Magnetic Nanoparticles in Macrophages and Cancer Cells Exhibit Different Signal Behavior on Magnetic Particle Imaging.
Cell labeling with magnetic nanoparticles (MNPs) is a promising method of cell tracking. In particular, a novel quantitative tomography method called magnetic particle imaging (MPI) has the potential to estimate the number of successfully transplanted MNP-labeled cells, thereby helping predict clinical outcomes. However, the biological factors that shape the MPI signals of MNPs during cell labeling are not well understood. To better understand these factors, the MPI signals of MNPs in various extracellular and intracellular conditions were assessed. Firstly, carboxydextran-coated MNPs (Resovist®) in the presence or absence of the transfection agents heparin and/or protamine were subjected to dynamic light scattering analysis and magnetic particle spectroscopy. Secondly, RAW264 macrophages and Colon26 carcinoma cells were labeled with Resovist® by using their intrinsic phagocytic activity or with the assistance of the transfection agents, respectively, after which the cells were visualized by our MPI scanner and transmission electron microscopy, and their absolute amounts of intracellular iron were measured by thiocyanate colorimetry. The MPI pixel values were normalized to intracellular iron concentrations. Finally, the effect of cell lysis on the MPI signal was assessed with magnetic particle spectroscopy. The presence of protamine, but not heparin, increased the hydrodynamic diameter of the MNPs and inhibited their MPI signals. Cell uptake drastically decreased the normalized MPI pixel values. This was particularly marked in the colon cancer cells. The transfection agents did not further alter the MPI signal of the MNP-labeled colon cancer cells. Transmission electron microscopy showed that there was much more MNP aggregation in colon cancer cells than in macrophages. After the MNP-labeled cells were lysed, the MPI signal recovered partially. In conclusion, MPI pixel values can be influenced by the cell-labeling process and cellular uptake. The MPI signals from intracellular magnetic nanoparticles may also differ depending on the cell type.


Lower back pain in physically demanding college academic programs: a questionnaire based study.
Lower back pain (LBP) is ranked first as a cause of disability and inability to work, and is expected to affect up to 90% of the worlds population at some point in their lifetime. The annual first time incidence of LBP is 5%, and the annual prevalence (i.e. those suffering at time of questioning) is between 15 and 63%. Prospective studies demonstrate that low back problems do not display a six-week spontaneous recovery pattern, as was once believed. The condition is regularly seen to worsen over time, becoming a chronic disorder, influenced by both physical and psychosocial factors. The current study assessed the level of LBP amongst students engaged in educational programs that were physically demanding, and its influence on lower back problems. A 1-year retrospective questionnaire consisting of 37 closed, open and multi-choice questions was designed to ascertain self-reported information on the occurrence, cause and type of LBP. Treatment, care seeking and general knowledge regarding LBP were also recorded. Students were enrolled in BSc Equine Science, BSc Physical Education and BSc Sports & Exercise Science degree programs and a total number of 188 valid questionnaires were collected. The self reported, anthropometrical data for participants in this study are: age 20.9 +/- 2.7 yrs; height 171.8 +/- 9.3 cm; weight 66.7 +/- 10.4 kg; female 64% (n = 120), male 36% (n = 68). The overall self reported prevalence of LBP was 32% (n = 61). Within the LBP population, 77% reported their problem as recurring. Two factors showed significance as having an influence on LBP. They were age (21.6 +/- 3.5 yrs, p = 0.005) and hours of personal training physical activity (14.0 +/- 8.2 hrs per week, p = 0.02). LBP sufferers also displayed poor management of their condition and an interest in education and treatment of their problem. The current study revealed high prevalence of LBP consistent with that of the literature, and unveiled a recurrence rate and behavioral habits of sufferers, which are warning signs of a more chronic state to come. Novel data presented here offers strong support for the need for prospective injury tracking, plus educational intervention and treatment aimed at prevention of LBP.


Pioglitazone treatment following spinal cord injury maintains acute mitochondrial integrity and increases chronic tissue sparing and functional recovery.
Pioglitazone is an FDA-approved PPAR-γ agonist drug used to treat diabetes, and it has demonstrated neuroprotective effects in multiple models of central nervous system (CNS) injury. Acute treatment after spinal cord injury (SCI) in rats is reported to suppress neuroinflammation, rescue injured tissues, and improve locomotor recovery. In the current study, we additionally assessed the protective efficacy of pioglitazone treatment on acute mitochondrial respiration, as well as functional and anatomical recovery after contusion SCI in adult male C57BL/6 mice. Mice received either vehicle or pioglitazone (10mg/kg) at either 15min or 3h after injury (75kdyn at T9) followed by a booster at 24h post-injury. At 25h, mitochondria were isolated from spinal cord segments centered on the injury epicenters and assessed for their respiratory capacity. Results showed significantly compromised mitochondrial respiration 25h following SCI, but pioglitazone treatment that was initiated either at 15min or 3h post-injury significantly maintained mitochondrial respiration rates near sham levels. A second cohort of injured mice received pioglitazone at 15min post injury, then once a day for 5days post-injury to assess locomotor recovery and tissue sparing over 4weeks. Compared to vehicle, pioglitazone treatment resulted in significantly greater recovery of hind-limb function over time, as determined by serial locomotor BMS assessments and both terminal BMS subscores and gridwalk performance. Such improvements correlated with significantly increased grey and white matter tissue sparing, although pioglitazone treatment did not abrogate long-term injury-induced inflammatory microglia/macrophage responses. In sum, pioglitazone significantly increased functional neuroprotection that was associated with remarkable maintenance of acute mitochondrial bioenergetics after traumatic SCI. This sets the stage for dose-response and delayed administration studies to maximize pioglitazone's efficacy for SCI while elucidating the precise role that mitochondria play in governing its neuroprotection; the ultimate goal to develop novel therapeutics that specifically target mitochondrial dysfunction.


Studying cerebral hemodynamics and metabolism using simultaneous near-infrared spectroscopy and transcranial Doppler ultrasound: a hyperventilation and caffeine study.
Caffeine is one of the most widely consumed psycho-stimulants in the world, yet little is known about its effects on brain oxygenation and metabolism. Using a double-blind, placebo-controlled, randomized cross-over study design, we combined transcranial Doppler ultrasound (TCD) and near-infrared spectroscopy (NIRS) to study caffeine's effect on middle cerebral artery peak blood flow velocity (Vp), brain tissue oxygenation (StO2), total hemoglobin (tHb), and cerebral oxygen metabolism (CMRO2) in five subjects. Hyperventilation-induced hypocapnia served as a control to verify the sensitivity of our measurements. During hypocapnia (~16 mmHg below resting values), Vp decreased by 40.0 ± 2.4% (95% CI, P < 0.001), while StO2 and tHb decreased by 2.9 ± 0.3% and 2.6 ± 0.4%, respectively (P = 0.003 and P = 0.002, respectively). CMRO2, calculated using the Fick equation, was reduced by 29.3 ± 9% compared to the isocapnic-euoxia baseline (P < 0.001). In the pharmacological experiments, there was a significant decrease in Vp, StO2, and tHb after ingestion of 200 mg of caffeine compared with placebo. There was no significant difference in CMRO2 between caffeine and placebo. Both showed a CMRO2 decline compared to baseline showing the importance of a placebo control. In conclusion, this study showed that profound hypocapnia impairs cerebral oxidative metabolism. We provide new insight into the effects of caffeine on cerebral hemodynamics. Moreover, this study showed that multimodal NIRS/TCD is an excellent tool for studying brain hemodynamic responses to pharmacological interventions and physiological challenges.


