with hydroxyurea, had no significant effect on the percentage of hemoglobin F-containing reticulocytes (F reticulocytes) or red cells (F cells). In contrast, hydroxyurea treatment was associated with a 3-to-25-fold increase in F reticulocytes, a 1.6-to-7-fold increase in F cells, and a 2.3-to-16-fold increase in the percentage of hemoglobin F. In all three patients given hydroxyurea, treatment with this drug was associated with reduced hemolysis, shown by decreases in serum bilirubin and lactic dehydrogenase and prolongation of red-cell survival. Hydroxyurea treatment also resulted in a decrease in the percentage of irreversibly sickled cells and sickling at partial oxygen saturation, an increase in oxygen affinity and total red-cell cation content, and a reduction in potassium-chloride cotransport. All three patients had a decrease in the number of pain crises. This study confirms that hydroxyurea therapy increases hemoglobin F production and provides objective evidence that hydroxyurea reduces the rate of hemolysis and intracellular polymerization of hemoglobin S. In contrast, recombinant human erythropoietin, whether alone or in combination with hydroxyurea, offers no measurable benefit.


Outcomes and costs of day hospital treatment and nonmedical day treatment for chemical dependency.
The purpose of this study was to estimate the outcomes and costs of day hospital and nonmedical community-based day treatment for chemical dependency. A community sample of 271 adults (179 men) dependent on alcohol and/or drugs was recruited and randomized to either a hospital-based (medical) day treatment program or to a community-based (nonmedical) day treatment program. The day hospital (DH) program lasted for 3 weeks. One community-based program (CP2) lasted for 4 weeks, and the other (CP1) lasted for 6 weeks but with shorter treatment days and more criminal justice clients. Because of our concerns regarding treatment fidelity, we replaced CP1 with CP2 as the randomization site for the nonmedical, community-based arm of the trial halfway through the study. Abstinence rates were similar between DH and CP2 subjects, with 53% and 60% of each group, respectively, reporting no drinking for the 30 days preceding both follow-up interviews. DH subjects were less likely than those in either of the nonmedical programs to report medical problems at both follow-ups. Average episode costs per client were significantly (p < .01) lower at CP1 (dollars 526) than at DH (dollars 1,274) or CP2 (dollars 1,163). A pattern of weaker effects was observed at the less costly problematic community program (CP1), including less abstinence than was reported at CP2 (only 40% of CP1 subjects were alcohol free at both follow-ups) and worse psychiatric, family/friend and employment outcomes than were reported at DH or CP2. Our results not only demonstrate the clinical diversity that exists between nonmedical, community-based day treatment programs but also show that nonmedical programs can compete with DH treatment in cost as well as in most outcomes.


Prophylactic oophorectomy: a historical perspective.
Removal of a woman's ovaries (known as bilateral oophorectomy, ovariectomy or, historically, ovariotomy) is undertaken in a number of countries. An estimated 19,000 women aged <60 years had a bilateral prophylactic oophorectomy in the UK in 2003, either as a planned response to an increased specific genetic risk of ovarian or breast cancer or, more frequently, as a prophylactic measure to prevent ovarian cancer. Despite its popularity, however, a full evaluation of the risks, costs and benefits of prophylactic oophorectomy in the absence of genetic markers and at the time of hysterectomy has not yet been undertaken. This paper seeks to provide a historical perspective on current practice by outlining approaches to the ovary in Britain from the 19th century onwards. Historically, ovarian removal has raised many questions about the costs and benefits of surgery. The aim of this article is to highlight the issues, and in so doing, to contribute to a more informed assessment of current practice.


Increasing bystander behavior to prevent adolescent relationship violence: A randomized controlled trial.
The present research reports a randomized controlled trial evaluating TakeCARE, a video bystander program designed to help prevent relationship and sexual violence among high school students. High school students (n = 165) were randomly assigned to view TakeCARE or a control video. Students completed self-report measures of bystander behavior and bystander self-efficacy before viewing the videos. One week later, students completed the self-efficacy measure and were observed in virtual reality simulations of situations that offered opportunities to engage in bystander behavior. Measures were readministered at a 6-month follow-up. Compared to students who viewed the control video, students who viewed TakeCARE self-reported more bystander behavior at the 6-month follow-up. They were also observed to engage in greater levels of bystander behavior in the virtual reality simulations at postintervention and 6-month follow-up. Self-efficacy partially mediated this effect on observed bystander behavior. Video bystander programs like TakeCARE might be an effective addition to high school efforts to prevent relationship and sexual violence. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Managed care organizations: an introduction--Part I of II.
Today, managed care organizations operate along a wide spectrum of healthcare delivery models. From staff model HMOs to EPOs, the common element remains the delivery of cost-effective healthcare services to the patient. Implicit in such a system is pharmaceutical care and its related services provided by a pharmacist. Just as the definition or specific delivery model for medical services in managed care has changed since the mid-1950s, pharmacy and pharmaceutical service is different today from our predecessors' practice. Contemporary pharmacist roles and responsibilities continue to change and expand beyond those which existed as little as 1 year ago. As has been accomplished in hospitals, MCO pharmacists are increasingly involved in determining and selecting the best course of rational drug therapy for selected patients' conditions in all managed care settings. This is manifested by drug formularies, drug review programs, clinical practice guidelines, coordinated care committee work, and direct patient counseling. In the next part, the different organizational and professional roles of a pharmacist will be explored.


Comparative Effectiveness of Routine Invasive Coronary Angiography for Managing Unstable Angina.
Non-ST-segment elevation acute coronary syndromes include unstable angina and non-ST-segment elevation myocardial infarction. Most randomized controlled trials of routine versus selective invasive coronary angiography have high rates of crossover from control to intervention groups and do not include subgroup analysis for unstable angina. Consequently, no clear, specific recommendations exist regarding the use of angiography in unstable angina. To assess the effect of angiography on mortality in unstable angina, incorporating the results of additional cardiac procedures and events. Longitudinal study using hospital discharge data, discrete-time survival analysis with propensity score adjustment, and sensitivity analysis. Victoria, Australia, 2001 to 2011. All residents, all ages. Routine invasive coronary angiography. 12-month all-cause mortality. Emergently admitted patients with unstable angina (n = 33 901) who did or did not receive angiography during their first hospitalization were balanced on 44 covariates of propensity score. Routine angiography was associated with a 52% decrease in 12-month mortality (hazard ratio, 0.48 [95% CI, 0.38 to 0.61]); revascularization offered no additional statistical mortality benefit compared with diagnostic angiography alone. The predicted cumulative probability of death at 12 months was 0.024 (CI, 0.021 to 0.027) for patients receiving angiography within 2 months of their index unstable angina versus 0.097 (CI, 0.090 to 0.105) for those not receiving it. Sensitivity analysis demonstrated that to negate the observed effect size, an unmeasured confounder must independently decrease mortality by 90% and have a prevalence gap of 15% or greater between the angiographic groups. Nonrandom allocation of angiography. Patients with unstable angina benefit from an invasive management pathway initiated by invasive coronary angiography during their hospitalization and up to 2 months after discharge. National Health and Medical Research Council, Australia and BUPA Health Foundation.


Factors affecting the use of hearing protectors in a population of printing workers.
This study examined the reasons offered by rotogravure printing workers from São Paulo, Brazil, for not consistently using hearing protectors. The study group was comprised of 124 workers exposed to various levels of noise. Data on work history, psychosocial aspects of their job, medical history, present health, stress, occupational and non-occupational exposures to noise or chemicals and lifestyle factors were collected through an interview. The participants underwent pure-tone audiometry and had their noise exposures assessed. Seventy-nine workers of a total of 124 noise-exposed (64%) indicated that they wore hearing protectors, but only 16 (20%) of that subgroup stated that they wore the device all the time when noise-exposed. The variables significantly associated with the decision for not consistently wearing hearing protectors included interference with communication, interference with job performance, comfort issues, and self-perception of hearing condition.


Taguchi DoE methodology for modeling of synthetic dye biosorption from aqueous effluents: parametric and phenomenological studies.
Biosorption technology has been acknowledged as one of the most successful treatment approaches for colored industrial effluents. The problems such as its high manufacturing cost and poor regeneration capability in the use of activated carbon as a biosorbent have prompted the environmental scientists to develop alternative biosorbent materials. In this context, as a sustainable green generation alternative biosorbent source, the discarded seed biomass from pepper (Capsicum annuum L.) processing industry was explored for the biotreatment of colored aqueous effluents in this study. To test the wastewater cleaning ability of biosorbent, Basic red 46 was selected as a typical model synthetic dye. Taguchi DoE methodology was employed to study the effect of important operational parameters, contact time, pH and synthetic dye concentration, on the biosorption process and to develop a mathematical model for the estimation of biosorption potential of biosorbent. The percentage contribution of each of these process variables on the dye biosorption was found to be 19.31%, 41.39%, and 38.74%, respectively. The biosorption capacity under the optimum environmental conditions, contact time of 360 min, pH of 8 and dye concentration of 30 mg L-1, was estimated to be 92.878 mg g-1 (R2: 99.45). This value was very close to the experimentally obtained dye removal performance value (92.095 mg g-1). These findings indicated the high ability of Taguchi DoE technique in the optimization and simulation of dye biosorption system. The kinetic and equilibrium modeling studies showed that the pseudo-second-order and Langmuir models were the best models for the elucidation of dye removal behavior of biosorbent. The thermodynamic studies displayed that the dye biosorption was a feasible, spontaneous and exothermic process. This parametric and phenomenological survey revealed that the discarded pepper seed biomass can be introduced as a potential and efficient biosorbent for the bioremediation of colored industrial effluents.