Fluorescent bioprobes: structural matching in the docking processes of aggregation-induced emission fluorogens on DNA surfaces.
Whereas most conventional DNA probes are flat disklike aromatic molecules, we explored the possibility of developing quadruplex sensors with nonplanar conformations, in particular, the propeller-shaped tetraphenylethene (TPE) salts with aggregation-induced emission (AIE) characteristics. 1,1,2,2-Tetrakis[4-(2-triethylammonioethoxy)phenyl]ethene tetrabromide (TPE-1) was found to show a specific affinity to a particular quadruplex structure formed by a human telomeric DNA strand in the presence of K(+) ions, as indicated by the enhanced and bathochromically shifted emission of the AIE fluorogen. Steady-state and time-resolved spectral analyses revealed that the specific binding stems from a structural matching between the AIE fluorogen and the DNA strand in the folding process. Computational modeling suggests that the AIE molecule docks on the grooves of the quadruplex surface with the aid of electrostatic attraction. The binding preference of TPE-1 enables it to serve as a bioprobe for direct monitoring of cation-driven conformational transitions between the quadruplexes of various conformations, a job unachievable by the traditional G-quadruplex biosensors. Methyl thiazolyl tetrazolium (MTT) assays reveal that TPE-1 is cytocompatible, posing no toxicity to living cells.


Cost-Effectiveness Analysis of Ixekizumab vs Etanercept and Their Manufacturer-Recommended Dosing Regimens in Moderate to Severe Plaque Psoriasis.
Biologic therapies have revolutionized the treatment of psoriasis; however, their use is limited by costs. Ixekizumab was more effective than etanercept in the UNCOVER trials, and the Food and Drug Administration (FDA) approved ixekizumab for treating psoriasis. Evaluating the cost-effectiveness of these therapies is crucial for medical decision making and our objective was to determine the cost-effectiveness of various ixekizumab dosing frequencies compared with etanercept. We utilized published data from the UNCOVER comparative efficacy trials, including transitional probabilities and treatment response rates, to create a Markov model simulating the clinical course and cost-effectiveness of three treatment algorithms for patients with moderate to severe plaque psoriasis over 60-weeks: (1) ixekizumab every 2 weeks for 12 weeks then every 4 weeks, (2) ixekizumab every 4 weeks throughout the treatment period, (3) biweekly etanercept for 12 weeks then once weekly. We utilized a standard willingness-to-pay (WTP) threshold of $150,000 per quality adjusted life year (QALY) and Medicaid drug acquisition costs for our calculations. Ixekizumab every 4 weeks was $28,681 (USD) less expensive than biweekly etanercept, and $21,375 less expensive, and 0.006 QALY less effective, than ixekizumab every 2 weeks-- a savings of $28.7 and $21.4 million, respectively, per 1,000 patients. A 95.6% cost reduction to $197.83 per dose is required for ixekizumab every 2 weeks to be more cost-effective than every 4 weeks. Biweekly etanercept requires a 29.5% cost reduction ($743.82 per dose) to be competitive with ixekizumab every 4 weeks. This cost-effectiveness model utilizes strong input data but is a limited approximation of real-life scenarios. Treatment with ixekizumab every 2 weeks is unlikely to be cost-effective compared with ixekizumab every 4 weeks at current U.S. market prices. Yet, the U.S. FDA approval and manufacturer's recommendation are for ixekizumab every 2 weeks. Accordingly, we suggested selecting biologic therapies using cost-effectiveness analyses.
J Drugs Dermatol. 2017;16(10):964-970.
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Palliative Care: Improving Nursing Knowledge, Attitudes, and Behaviors .
Oncology nurses affect patient care at every point along the cancer journey. This creates the perfect opportunity to educate patients and caregivers about palliative care early and often throughout treatment. However, healthcare providers frequently do not have the knowledge and confidence to engage in meaningful conversations about palliative care. . The specific aims were to improve oncology nurses' palliative care knowledge, attitudes, and behaviors by providing a palliative care nursing education program. An additional aim was to increase the number of conversations with patients and families about palliative care. . This project had a pre-/post-test design to assess knowledge, attitudes, and behaviors at baseline and one month after implementation of an established education curriculum. The teaching strategy included one four-hour class for oncology RNs with topics about the definition of palliative care, pain and symptom management, and how to have palliative care conversations. . Results showed a statistically significant difference after the educational intervention for knowledge, attitudes, and behaviors. The number of conversations with patients and caregivers about palliative and end-of-life care increased significantly.


Loquat leaf extract enhances myogenic differentiation, improves muscle function and attenuates muscle loss in aged rats.
A main characteristic of aging is the debilitating, progressive and generalized impairment of biological functions, resulting in an increased vulnerability to disease and death. Skeletal muscle comprises approximately 40% of the human body; thus, it is the most abundant tissue. At the age of 30 onwards, 0.5‑1% of human muscle mass is lost each year, with a marked acceleration in the rate of decline after the age of 65. Thus, novel strategies that effectively attenuate skeletal muscle loss and enhance muscle function are required to improve the quality of life of older subjects. The aim of the present study was to determine whether loquat (Eriobotrya japonica) leaf extract (LE) can prevent the loss of skeletal muscle function in aged rats. Young (5-month-old) and aged (18‑19-month-old) rats were fed LE (50 mg/kg/day) for 35 days and the changes in muscle mass and strength were evaluated. The age‑associated loss of grip strength was attenuated, and muscle mass and muscle creatine kinase (CK) activity were enhanced following the administration of LE. Histochemical analysis also revealed that LE abrogated the age‑associated decrease in cross‑sectional area (CSA) and decreased the amount of connective tissue in the muscle of aged rats. To investigate the mode of action of LE, C2C12 murine myoblasts were used to evaluate the myogenic potential of LE. The expression levels of myogenic proteins (MyoD and myogenin) and functional myosin heavy chain (MyHC) were measured by western blot analysis. LE enhanced MyoD, myogenin and MyHC expression. The changes in the expression of myogenic genes corresponded with an increase in the activity of CK, a myogenic differentiation marker. Finally, LE activated the Akt/mammalian target of rapamycin (mTOR) signaling pathway, which is involved in muscle protein synthesis during myogenesis. These findings suggest that LE attenuates sarcopenia by promoting myogenic differentiation and subsequently promoting muscle protein synthesis.


Effect of protein/essential amino acids and resistance training on skeletal muscle hypertrophy: A case for whey protein.
Regardless of age or gender, resistance training or provision of adequate amounts of dietary protein (PRO) or essential amino acids (EAA) can increase muscle protein synthesis (MPS) in healthy adults. Combined PRO or EAA ingestion proximal to resistance training, however, can augment the post-exercise MPS response and has been shown to elicit a greater anabolic effect than exercise plus carbohydrate. Unfortunately, chronic/adaptive response data comparing the effects of different protein sources is limited. A growing body of evidence does, however, suggest that dairy PRO, and whey in particular may: 1) stimulate the greatest rise in MPS, 2) result in greater muscle cross-sectional area when combined with chronic resistance training, and 3) at least in younger individuals, enhance exercise recovery. Therefore, this review will focus on whey protein supplementation and its effects on skeletal muscle mass when combined with heavy resistance training.