Treatment of avulsion fractures of the intercondylar eminence by medial parapatellar approach, open reduction and cross wire fixation.
Avulsion fractures of the intercondylar eminence in children and adolescents are relatively uncommon and can lead to significant disability with improper union. Many operative techniques have been developed to fixate these fractures, most of them utilizing sophisticated fixation modes. In this study, a small medial parapatellar approach was used with open reduction and percutaneous cross Kirschner wire fixation. The aim of this study was to evaluate the effectiveness of this method. From 2007 to 2012, eight children were treated, mean age 11.8 years (range 10-14 years). All underwent open reduction by a medial parapatellar incision and fixation by two cross Kirschner wires introduced in an oblique crossed manner from the medial and lateral aspects of the proximal tibia. Fractures were classified as Meyers and McKeever type III and were not candidates for conservative treatment. All operated limbs were immobilized postoperatively in a circular cast in extension for 6 weeks and allowed partial weight bearing from day 1 after the procedure. Outcomes were evaluated clinically and through radiographs taken during follow-up. All fractures were successfully reduced and healed, with no occurrences of malunion or nonunion. At follow-up, all patients had full knee range of motion, there was no gross laxity of the knee compared with the contralateral knee, and good functional outcome was achieved. On the basis of our experience, we believe that the procedure that we used is a simple, low-tech, and minimally invasive technique for the treatment of these fractures, with good functional outcome.


Body mass index in multiethnic midlife women: influence of demographic characteristics and physical activity.
We examined the influence of demographic characteristics and physical activity on body mass index (BMI) in multiethnic midlife women. A sample of 236 African, European, and Mexican/Central Americans aged 40-50 completed the initial, 1-year, and 2-year assessments. The effects of demographic characteristics and physical activity on BMI at the 2-year assessment were evaluated using hierarchical multiple regression analysis. After controlling for other demographic factors, ethnicity, annual household income, and physical activity at the initial assessments were significant predictors of BMI. Body mass index (BMI) may be influenced by socioeconomic status as well as ethnicity. Regular physical activity should be encouraged to maintain a healthy BMI in midlife women.


Smartphone GPS signatures of patients undergoing spine surgery correlate with mobility and current gold standard outcome measures.
Patient-reported outcome measures (PROMs) are currently the gold standard to evaluate patient physical performance and ability to recover after spine surgery. However, PROMs have significant limitations due to the qualitative and subjective nature of the information reported as well as the impossibility of using this method in a continuous manner. The smartphone global positioning system (GPS) can be used to provide continuous, quantitative, and objective information on patient mobility. The aim of this study was to use daily mobility features derived from the smartphone GPS to characterize the perioperative period of patients undergoing spine surgery and to compare these objective measurements to PROMs, the current gold standard. Eight daily mobility features were derived from smartphone GPS data in a population of 39 patients undergoing spine surgery for a period of 2 months starting 3weeks before surgery. In parallel, three different PROMs for pain (visual analog scale [VAS]), disability (Oswestry Disability Index [ODI]) and functional status (Patient-Reported Outcomes Measurement Information System [PROMIS]) were serially measured. Segmented linear regression analysis was used to assess trends before and after surgery. The Student paired t-test was used to compare pre- and postoperative PROM scores. Pearson's correlation was calculated between the daily average of each GPS-based mobility feature and the daily average of each PROM score during the recovery period. Smartphone GPS features provided data documenting a reduction in mobility during the immediate postoperative period, followed by a progressive and steady increase with a return to baseline mobility values 1 month after surgery. PROMs measuring pain, physical performance, and disability were significantly different 1 month after surgery compared to the 2 immediate preoperative weeks. The GPS-based features presented moderate to strong linear correlation with pain VAS and PROMIS physical score during the recovery period (Pearson r > 0.7), whereas the ODI and PROMIS mental scores presented a weak correlation (Pearson r approximately 0.4). Smartphone-derived GPS features were shown to accurately characterize perioperative mobility trends in patients undergoing surgery for spine-related diseases. Features related to time (rather than distance) were better at describing patient physical and performance status. Smartphone GPS has the potential to be used for the development of accurate, noninvasive and personalized tools for patient mobility monitoring after surgery.


Surface-Enhanced Raman Scattering Based Microfluidics for Single-Cell Analysis.
The integration of surface-enhanced Raman scattering (SERS) with droplet microfluidics has the potential to improve our understanding of cellular systems. Herein, we present the first application of SERS droplet microfluidics for single-cell analysis. A microfluidic device was used to encapsulate single prostate cancer cells and wheat germ agglutin (WGA)-functionalized SERS nanoprobes in water-in-oil droplets that were subsequently locked into a storage droplet array for spectroscopic investigation. The stationary droplets enabled the rapid identification of SERS regions of interest in live cancer cells by allowing collection of "fast" coarse maps over an area of several square millimeters followed by "slower" detailed interrogation of the identified hotspots. We demonstrate SERS at cellular resolution via a proof-of-concept assay that detects glycan expression on the surface of prostate cancer cells using WGA-modified metallic nanoparticles. The data illustrates the potential of SERS optofluidic systems for high-throughput cell screening and illustrates a previously unobserved high degree of cell-to-cell variability in the size and number of glycan islands.


[Dynamics of matrix synthesis in molecular biophysics].
The paper deals with connections of structural-functional and dynamic approaches in the problems of molecular biophysics with reversible problems of the dynamics of matrix synthesis of biopolymers. Operator equation of dynamics describing such connections is obtained.


Raising questions about antidepressants.
Antidepressant medication has apparently become the most popular treatment for depression in the USA. Several beliefs about the efficacy of antidepressant medications prevail among mental health professionals and the public. This paper explores relevant research data and raises questions about these beliefs. Many of the common beliefs about these medications are not adequately supported by scientific data. The following issues are raised: (1) industry-funded research studies which result in negative findings sometimes do not get published; (2) placebo washout procedures may bias results in some studies; (3) there are serious questions about the integrity of the double-blind procedure; (4) the 'true' antidepressant drug effect in adults appears to be relatively small; (5) there is minimal evidence of antidepressant efficacy in children; (6) side effects are fairly common even with the newer antidepressants; (7) combining medications raises the risk for more serious complications; (8) all antidepressants can cause withdrawal symptoms; (9) genetic influences on unipolar depression appear to be weaker than environmental influences; (10) biochemical theories of depression are as yet unproven; (11) biological markers specific for depression have been elusive; (12) dosage and plasma levels of antidepressants have been minimally related to treatment outcome; (13) preliminary evidence suggests that patients who improve with cognitive-behavioral psychotherapy show similar biological changes as those who respond to medication, and (14) the evidence suggests that psychological interventions are at least as effective as pharmacotherapy in treating depression, even if severe, especially when patient-rated measures are used and long-term follow-up is considered.


G-Strands on symmetric spaces.
We study the G-strand equations that are extensions of the classical chiral model of particle physics in the particular setting of broken symmetries described by symmetric spaces. These equations are simple field theory models whose configuration space is a Lie group, or in this case a symmetric space. In this class of systems, we derive several models that are completely integrable on finite dimensional Lie group G, and we treat in more detail examples with symmetric space SU(2)/S1 and SO(4)/SO(3). The latter model simplifies to an apparently new integrable nine-dimensional system. We also study the G-strands on the infinite dimensional group of diffeomorphisms, which gives, together with the Sobolev norm, systems of 1+2 Camassa-Holm equations. The solutions of these equations on the complementary space related to the Witt algebra decomposition are the odd function solutions.


Injury comparisons between paired drivers and front-seat passengers in frontal collisions using publicly available crash and injury data.
Forensic engineers and crash safety researchers sometimes use the injuries of a seatbelted occupant to infer the injury risk of an unbelted occupant in the same crash, had they instead been wearing a seatbelt. It is unclear, however, whether this inference is valid or how often two occupants in the same collision have similar injuries. Here, we sought to compare the injury outcomes between drivers and front-seat passengers in frontal collisions using real-world collision data. We compared the injury severity, quantified using the Abbreviated Injury Scale (AIS), of 22 injury categories between front-seat occupants with matching seatbelt use and airbag deployment in single-event frontal collisions recorded in the publicly available National Automotive Sampling System, Crashworthiness Data System (years 1993-2015) database to assess whether they had similar severity injuries. We analyzed the four combinations of seatbelt use and airbag deployment and all seatbelt/airbag conditions combined. In only 3 of 88 combinations of injuries and seatbelt/airbag conditions did more than 50% of occupant pairs have the same AIS score, although the related confidence intervals showed these proportions were not significantly greater than 50%. In contrast, we found 19 combinations of injuries and seatbelt/airbag conditions where one occupant was consistently injured more severely than the other. Our findings show that injury outcome is not similar for both front-seat occupants in the same frontal collision with similar seatbelt and airbag conditions; however, one may be able to predict that one occupant would be more severely injured than their fellow occupant.


[Clinical characteristics of acute toxic liver injury].
Recently, acute toxic liver injury has been reported to be the most common cause of acute hepatitis. The frequency and clinical manifestations of acute toxic liver injury was evaluated. The medical records of 68 patients demonstrating clinically significant acute toxic liver injury were retrospectively reviewed. Patients with mild biochemical abnormalities were excluded. The annual percentage of toxic liver injury ranged from 50% to 90% among acute hepatitis groups. Among the causes, prescribed drugs (group D) accounted for 55%, herbs or plant products (group H) for 42% and both accounted for 3%. Antibiotics and anti-inflammatory drugs were the most common agents (78%) among group D. The mean age of the patients was 43 and 70% of patients were female. Of the population, common symptoms were jaundice, weakness, fatigue, and nausea. Initial ALT and AST levels were 847 +/- 879 and 664 +/- 625 IU/L, and initial total bilirubin was 7.5 +/- 8.1 mg/dL. Acute toxic liver injury occurred after a mean of 32 days after first exposure. Liver injury resolved within a mean of 32 days. Hepatocellular, mixed, and cholestatic type was 45.2%, 32.3%, 22.5%, respectively. Recently, acute toxic liver injury has been the most common cause of acute hepatitis in Korea. Prescribed drugs and herbs or plant products are equally important etiologic agents of toxic liver injury. However, etiologic difference may not affect clinical courses or outcomes. A nationwide investigation of the hepatotoxicity of drugs, herbs or other plant products is required.