Absorption of 308-nm excimer laser radiation by balanced salt solution, sodium hyaluronate, and human cadaver eyes.
Absorption of the excimer laser radiations of 193-nm argon fluorine and 308-nm xenon chloride in balanced salt solution, sodium hyaluronate, and human cadaver eyes was measured. The absorption of these materials as considerably different for the two wavelengths; we found that 308-nm light experienced much less absorption than the 193-nm light. The extinction coefficient (k) for 308 nm was k = 0.19/cm for balanced salt solution and k = 0.22/cm for sodium hyaluronate. In contrast to this, the extinction coefficient for 193 nm was k = 140/cm for balanced salt solution and k = 540/cm for sodium hyaluronate. Two 1-day-old human phakic cadaver eyes showed complete absorption with both wavelengths. Using aphakic eyes, incomplete absorption was noted at the posterior pole with 308 nm and complete absorption was noted with 193 nm. The extinction in the anterior part of aphakic eyes (the first 6 mm) was 4.2/cm for 308 nm, meaning that the intensity of the light is reduced by a factor of 10 after traveling the first 5.5 mm. However, we observed that the material in the eye fluoresces, meaning the 308 nm is transformed into other (longer) wavelengths that travel through the total eye with minimal absorption. Conclusions drawn from this experiment are that the use of the 308-nm wavelength may have undesirable side effects, while the use of the 193-nm wavelength should be consistent with ophthalmic use on both the cornea and the lens.


Glucose fluctuations aggravated the late sodium current induced ventricular arrhythmias via the activation of ROS/CaMKII pathway.
Recent evidence revealed that glucose fluctuation might be more likely to cause arrhythmia than persistent hyperglycemia, whereas its mechanisms were elusive. We aimed to investigate the effect of glucose fluctuation on the occurrence of ventricular arrhythmia and its mechanism. Streptozotocin (STZ) induced diabetic rats were randomized to five groups: the controlled blood glucose (C-STZ) group, uncontrolled blood glucose (U-STZ) group, fluctuated blood glucose (GF-STZ) group, and GF-STZ rats with 100 mg/kg Tempol (GF-STZ + Tempol) group or with 5 mg/kg KN93 (GF-STZ + KN93) group. Six weeks later, the susceptibility of ventricular arrhythmias and the electrophysiological dysfunctions of ventricular myocytes were evaluated using electrocardiogram and patch-clamp technique, respectively. The levels of reactive oxygen species (ROS) and oxidized CaMKII (ox-CaMKII) were determined by fluorescence assay and Western blot, respectively. Neonatal rat cardiomyocytes and H9C2 cells in vitro were used to explore the underlying mechanisms. The induction rate of ventricular arrhythmias was 10%, 55%, and 90% in C-STZ group, U-STZ group, and GF-STZ group, respectively (P < 0.05). The electrophysiological dysfunctions of ventricular myocytes, including action potential duration at repolarization of 90% (APD90), APD90 short-term variability (APD90-STV), late sodium current (INa-L), early after depolarization (EAD) and delayed after depolarizations (DAD), as well as the levels of ROS and ox-CaMKII, were significantly increased in GF-STZ group. In vivo and ex vivo, inhibition of ROS or ox-CaMKII reversed these effects. Inhibition of INa-L also significantly alleviated the electrophysiological dysfunctions. In vitro, inhibition of ROS increase could significantly decrease the ox-CaMKII activation induced by glucose fluctuations. Glucose fluctuations aggravated the INa-L induced ventricular arrhythmias though the activation of ROS/CaMKII pathway.


Satellite DNAs in the embryos of various species of the genus Drosophila.
A tentative evolutionary pattern has been found for two classes of the multiple satellite DNA's found in the genus Drosophila. The satellite DNA's from five Drosophila species (D. melanogaster, D. simulans, D. nasuta, D. virilis and D. hydei) were analyzed and found to fall into three arbitrary CsCl buoyant density classes: Class I, rho = 1.661-1.669 g cm(-3), DNA molecules composed of primarily dA and dT moieties; Class II, rho = 1.685 and rho = 1.692, DNA molecules of low GC content; and Class III, rho = 1.711, a DNA of high GC composition. The dAT satellite DNA's appear in all the species studied except D. hydei, the species of most recent evolutionary divergence, whereas the heavy satellite appears only in the two species of most recent divergence, D. virilis and D. hydei.


Adrenal MT1 melatonin receptor expression is linked with seasonal variation in social behavior in male Siberian hamsters.
Many animals exhibit pronounced changes in physiology and behavior on a seasonal basis, and these adaptations have evolved to promote survival and reproductive success. While the neuroendocrine pathways mediating seasonal reproduction are well-studied, far less is known about the mechanisms underlying seasonal changes in social behavior, particularly outside of the context of the breeding season. Our previous work suggests that seasonal changes in melatonin secretion are important in regulating aggression in Siberian hamsters (Phodopus sungorus); it is unclear, however, how melatonin acts via its receptors to modulate seasonal variation in social behavior. In this study, we infused a MT1 melatonin receptor-expressing (MT1) or control (CON) lentivirus into the adrenal glands of male Siberian hamsters. We then housed hamsters in long-day (LD) or short-day (SD) photoperiods, administered timed melatonin or control injections, and quantified aggressive and non-aggressive social behaviors (e.g., investigation, self-grooming) following 10 weeks of treatment. LD hamsters infused with the MT1 lentivirus had significantly higher adrenal mt1 expression than LD CON hamsters, as determined via quantitative PCR. While melatonin administration was necessary to induce SD-like reductions in body and relative reproductive mass, only LD hamsters infused with the MT1 lentivirus displayed SD-like changes in social behavior, including increased aggression and decreased investigation and grooming. In addition, SD CON and LD hamsters infused with the MT1 lentivirus exhibited similar relationships between adrenal mt1 expression and aggressive behavior. Together, our findings suggest a role for adrenal MT1 receptor signaling in regulating behavior, but not energetics or reproduction in seasonally breeding species.


Synaptic proteins promote calcium-triggered fast transition from point contact to full fusion.
The molecular underpinnings of synaptic vesicle fusion for fast neurotransmitter release are still unclear. Here, we used a single vesicle-vesicle system with reconstituted SNARE and synaptotagmin-1 proteoliposomes to decipher the temporal sequence of membrane states upon Ca(2+)-injection at 250-500 μM on a 100-ms timescale. Furthermore, detailed membrane morphologies were imaged with cryo-electron microscopy before and after Ca(2+)-injection. We discovered a heterogeneous network of immediate and delayed fusion pathways. Remarkably, all instances of Ca(2+)-triggered immediate fusion started from a membrane-membrane point-contact and proceeded to complete fusion without discernible hemifusion intermediates. In contrast, pathways that involved a stable hemifusion diaphragm only resulted in fusion after many seconds, if at all. When complexin was included, the Ca(2+)-triggered fusion network shifted towards the immediate pathway, effectively synchronizing fusion, especially at lower Ca(2+)-concentration. Synaptic proteins may have evolved to select this immediate pathway out of a heterogeneous network of possible membrane fusion pathways.DOI:http://dx.doi.org/10.7554/eLife.00109.001.


Significance of MD-2 and MD-2B expression in rat liver during acute cholangitis.
To investigate the expression of myeloid differentiation protein-2 (MD-2), MD-2B (a splicing isoform of MD-2 that can block Toll-like receptor 4 (TLR4)/MD-2 LPS-mediated signal transduction) and TLR4 in the liver of acute cholangitis rats. Male Sprague-Dawley rats (SPF level) were randomly divided into four groups: (A) sham-operated group; (B) simple common bile duct ligation group; (C) acute cholangitis group; and (D) acute cholangitis anti-TLR4 intervention group (n = 25 per group). Rat liver tissue samples were used to detect TLR4, MD-2 and MD-2B mRNA expression by fluorescence quantitative PCR in parallel with pathological changes. In acute cholangitis, liver TLR4 and MD-2 mRNA expression levels at 6, 12, 24, 48 and 72 h were gradually up-regulated but MD-2B mRNA expression gradually down-regulated (P < 0.05). After TLR4 antibody treatment, TLR4 and MD-2 mRNA expression were lower compared with the acute cholangitis group (P < 0.05). However, MD-2B mRNA expression was higher than in the acute cholangitis group (P < 0.05). MD-2 and TLR4 mRNA expressions were positively correlated (r = 0.94981, P < 0.05) and MD-2B mRNA expression was negatively correlated with MD-2 and TLR4 mRNA (r = -0.89031, -0.88997, P < 0.05). In acute cholangitis, MD-2 plays an important role in the process of TLR4- mediated inflammatory response to liver injury while MD-2B plays a negative regulatory role.


Somatostatin immunocytochemistry in the rabbit retina.
In previous work, radioimmunoassay was used to document the presence of somatostatin-like immunoreactive material in the rabbit retina. The present study was undertaken to determine the cellular localization of that material by light microscopic immunocytochemistry. Rabbit retinas were fixed by immersion in paraformaldehyde-lysine-periodate and reacted, either as whole retinas or as 50 microns Vibratome cross-sections, with an antiserum directed against somatostatin-14. Consistent staining of neuronal perikarya was seen only in the retinas of rabbits that had been pretreated with intravitreal injections of colchicine. Specifically stained cell bodies are present in the ganglion cell layer; the cells give rise to fibers in both the innermost and outermost sublaminas of the inner plexiform layer. In retinal whole mounts, the cells possess two or three primary dendrites with sparse branching. The dendritic fields are up to 1 mm in diameter, and adjacent dendritic fields overlap. Many cells have a thin varicose process arising from the soma or a proximal primary dendrite; these processes branch repeatedly within the retina and resemble intraretinal axons. The somatostatin-reactive cells may be associational ganglion cells or displaced amacrine cells; it is less likely that they are ganglion cells with axons projecting to the brain.


Effect of Alendronate with β - TCP Bone Substitute in Surgical Therapy of Periodontal Intra-Osseous Defects: A Randomized Controlled Clinical Trial.
Alendronate (ALN), an aminobisphosphonate, inhibits osteoclastic bone resorption and also stimulates osteogenesis. Beta-Tricalcium Phosphate (β-TCP) is an osteoconductive graft material which provides a scaffold for bone formation and also a widely used drug delivery vehicle for growth factors and antibiotics. Drug delivery vehicles, like β-TCP, improve the potency of the drugs by specific local site delivery of the drug, optimal release characteristics and easy handling. The aim of the this study was to evaluate the bone formation potential of 400μg ALN delivered in β-TCP in the treatment of periodontal intra-osseous defects. Thirty patients with periodontal defects were randomly assigned to 400μg ALN + β-TCP + Saline (test) group and β-TCP + Saline (active-control) group. Clinical parameters like Clinical Attachment Level (CAL) gain, Probing Depth (PD) reduction, post-operative Gingival Recession (GR) were assessed from the baseline, 3 months and 6 months recordings. Radiographic parameters like Linear Bone Growth (LBG), Percentage Bone Fill (%BF), and change in alveolar crest height (ACH) were assessed from baseline and 6 months radiographs. Mean measurements in the ALN test group for CAL gain (3.4 ± 0.74 mm), PD reduction (4.33 ± 0.82 mm), LBG (2.88 ± 0.88 mm), and %BF (51.98 ± 15.84%) were significantly greater with a p-value <0.05 compared to the mean measurements of CAL gain (2.20 ± 0.86 mm), PD reduction (3.20 ± 1.15 mm), LBG (1.70 ± 0.39 mm), and %BF (30.35 ± 6.88%) of the control group. There was mild alveolar crestal apposition (0.32 ± 0.68 mm) in the ALN test group and mild alveolar crestal resorption (-0.24 ± 0.40 mm) in the control group. 400μg ALN combined with β-TCP bone graft material was effective in improving soft tissue parameters, inhibiting alveolar crestal resorption and enhancing bone formation, compared to β-TCP alone.


Weight and body mass index change after total joint arthroplasty.
Obesity has become a leading public health issue in the United States. The goal of this study was to examine whether patients experience a significant change in body mass index (BMI) or weight after total joint arthroplasty. Previous studies have not corrected for the natural, annual positive BMI change in North Americans aged 29 to 73 years. Our study takes this natural weight gain into consideration in examination of total hip arthroplasty (THA) and total knee arthroplasty (TKA) populations. Our study population trended toward weight loss and BMI loss when weight was corrected for natural gain. Clinically significant weight loss, as determined by US Food and Drug Administration parameters, occurred in 19.9% of the study population when weight was corrected for natural gain. The TKA population exhibited a statistically significant (P<.05) weight loss and a clinically significant weight loss in 21.5% of the population. Patients with an initial BMI >30 exhibited a trend toward weight loss. This study was a level II retrospective study.


Dendritic nonlinearities are tuned for efficient spike-based computations in cortical circuits.
Cortical neurons integrate thousands of synaptic inputs in their dendrites in highly nonlinear ways. It is unknown how these dendritic nonlinearities in individual cells contribute to computations at the level of neural circuits. Here, we show that dendritic nonlinearities are critical for the efficient integration of synaptic inputs in circuits performing analog computations with spiking neurons. We developed a theory that formalizes how a neuron's dendritic nonlinearity that is optimal for integrating synaptic inputs depends on the statistics of its presynaptic activity patterns. Based on their in vivo preynaptic population statistics (firing rates, membrane potential fluctuations, and correlations due to ensemble dynamics), our theory accurately predicted the responses of two different types of cortical pyramidal cells to patterned stimulation by two-photon glutamate uncaging. These results reveal a new computational principle underlying dendritic integration in cortical neurons by suggesting a functional link between cellular and systems--level properties of cortical circuits.