Microfluidics expanding the frontiers of microbial ecology.
Microfluidics has significantly contributed to the expansion of the frontiers of microbial ecology over the past decade by allowing researchers to observe the behaviors of microbes in highly controlled microenvironments, across scales from a single cell to mixed communities. Spatially and temporally varying distributions of organisms and chemical cues that mimic natural microbial habitats can now be established by exploiting physics at the micrometer scale and by incorporating structures with specific geometries and materials. In this article, we review applications of microfluidics that have resulted in insightful discoveries on fundamental aspects of microbial life, ranging from growth and sensing to cell-cell interactions and population dynamics. We anticipate that this flexible multidisciplinary technology will continue to facilitate discoveries regarding the ecology of microorganisms and help uncover strategies to control microbial processes such as biofilm formation and antibiotic resistance.


Iloprost therapy acutely decreases oxidative stress in patients affected by systemic sclerosis.
Oxidative stress has been considered a leading factor in the pathogenesis of systemic sclerosis (SSc). Consistently with this hypothesis the determination of urinary isoprostanes, a reliable method for evaluation of oxidative stress, has recently showed increased levels of isoprostanes in SSc patients. Data about the effect on oxidative stress of accepted therapies for SSc such as iloprost therapy are lacking. The aim of this prospective study was to verify whether iloprost therapy in patients with SSc acutely reduces oxidative stress assessed by determination of 8-Iso PGF<inf>2alpha</inf> urinary levels. urine samples were obtained before and after a five-day cycle of iloprost infusion and urinary 8-Iso PGF<inf>2alpha</inf> levels were determined using a commercially available enzyme immunoassay. Consistent with previous reports, we found an increased level of oxidative stress in SSc patients with respect to healthy controls. Basal urinary 8-iso PGF<inf>2alpha</inf> levels in SSc patients were significantly higher than those in healthy controls [2002(1122-3575) pg/mg creatinine vs. 334(225.7-441) pg/mg creatinine, p<0.001]. Moreover, as expected, urinary 8-iso PGF<inf>2alpha</inf> levels after iloprost therapy were significantly lower than basal levels [1277.5 pg/mg creatinine (742.7-2017.3) vs. 2002 pg/mg creatinine (1122-3575), p=0.001] but persisted significantly elevated respect to the levels of healthy controls (p<0.001). The effect of iloprost on oxidative stress appeared significant in patients with early and limited form of disease. This prospective open-label explorative study suggests that standard course of iloprost therapy may acutely reduce oxidative stress in SSc patients. This effect appears to be more consistent in the early phases and in the limited subset of disease. Further larger trials are needed to confirm our results and to explain the pathway of such reduction, its clinical significance and potential therapeutic implications.


Cue-Reactive Imagery Mediates the Relationships of Reward Responsiveness with Both Cue-Reactive Urge to Gamble and Positive Affect in Poker-Machine Gamblers.
Previous research has demonstrated that gambling cues (e.g., flashing lights on poker-machines) can trigger an urge to gamble in poker-machine gamblers. However, the psychological mechanisms that promote the urge to gamble remain poorly understood. The present study explored whether reward responsiveness predicted urge to gamble and positive affect, and whether cue-reactive rationality, volitional control and imagery mediated these relationships. Ninety-three (45% male and 55% female) Australian regular poker-machine gamblers aged between 18 and 77 participated in an online cue-reactivity experiment. Participants initially completed the Problem Gambling Severity Index and Reward Responsiveness scale. Subsequently, at three time points (i.e., baseline, directly after a neutral cue and directly after a gambling cue) participants completed the rationality, volitional control and imagery subscales of the Phenomenology of Consciousness Inventory and two visual analogue scales that measured urge to gamble and positive affect. Analyses indicated that gambling cues triggered statistically significant increases in both urge to gamble and positive affect and these variables were statistically significantly positively correlated with reward responsiveness. Furthermore, only cue-reactive imagery mediated the relationships between reward responsiveness and the two outcome variables (i.e., cue-reactive urge to gamble and positive affect). These findings highlight the potential importance of targeting reward responsiveness and cue-reactive mental imagery in the context of exposure therapies for poker-machine problem gamblers.


Comparison of diflunisal and aspirin in long-term treatment of patients with rheumatoid arthritis.
A multicenter, open-label clinical trial evaluated the efficacy and tolerability of diflunisal given twice daily and aspirin given four times daily in the long-term treatment of patients with rheumatoid arthritis. Patients who successfully completed a 12-week, double-blind, parallel study comparing diflunisal (500 to 750 mg daily) with aspirin (2.6 to 3.9 gm daily) continued on the same medication in a 40-week, open-label segment of the study. The dosage of diflunisal could be increased to a maximum of 1 gm daily during the open-label phase. Both regimens were effective during the 40-week study. Diflunisal was better tolerated than aspirin as judged by the overall incidence of clinical adverse experiences. Patients treated with diflunisal had significantly fewer adverse experiences involving the digestive system and organs of special sense than did those treated with aspirin.


Wnt signaling in osteosarcoma.
Osteosarcoma (OS) is the most common primary bone malignancy diagnosed in children and adolescents with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the last two decades. With current treatments, 60-70 % of patients with localized disease survive. Given a propensity of Wnt signaling to control multiple cellular processes, including proliferation, cell fate determination, and differentiation, it is a critical pathway in OS disease progression. At the same time, this pathway is extremely complex with vast arrays of cross-talk. Even though decades of research have linked the role of Wnt to tumorigenesis, there are still outstanding areas that remain poorly understood and even controversial. The canonical Wnt pathway functions to regulate the levels of the transcriptional co-activator β-catenin, which ultimately controls key developmental gene expressions. Given the central role of this mediator, inhibition of Wnt/β-catenin signaling has been investigated as a potential strategy for cancer control. In OS, several secreted protein families modulate the Wnt/β-catenin signaling, including secreted Frizzled-related proteins (sFRPs), Wnt inhibitory protein (WIF), Dickkopf proteins (DKK-1,2,3), sclerostin, and small molecules. This chapter focuses on our current understanding of Wnt/β-catenin signaling in OS, based on recent in vitro and in vivo data. Wnt activates noncanonical signaling pathways as well that are independent of β-catenin which will be discussed. In addition, stem cells and their association with Wnt/β-catenin are important factors to consider. Ultimately, the multiple canonical and noncanonical Wnt/β-catenin agonists and antagonists need to be further explored for potential targeted therapies.


Clinical assessment of oral meptazinol in postoperative pain.
The pain relieving properties of orally administered meptazinol, a new hexahydroazepine analgesic, were studied in 51 patients recovering from major surgery. In doses of 250, 400 and 500 mg it produced significant analgesia which was maximal at the end of one hour and had a duration of action of approximately four hours. Arterial pressure and heart rate were not affected significantly by meptazinol. Nausea and vomiting were the main side-effects observed in a few patients and there were no abnormal hematological or biochemical findings.


Adverse drug reactions/interactions in maintenance therapy.
This paper begins with a brief review of the early onset, recidivism, and multiple consequences of recurrent major depressions. Increasing attention to these factors underscores the importance of long-term maintenance therapy. Successful maintenance rests on optimizing the risk:benefit profile for the patient. Literature is reviewed that the serotonin selective reuptake inhibitors exhibit a significantly lower discontinuation rate due to adverse events than do other conventional antidepressants. Adverse events clearly detract from patient compliance and, in turn, ultimately contribute to the risk of depressive recurrence. An overview of adverse events, in both short- and long-term anti-depressant trial experience is provided. In addition, extended pharmacotherapy carries an increased probability of concomitant drug therapy. Relevant drug:drug interaction issues are reviewed, including specific attention to those mediated by the hepatic isoenzyme cytochrome P450 IID6. Lastly, long-term clinical trial experience with fluoxetine relative to short- and long-term emergence of adverse events and adverse event experience following drug discontinuation is presented. Overall fluoxetine adverse events do not increase with chronic administration. When side effects occur, they typically emerge early in the course of acute treatment and wane in the face of continued treatment. Upon drug discontinuation, these events usually reverse at a much faster pace than the drug's half-life. In conclusion, the importance of maintenance therapy in recurrent major depression is increasingly recognized as a critical care issue. To optimize a therapeutic outcome, the clinician is challenged to maximize patient compliance through depression awareness education, regular follow-up, minimization of adverse drug events, and sensitivity to other intercurrent psychosocial events.


Regional Nanoindentation Properties in Different Locations on the Mouse Tibia From C57BL/6 and Balb/C Female Mice.
The local spatial heterogeneity of the material properties of the cortical and trabecular bone extracted from the mouse tibia is not well-known. Nevertheless, its characterization is fundamental to be able to study comprehensively the effect of interventions and to generate computational models to predict the bone strength preclinically. The goal of this study was to evaluate the nanoindentation properties of bone tissue extracted from two different mouse strains across the tibia length and in different sectors. Left tibiae were collected from four female mice, two C57BL/6, and two Balb/C mice. Nanoindentations with maximum 6 mN load were performed on different microstructures, regions along the axis of the tibiae, and sectors (379 in total). Reduced modulus (Er) and hardness (H) were computed for each indentation. Trabecular bone of Balb/C mice was 21% stiffer than that of C57BL/6 mice (20.8 ± 4.1 GPa vs. 16.5 ± 7.1 GPa). Moreover, the proximal regions of the bones were 13-36% less stiff than the mid-shaft and distal regions of the same bones. No significant differences were found for the different sectors for E r and H for Balb/C mice. The bone in the medial sector was found to be 8-14% harder and stiffer than the bone in the anterior or posterior sectors for C57BL/6 mice. In conclusion, this study showed that the nanoindentation properties of the mouse tibia are heterogeneous across the tibia length and the trabecular bone properties are different between Balb/C and C57BL/6 mice. These results will help the research community to identify regions where to characterize the mechanical properties of the bone during preclinical optimisation of treatments for skeletal diseases.