[The contribution of violence to maternal mortality in Morelos, Mexico].
To document the under-registration of violent deaths related to pregnancy and the importance of considering these violent deaths within the definition of maternal mortality. The study was carried out in the state of Morelos, based on the review of all death certificates (394) of reproductive aged women (12-49 years) who died during 2001. Based on a list of diagnostic criteria we eliminated 167 certificates that were neither violent deaths nor maternal deaths. The remaining 227 certificates were further evaluated through verbal autopsy and/or review of medical charts. Fifty-one violent deaths were found. Eighteen maternal deaths were officially reported in 2001, however, our study identified 23 direct maternal deaths and four violent deaths during pregnancy and the post-partum period. We found that this reproductive event was the direct trigger for the homicide or suicide of these four women, and only one of these cases was documented officially. Violent deaths related to pregnancy should be included in official maternal mortality statistics as indirect causes of maternal deaths. This would allow for a greater and more accurate understanding of violent maternal deaths and guide appropriate prevention and care policies, programs and services. Verbal autopsy is a useful technique for identifying cases of violent maternal deaths.


[Cellular contacts and "cytoplasmic bridges" in the inflammation focus (scanning and transmission electron microscopic study)].
Contacts between cells in an inflammation focus were studied by the methods of scanning (raster) and transmission electron microscopy on a model of aseptic inflammation in the subcutaneous connective tissue in rats. It is shown that contacts among the cells of the connective tissue and the blood in the form of "cytoplasmatic bridges", observed in the scanning electron microscope, were not confirmed by the studies in the transmission microscope. The investigation of the "cytoplasmatic bridges" in the transmission electron microscope revealed a close adjacence of the cytolemma of the contacting cells, or a harrow space between them as wide as 10-30 micron.


Corticosteroid-exacerbated symptoms in an Andersen's syndrome kindred.
Periodic paralysis, cardiac arrhythmia and bone features are the hallmark of Andersen's syndrome (AS), a rare disorder caused by mutations in the KCNJ2 gene that encodes for the inward rectifier K(+)-channel Kir2.1. Rest following strenuous physical activity, carbohydrate ingestion, emotional stress and exposure to cold are the precipitating triggers. Most of the mutations act in a dominant-negative fashion, either through a trafficking dysfunction or through Kir2.1-phosphatidyl inositol bisphosphate binding defect. We have identified two families that were diagnosed with periodic paralysis and cardiac abnormalities, but only discrete development features. The proband in one of the two families reported having his symptoms occurring twice within the day following corticosteroids ingestion, and alleviated after stopping the corticosteroid treatment. Electromyographic evaluations pointed out to a typical hypokalemic periodic paralysis pattern. Molecular screening of the KCNJ2 gene identified two mutations leading to C54F and T305P substitutions in the Kir2.1 protein. Functional expression in mammalian cells revealed a loss-of-function of the mutated channels and a dominant-negative effect when both mutants and wild-type channels are present in the same cell. However, channel trafficking and assembly are not affected. Substitutions at these residues may interfere with phosphatidyl inositol bisphosphate binding to Kir2.1 channels. Sensitivity of our patients to multiple corticosteroid administrations shows that care must be taken in the use of such treatments in AS patients. Taken together, our data suggest the inclusion of the KCNJ2 gene in the molecular screening of patients with periodic paralysis, even when the classical AS dysmorphic features are not present.


Deep Eutectic Solvent Based on Lithium Bis[(trifluoromethyl)sulfonyl] Imide (LiTFSI) and 2,2,2-Trifluoroacetamide (TFA) as a Promising Electrolyte for a High Voltage Lithium-Ion Battery with a LiMn2O4 Cathode.
To design safe and electrochemically stable electrolytes for lithium-ion batteries, this study describes the synthesis and the utilization of new deep eutectic solvents (DESs) based on the mixture of 2,2,2-trifluoroacetamide (TFA) with a lithium salt (LiTFSI, lithium bis[(trifluoromethane)sulfonyl]imide). These prepared DESs were characterized in terms of thermal properties, ionic conductivity, viscosity, and electrochemical properties. Based on the appearance of the product and DSC measurements, it appears that this system is liquid at room temperature for LiTFSI mole fraction ranging from 0.25 to 0.5. At χLiTFSI = 0.25, DESs exhibited favorable electrolyte properties, such as thermal stability (up to 148 °C), relatively low viscosity (42.2 mPa.s at 30 °C), high ionic conductivity (1.5 mS.cm-1 at 30 °C), and quite large electrochemical stability window up to 4.9-5.3 V. With these interesting properties, selected DES was diluted with slight amount of ethylene carbonate (EC). Different amounts of EC (x = 0-30 %wt) were used to form hybrid electrolytes for battery testing with high voltage LiMn2O4 cathode and Li anode. The addition of the EC solvent into DES expectedly aims at enhancing the battery cycling performance at room temperature due to reducing the viscosity. Preliminary results tests clearly show that LiTFSI-based DES can be successfully introduced as an electrolyte in the lithium-ion batteries cell with a LiMn2O4 cathode material. Among all of the studied electrolytes, DES (LiTFSI: TFA = 4:1 + 10 %wt EC) is the most promising. The EC-based system exhibited a good specific capacity of 102 mAh.g-1 at C/10 with the theoretical capacity of 148 mAh.g-1 and a good cycling behavior maintaining at 84% after 50 cycles.


Dose-Related and Time-Dependent Development of Collagenase-Induced Tendinopathy in Rats.
Tendinopathy is a big burden in clinics and it represents 45% of musculoskeletal lesions. Despite the relevant social impact, both pathogenesis and development of the tendinopathy are still under-investigated, thus limiting the therapeutic advancement in this field. The purpose of this study was to evaluate the dose-dependent and time-related tissue-level changes occurring in a collagenase-induced tendinopathy in rat Achilles tendons, in order to establish a standardized model for future pre-clinical studies. With this purpose, 40 Sprague Dawley rats were randomly divided into two groups, treated by injecting collagenase type I within the Achilles tendon at 1 mg/mL (low dose) or 3 mg/mL (high dose). Tendon explants were histologically evaluated at 3, 7, 15, 30 and 45 days. Our results revealed that both the collagenase doses induced a disorganization of collagen fibers and increased the number of rounded resident cells. In particular, the high dose treatment determined a greater neovascularization and fatty degeneration with respect to the lower dose. These changes were found to be time-dependent and to resemble the features of human tendinopathy. Indeed, in our series, the acute phase occurred from day 3 to day 15, and then progressed towards the proliferative phase from day 30 to day 45 displaying a degenerative appearance associated with a very precocious and mild remodeling process. The model represents a good balance between similarity with histological features of human tendinopathy and feasibility, in terms of tendon size to create lesions and costs when compared to other animal models. Moreover, this model could contribute to improve the knowledge in this field, and it could be useful to properly design further pre-clinical studies to test innovative treatments for tendinopathy.