Possible role of serum testosterone, gonadotropins and prolactin in patients with premature ejaculation.
Premature ejaculation (PE) is the most common male sexual dysfunction. This study aimed to investigate the role of serum testosterone, gonadotropins and prolactin in patients with PE. In a prospective a case-controlled study, it was conducted on 90 male patients with PE and 90 male healthy participants as controls. Patients were evaluated by Premature Ejaculation Diagnostic Tool (PEDT) and intravaginal ejaculatory latency time (IELT). Patients with mean IELT values ≤60 s and PEDT total scores ≥11 were considered to have PE. Serum levels of total testosterone (TT), free testosterone (FT), follicle-stimulating hormone (FSH), luteinising hormone (LH) and prolactin (PL) were investigated in patients with PE and controls. There was no statistically significant difference between patients with PE and controls regarding the serum levels of TT, FT, FSH, LH and PL (p value ˃.05). There was no significant correlation between the sex hormones levels (TT, FT, FSH, LH and PL) and (age, body mass index (BMI), IELTS and total PEDT scores of the patients; p value ˃.05). This study concluded that there was no disturbance in serum levels of testosterone, gonadotropins and prolactin in patients with PE and controls. These hormones could not relate to pathogenesis of PE.


Zinc uptake in the Basidiomycota: Characterization of zinc transporters in Ustilago maydis.
At present, the planet faces a change in the composition and bioavailability of nutrients. Zinc deficiency is a widespread problem throughout the world. It is imperative to understand the mechanisms that organisms use to adapt to the deficiency of this micronutrient. In the Ascomycetes fungi, the ZIP family of proteins is one of the most important for zinc transport and includes high affinity Zrt1p and low zinc affinity Zrt2p transporters. After identification and characterization of ZRT1/ZRT2-like genes in Ustilago maydis we conclude that they encode for high and low zinc affinity transporters, with no apparent iron transport activity. These conclusions were supported by the gene deletion in Ustilago and the functional characterization of ZRT1/ZRT2-like genes by measuring the intracellular zinc content over a range of zinc availability. The functional complementation of the S. cerevisiae ZRT1Δ ZRT2Δ mutant with U. maydis genes supports this as well. U. maydis ZRT2 gene, was found to be regulated by pH through Rim101 pathway, thus providing novel insights into how this Basidiomycota fungus can adapt to different levels of Zn availability.


Imaging and characterizing fluid invasion in micro-3D printed porous devices with variable surface wettability.
Fluid invasion in porous media widely exists in many applications, such as waterflooded oil/gas recovery, carbon geo-sequestration, water filtration and membrane distillation. The invasion dynamics is significantly affected by the surface wettability, interfacial tension, pore-throat topology and many other parameters. In this work, we experimentally investigate the effect of surface wettability on the multiphase flow behavior, particularly the interfacial dynamics, through direct visualization of fluid invasion in a porous microfluidic device (micromodel). The micromodels have been fabricated by using a micro-stereolithography 3D printer with acrylate-based resins. With a high printing resolution of up to 2 μm, these micromodels successfully mimic the complex pore-throat features of natural porous media (i.e. rocks) based on their thin-section or micro-CT images. Moreover, the transparency of the as-printed micromodel also enables microfluidic flow imaging. By injecting different fluids into surface-modified micromodels, we observe and study the invasion dynamics, including the lateral interfacial curvature, multiphase flow path and fluid trapping behavior, under various surface wettability conditions. By combining optical flow imaging and numerical simulation, we have systematically analyzed the wettability-dependent residue distribution and revealed four different types of trapping mechanisms. This work offers a novel methodology to study microscale flow in porous media with micro-3D printing and multiphase flow imaging.


Reproductive character displacement and potential underlying drivers in a species-rich and florally diverse lineage of tropical angiosperms (Ruellia; Acanthaceae).
Reproductive character displacement is a pattern whereby sympatric lineages diverge more in reproductive character morphology than allopatric lineages. This pattern has been observed in many plant species, but comparably few have sought to disentangle underlying mechanisms. Here, in a diverse lineage of Neotropical plants (Ruellia; Acanthaceae), we present evidence of reproductive character displacement in a macroevolutionary framework (i.e., among species) and document mechanistic underpinnings. In a series of interspecific hand pollinations in a controlled glasshouse environment, we found that crosses between species that differed more in overall flower size, particularly in style length, were significantly less likely to produce viable seeds. Further, species pairs that failed to set seed were more likely to have sympatric distributions in nature. Competition for pollinators and reinforcement to avoid costly interspecific mating could both result in these patterns and are not mutually exclusive processes. Our results add to growing evidence that reproductive character displacement contributes to exceptional floral diversity of angiosperms.