Ultrasonographic Features of Nonneoplastic Protrusions in Pancreatic Cysts by Contrast-Enhanced Endoscopic Ultrasound.
Most of the pancreatic cyst protrusions detected by B-mode endoscopic ultrasound (BM-EUS) are nonneoplastic and are not enhanced by contrast-enhanced EUS (CE-EUS) using ultrasound contrast agent (USCA). This study aimed to identify useful findings for distinguishing between neoplastic and nonneoplastic pancreatic cyst protrusions on BM-EUS to facilitate efficient USCA use. A total of 151 pancreatic cyst protrusions in 119 consecutive patients who underwent CE-EUS were analyzed. We focused on the echo level (hyperechoic/isoechoic/hypoechoic/anechoic), base type (sessile without a basal waist/sessile with a basal waist/pedunculated), surface type (smooth/irregular), and the presence/absence of a hyperechoic surface layer. Enhanced and unenhanced protrusions on CE-EUS were interpreted as neoplastic and nonneoplastic, respectively. Forty-five and 106 protrusions were enhanced and unenhanced, respectively, on CE-EUS performed using USCA. In univariable analysis of predictors of nonneoplastic protrusion on BM-EUS, the following factors were found to be significant: echo level (hypoechoic/anechoic), base type (sessile with a basal waist/pedunculated), a smooth surface, and a hyperechoic surface layer. Of these, only a hyperechoic surface layer remained significant in the multivariable analysis (P < 0.0001; odds ratio, 40.74; 95% confidence interval, 7.07-387.49). Pancreatic cyst protrusions with a hyperechoic surface layer on BM-EUS are suggestive of nonneoplastic disease.


Resection of a rapid-growing 40-cm giant liver hemangioma.
Hemangiomas are the most frequent benign tumors of the liver. Most hemangiomas are asymptomatic and therefore largely diagnosed only in routine screening tests. Usually they are small and require no specific treatment. In some situations they can reach great dimensions, causing some discomfort to the patient. Resection of liver hemangioma is indicated in cases of great dimension tumors causing symptoms such as pain, nausea or bloating caused by compression of adjacent organs. We report a case of a rare giant hemangioma with rapid growth in short time: a 50 year old female reported to our institution with a 40 cm giant liver hemangioma and then underwent a left hepatectomy.


[The Lyon effect of the lens: findings in the carriers of X chromosome-linked cataract and in Lowe syndrome].
In carrier women for X-linked diseases the random X-inactivation and the subsequent embryonic process of development and differentiation induce characteristic patterns of tissue mosaicism. In the lens, the random mosaic pattern of equatorial epithelial cells and their proliferation oriented toward the posterior pole induce a radial or segmental distribution pattern of clonal cell populations. This can be shown in carrier women for X-linked cataracts. Findings in a carrier woman for X-linked cataract and for Lowe's syndrome respectively are reported.


The synaptic glycoprotein neuroplastin is involved in long-term potentiation at hippocampal CA1 synapses.
Neuroplastin-65 and -55 (previously known as gp65 and gp55) are glycoproteins of the Ig superfamily that are enriched in rat forebrain synaptic membrane preparations. Whereas the two-Ig domain isoform neuroplastin-55 is expressed in many tissues, the three-Ig domain isoform neuroplastin-65 is brain-specific and enriched in postsynaptic density (PSD) protein preparations. Here, we have assessed the function of neuroplastin in long-term synaptic plasticity. Immunocytochemical studies with neuroplastin-65-specific antibodies differentially stain distinct synaptic neuropil regions of the rat hippocampus with most prominent immunoreactivity in the CA1 region and the proximal molecular layer of the dentate gyrus. Kainate-induced seizures cause a significant enhancement of neuroplastin-65 association with PSDs. Similarly, long-term potentiation (LTP) of CA1 synapses in hippocampal slices enhanced the association of neuroplastin-65 with a detergent-insoluble PSD-enriched protein fraction. Several antibodies against the neuroplastins, including one specific for neuroplastin-65, inhibited the maintenance of LTP. A similar effect was observed when recombinant fusion protein containing the three extracellular Ig domains of neuroplastin-65 was applied to hippocampal slices before LTP induction. Microsphere binding experiments using neuroplastin-F(c) chimeric proteins show that constructs containing Ig1-3 or Ig1 domains, but not Ig2-3 domains mediate homophilic adhesion. These data suggest that neuroplastin plays an essential role in implementing long-term changes in synaptic activity, possibly by means of a homophilic adhesion mechanism.


Massage therapy decreases cancer-related fatigue: Results from a randomized early phase trial.
Cancer-related fatigue (CRF) is a prevalent and debilitating symptom experienced by cancer survivors, yet treatment options for CRF are limited. In this study, we evaluated the efficacy of weekly Swedish massage therapy (SMT) versus an active control condition (light touch [LT]) and waitlist control (WLC) on persistent CRF in breast cancer survivors. This early phase, randomized, single-masked, 6-week investigation of SMT, LT, and WLC enrolled 66 female stage 0-III breast cancer survivors (age range, 32-72 years) who had received surgery plus radiation and/or chemotherapy/chemoprevention with CRF (Brief Fatigue Inventory > 25). The primary outcome was the Multidimensional Fatigue Inventory (MFI), with the National Institutes of Health PROMIS Fatigue scale secondary. Mean baseline MFI scores for 57 evaluable subjects were 62.95 for SMT, 55.00 for LT, and 60.41 for WLC. SMT resulted in a mean (standard deviation) 6-week reduction in MFI total scores of -16.50 (6.37) (n = 20) versus -8.06 (6.50) for LT (n = 20) and an increase of 5.88 (6.48) points for WLC (n = 17) (treatment-by-time P < .0001). The mean baseline PROMIS Fatigue scores were SMT, 22.25; LT, 22.05; and WLC, 23.24. The mean (standard deviation) reduction in PROMIS Fatigue scores was -5.49 (2.53) points for SMT versus -3.24 (2.57) points for LT and -0.06 (1.88) points for WLC (treatment-by-time P = .0008). Higher credibility, expectancy, and preference for SMT than for LT did not account for these results. SMT produced clinically significant relief of CRF. This finding suggests that 6 weeks of a safe, widely accepted manual intervention causes a significant reduction in fatigue, a debilitating sequela for cancer survivors. Cancer 2018;124:546-54. © 2017 American Cancer Society.


Occult traumatic nasolacrimal duct obstruction causing anophthalmic socket contraction presenting 20 years later: a case report.
To highlight undiagnosed nasolacrimal duct obstruction as a cause of multiple problems related to the anophthalmic socket and the importance of early diagnosis and treatment in their prevention. Case report with high resolution digital clinical photography. A 43-year-old Asian gentleman sustained penetrating trauma to the right globe and midface in 1984. At the time, he underwent primary repair of the globe, followed by enucleation. Over the next ten years, he suffered a myriad of problems with recurrent entropion and trichiasis of upper and lower lids, a dry socket with an uncomfortable artificial eye and chronic mucoid discharge. Twenty years later he had a contracted socket with mucosal keratinization, cicatricial entropion of the eyelids, forniceal shortening and mucoid discharge. There was also nasolacrimal duct obstruction with an occult mucoceole. He underwent external dacrocystorhinostomy with correction of the entropions and anophthalmic socket refashioning. He remains symptom free twelve months following surgery. Contracted anophthalmic sockets can occur spontaneously or secondarily to a disease process. These may lead to changes in tear composition and have pro-inflammatory effects on the ocular surface. We hyphothesize that the chronic toxic tear film secondary to the mucocoele led to chronic conjunctivitis with cicatrisation over time and multiple structural lid & socket problems that ensued. This case highlights the importance of looking for occult causes of chronic cicatrization in the anophthalmic socket.


Sarcoid reactions in malignant tumours.
Tumour-related tissue reactions resulting in the formation of epithelioid-cell granulomas have been known for almost 70 years. Such sarcoid reactions may occur in lymph-nodes draining an area housing a malignant tumour, in the tumour itself, and even in non-regional tissues. Overall, sarcoid reactions occur in 4.4% of carcinomas, in 13.8% of patients with Hodgkin's disease, and in 7.3% of cases of non-Hodgkin lymphomas. Similar histologic changes in sarcoma appear to be extremely rare. Most probably, sarcoid reactions are caused by antigenic factors derived from the tumour cells, eliciting an immunological hypersensitivity reaction leading to the formation of epithelioid-cell granulomas. Sarcoid reactions may be a marker of an immunologically mediated antitumour response of macrophages activated by T-lymphocytes, and in Hodgkin's disease there is evidence that patients with sarcoid reactions have a better prognosis. On occasion sarcoid reactions may be so extensive that they complicate the diagnosis of an underlying malignant disease. Problems may also arise of distinguishing between tumour-related sarcoid reactions and true systemic sarcoidosis.


Functionalization of Human Serum Albumin by Tyrosine Click.
Human serum albumin (HSA) is a promising drug delivery carrier. Although covalent modification of Cys34 is a well-established method, it is desirable to develop a novel covalent modification method that targets residues other than cysteine to introduce multiple functions into a single HSA molecule. We developed a tyrosine-selective modification of HSA. Three tyrosine selective modification methods, hemin-catalyzed, horseradish peroxidase (HRP)-catalyzed, and laccase-catalyzed reactions were performed, and the modification efficiencies and modification sites of the modified HSAs obtained by these methods were evaluated and compared. We found that the laccase-catalyzed method could efficiently modify the tyrosine residue of HSA under mild reaction conditions without inducing oxidative side reactions. An average of 2.2 molecules of functional groups could be introduced to a single molecule of HSA by the laccase method. Binding site analysis using mass spectrometry suggested Y84, Y138, and Y401 as the main modification sites. Furthermore, we evaluated binding to ibuprofen and found that, unlike the conventional lysine residue modification, the inhibition of drug binding was minimal. These results suggest that tyrosine-residue selective chemical modification is a promising method for covalent drug attachment to HSA.


RIFM fragrance ingredient safety assessment, hexyl isovalerate, CAS Registry Number 10032-13-0.
The existing information supports the use of this material as described in this safety assessment. Hexyl isovalerate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog hexyl isobutyrate (CAS # 2349-07-7) show that hexyl isovalerate is not expected to be genotoxic. Data on read-across analog propyl (2S)-2-(1,1-dimethylpropoxy)-propanoate (CAS # 319002-92-1) provide a calculated MOE >100 for the repeated dose toxicity and reproductive toxicity endpoints. Data from read-across analog hexyl 2-methylbutyrate (CAS # 10032-15-2) do not indicate that hexyl isovalerate is a skin sensitizer. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; hexyl isovalerate is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the TTC for a Cramer Class I material, and the exposure to hexyl isovalerate is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; hexyl isovalerate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.


10 years' experience with regular haemodialysis and renal transplantation.
75 children aged under 15 years have entered the regular haemodialysis/renal transplant programme at Guy's Hospital in the 10 years since its inception; 13 children have subsequently died. A combination of hospital and home haemodialysis and renal transplantation was used. 64 children received 80 renal allografts; 37 1st grafts were from live, related donors and 27 were from cadaver donors. The 5-year acturial patient survival for the whole group and for those who had transplants was 76%. Live donor graft survival was 65% at 3 years, and 55% at 5 years; 1st cadaver graft survival was 42% at 3 years. Results obtained during the last 6 years of the 10-year period showed an improvement with a live related donor graft survival rate of 71%, and a 1st cadaver graft survival rate of 47% at 3 years. Particular experience was gained with home haemodialysis and live, related donor transplantation. Despite growth, and psychosocial and rehabilitation problems, the overall results were encouraging, particularly for the 46 children who had successful transplants. These children grew better, had fewer psychosocial difficulties, and were rehabilitated more successfully into normal life than those on long-term dialysis. We conclude that dialysis and transplantation should be offered to all suitable children with terminal renal failure.


Cecal necrosis in the dialysis-dependent patient.
Necrosis of the cecum occurs in various settings, including low-flow states. Cecal necrosis in two dialysis patients with documented, sustained hypotension is presented. Spontaneous left colon perforations, which have been previously reported in renal failure patients, were considered secondary to distention from constipation. The cecum may be more susceptible to ischemia than the remainder of the colon. Maximal distention develops at this point. With an associated low-flow state, in a possible watershed area, necrosis can occur. The diagnosis of cecal necrosis and perforation should be entertained in any dialysis patient with an acute abdomen. Early exploration may be necessary.


Surgical therapy for craniocerebral firearm injury.
The current study aims to explore the clinical characteristics of craniocerebral firearm injury and to improve the diagnosis and treatment of this condition. Data from 56 patients with craniocerebral firearm injury were analyzed retrospectively for projectile types, traumatic conditions, and treatment approaches. 43 patients exhibited intracranial foreign body residence. Of them, 40 were subjected to complete foreign body removal and 2 to partial removal, leaving 1 without receiving removal treatment. 54 patients (96.4%) survived and 2 (3.6%) died. Of the survivors, 36 (64.3%) recovered well, 15 (26.8%) were moderately disabled, 2 (3.6%) were severely disabled, and 1 (1.8%) lapsed into vegetative state. Patients receiving debridement within 8 h after injury had a significantly higher recovery rate than those receiving such treatment after 8 h (82.1% vs. 26.7%; P < 0.001). Craniocerebral firearm injury is characterized by rapid traumatic condition development as well as serious trauma and contamination. Accurately judging the traumatic condition and the ballistic tract, performing complete debridement as early as possible, reasonably deciding on the operative mode and approach for intracranial residing foreign body removal, and increasing vigilance regarding concomitant injuries are the keys to the improvement of the overall treatment of craniocerebral firearm injury.


Isolation and evaluation of Qatari soil rhizobacteria for antagonistic potential against phytopathogens and growth promotion in tomato plants.
Plant growth promoting rhizobacteria are a diverse group of microorganisms that enhance the growth of plants under various conditions. In this study, 55 isolates of endogenous rhizobacteria were collected from the rhizosphere of Avicennia marina, Suaeda vermiculata, Salsola soda, Anabasis setifera, Salicornia europaea, Arthrocnemum macrostachyum, Limonium axillare, Tetraena qatarensis, Aeluropus lagopoides, and Prosopis juliflora. The isolates were evaluated in-vitro for their antagonist potential against Fusarium oxysporum and Botrytis cinerea using the dual culture technique, where the maximum growth inhibition reached 49% and 57%, respectively. In-vivo evaluation was accomplished to determine the growth-promoting potential of the rhizobacteria under greenhouse conditions where the strain ANABR3 (Bacillus subtilis) showed the strongest growth-promoting effects. Further in-vivo testing regarding the effectiveness of rhizobacteria in the presence of the phytopathogen was also completed using the Hoagland medium. LEMR3 and SALIR5 (both identified as two strains of B. subtilis) supported the tomato seedlings to overcome the disease and significantly (p ≤ 0.05) increased above and belowground biomass compared to the control. Additionally, several characterizing tests were carried out on the selected strains, these strains were found to possess numerous features that promote plant growth directly and indirectly such as the production of IAA, HCN, hydrolytic enzymes, ACC deaminase, NH3, and some rhizobacteria were capable of phosphate solubilization. In conclusion, this study showed that local rhizobacterial isolates collected from arid lands possess valuable traits, making them promising bio-control agents and bio-fertilizers for agricultural purposes.