Fine-needle aspiration diagnosis of an intraosseous amyloidoma.
Fine-needle aspiration (FNA) is frequently used as the initial diagnostic procedure for the investigation of bone and soft tissue masses. The majority of the lesions detected will represent metastatic carcinoma. Amyloid is a rare cause of a bone mass, with less than 15 published reports describing amyloid deposition within bone. The majority of reported cases involve the vertebral column. We report the finding of a massive amyloidoma of the iliac wing in a 46-year-old man. FNA smears and cell block preparations demonstrated fragments of waxy acellular material misinterpreted as necrotic debris. Subsequent open biopsy established the diagnosis of amyloid with congo red staining demonstrating apple green birefringence. Subsequent workup disclosed the patient to have anemia, hypogammaglobulinemia and trace monoclonal light chain gammopathy. Bone marrow examination revealed CD138a positive lambda restricted plasma cells consistent with plasma cell dyscrasia. Careful attention to the staining characteristics of amyloid in FNA derived material should allow the diagnosis of amyloidoma.


Hangover frequency and risk for alcohol use disorders: evidence from a longitudinal high-risk study.
Data from a prospective high-risk study (N=489; 51% with a family history of alcoholism) were used to test whether family history is associated with greater hangover proneness and whether hangover is a risk factor for alcohol use disorders. Hangover was more frequent in family-history-positive participants during the college years. Persons with an alcohol diagnosis showed excess hangover before earning a diagnosis. Year 1 hangover predicted alcohol use disorders at Years 7 and 11, even when family history, sex, Year 1 diagnoses, and Year 1 drinking were statistically controlled. Several nonhangover drinking symptoms failed to predict later diagnoses. Taken together, the findings suggest a need for further research and theory on the role of hangover in the etiology of drinking problems.


Angiotensin II and stretch activate NADPH oxidase to destabilize cardiac Kv4.3 channel mRNA.
Pathological and physiological hypertrophy of the heart is associated with decreased expression of the Kv4.3 transient outward current (Ito) channel. The downregulation of channel mRNA and protein, which may be proarrhythmic, is recapitulated with cultured neonatal rat ventricular myocytes treated with angiotensin II (Ang II). Here we show that the 4.9 kb 3' untranslated region (3' UTR) of the Kv4.3 channel transcript confers Ang II sensitivity to a promoter-reporter construct. In contrast, Kv4.2 and Kv1.5 3'-UTR sequences are insensitive to Ang II. Both Kv4.3 3'-UTR reporter mRNA and activity are decreased in Ang II-treated cardiac myocytes, in accordance with a decrease in mRNA stability. This regulation is mediated by Ang II type 1 (AT1) receptors and abolished by NADPH oxidase inhibitors and dominant negative rac. The Ang II effect is also blocked by expression of superoxide dismutase (SOD), but not catalase, showing that superoxide is required. Dominant negative subunits, enzyme inhibitors and hydrogen peroxide experiments show that the apoptosis signal-regulating kinase 1 (ASK1)-p38 kinase pathway mediates downstream signaling from NADPH oxidase. Mechanical stretch also downregulates Kv4.3 3'-UTR reporter activity and this requires AT1 receptors and NADPH oxidase. Thus, activation of AT1 receptors by Ang II or stretch specifically destabilizes cardiac myocyte Kv4.3 channel mRNA by activating NADPH oxidase. These results link long-term control of cardiac K+ channel gene expression to a physiological reactive oxygen species signaling pathway.


Multiple evolutionary origins of the fungus causing Panama disease of banana: concordant evidence from nuclear and mitochondrial gene genealogies.
Panama disease of banana, caused by the fungus Fusarium oxysporum f. sp. cubense, is a serious constraint both to the commercial production of banana and cultivation for subsistence agriculture. Previous work has indicated that F. oxysporum f. sp. cubense consists of several clonal lineages that may be genetically distant. In this study we tested whether lineages of the Panama disease pathogen have a monophyletic origin by comparing DNA sequences of nuclear and mitochondrial genes. DNA sequences were obtained for translation elongation factor 1alpha and the mitochondrial small subunit ribosomal RNA genes for F. oxysporum strains from banana, pathogenic strains from other hosts and putatively nonpathogenic isolates of F. oxysporum. Cladograms for the two genes were highly concordant and a partition-homogeneity test indicated the two datasets could be combined. The tree inferred from the combined dataset resolved five lineages corresponding to "F. oxysporum f. sp. cubense" with a large dichotomy between two taxa represented by strains most commonly isolated from bananas with Panama disease. The results also demonstrate that the latter two taxa have significantly different chromosome numbers. F. oxysporum isolates collected as nonpathogenic or pathogenic to other hosts that have very similar or identical elongation factor 1alpha and mitochondrial small subunit genotypes as banana pathogens were shown to cause little or no disease on banana. Taken together, these results indicate Panama disease of banana is caused by fungi with independent evolutionary origins.