The alcohol supply: its importance to public health and safety, and essential research questions.
This paper seeks to identify the main questions which have emerged from the preceding papers concerning the supply side of alcohol. On any rational analysis these issues are of thoroughly legitimate concern to public health researchers. We list them under seven headings: (1) what drives the alcohol supply side? (2) What is the impact of alcohol supply on demand? (3) What are the benefits and risks to health and safety stemming from deregulation and what are the possibilities to avoid negative effects? (4) What is the size and significance of the alcohol supply which may derive from other than the officially approved channels? (5) Who are the important actors in the alcohol supply system? (6) What are local influences on alcohol supply and its distribution throughout communities? (7) What is to be learned from tobacco and other risky commodities about the importance of supply? Finally, we outline a series of possible next steps for a supply side initiative.


Childhood and adolescent ovarian malignant tumors in Israel. A nationwide study.
To determine the incidence of ovarian malignant tumors in childhood and adolescence, to ascertain the frequency distribution of the various tumor types and to assess time trends in Israel on a nationwide basis. The study group included all Israeli Jewish patients < or = 19 years old with histologically confirmed ovarian malignancies, diagnosed in Israel from 1970 to 1994. Data were obtained from the Israel Cancer Registry. The effects of age at diagnosis and period of diagnosis were analyzed using the Poisson regression. Among the 82 patients identified, the most frequent tumors (72.0%) were of germ cell origin and among those about one third were dysgerminomas. Epithelial tumors were diagnosed in 26.6% of the patients and most of these were borderline malignancies. The incidence rate (IR) for the total group of ovarian malignancies in the 0-19 age group was 0.52 and for ages 5-19 it was 0.71 per 100,000. After adjustment for age, a significant linear trend for a decrease of germ cell tumors over time was found, stemming from a decrease of dysgerminomas. A significant trend for increase in the IRs with age was also found. In addition, a steep rise in the age specific IRs of epithelial borderline tumors was noted in the last 5 year period. The IRs of ovarian malignancies in childhood and adolescence in Israel, as in other countries, is very low as compared to adults and the most common tumors are of germ cell origin while malignant epithelial tumors are very rare. A time period effect in the germ cell tumors that resulted from an inexplicable significant decrease in the age specific IRs of dysgerminomas, was observed. A significant increase in borderline tumors was also noted and may be attributed to greater awareness of pathologists to this entity.


Neuropathologic correlates of trial-related instruments for Alzheimer's disease.
To advance disease-modifying therapies, it is critical to understand the relationship between the neuropathological changes of Alzheimer's Disease (AD) and the clinical measures used in therapeutic trials. We reviewed neuropathologically proven cases of AD from the National Alzheimer's Coordinating Center (NACC) and examined correlations between neuropathological changes and clinical-trial related instruments collected as part of the Uniform Dataset (UDS). We explored the relationships between neurofibrillary tangles, neuritic plaques, and total pathology burden with immediate and delayed recall, Clinical Dementia Rating-Sum of Boxes, Functional Activity Questionnaire, Neuropsychiatric Inventory Questionnaire, and Mini-Mental State Examination scores. 169 patients in NACC database had appropriate neuropathological and clinical data. All instruments correlated highly with neuritic plaques, Braak staging, and total pathology. Correlation coefficients for the relationships were relatively modest, suggesting that the pathologic burden examined accounts for between 13 and 40% of the variance of each of the instruments assessed. We conclude that there is a strong correlation between clinical trial-related measures and neuropathology identified at autopsy in AD. The amount of variance explained by the pathology is limited and other factors, both disease- and measurement-related, contribute to the variability observed in clinical measurements.


N-acetylcysteine Amide AD4/NACA and Thioredoxin Mimetic Peptides Inhibit Platelet Aggregation and Protect against Oxidative Stress.
In the present study, we tested the effect of small-molecular-weight redox molecules on collagen-induced platelet aggregation. We used N-acetylcysteine amide (AD4/NACA), the amide form of N-acetylcysteine (NAC), a thiol antioxidant with improved lipophilicity and bioavailability compared to NAC, and the thioredoxin-mimetic (TXM) peptides, TXM-CB3, TXM-CB13, and TXM-CB30. All compounds significantly inhibited platelet aggregation induced by collagen, with TXM-peptides and AD4 being more effective than NAC. The levels of TxB2 and 12-HETE, the main metabolites derived from the cyclooxygenase and lipoxygenase pathways following platelet activation, were significantly reduced in the presence of AD4, TXM peptides, or NAC, when tested at the highest concentration (0.6 mM). The effects of AD4, TXM-peptides, and NAC were also tested on the clotting time (CT) of whole blood. TXM-CB3 and TXM-CB30 showed the greatest increase in CT. Furthermore, two representative compounds, TXM-CB3 and NAC, showed an increase in the anti-oxidant free sulfhydryl groups of plasma detected via Ellman's method, suggesting a contribution of plasma factors to the antiaggregating effects. Our results suggest that these small-molecular-weight redox peptides might become useful for the prevention and/or treatment of oxidative stress conditions associated with platelet activation.


A plethora of carbapenem resistance in Acinetobacter baumannii: no end to a long insidious genetic journey.
Acinetobacter baumannii, notorious for causing nosocomial infections especially in patients admitted to intensive care unit (ICU) and burn units, is best at displaying resistance to all existing antibiotic classes. Consequences of high potential for antibiotic resistance has resulted in extensive drug or even pan drug resistant A. baumannii. Carbapenems, mainly imipenem and meropenem, the last resort for the treatment of A. baumannii infections have fallen short due to the emergence of carbapenem resistant A. baumannii (CRAB). Though enzymatic degradation by production of class D β-lactamases (Oxacillinases) and class B β-lactamases (Metallo β-lactamases) is the core mechanism of carbapenem resistance in A. baumannii; however over-expression of efflux pumps such as resistance-nodulation cell division (RND) family and variant form of porin proteins such as CarO have been implicated for CRAB inception. Transduction and outer membrane vesicles-mediated transfer play a role in carbapenemase determinants spread. Colistin, considered as the most promising antibacterial agent, nevertheless faces adverse effects flaws. Cefiderocol, eravacycline, new β-lactam antibiotics, non-β-lactam-β-lactamase inhibitors, polymyxin B-derived molecules and bacteriophages are some other new treatment options streamlined.


Exploring the Coordination of Plutonium and Mixed Plutonyl-Uranyl Complexes of Imidodiphosphinates.
The coordination chemistry of plutonium(IV) and plutonium(VI) with the complexing agents tetraphenyl and tetra-isopropyl imidodiphosphinate (TPIP- and TIPIP-) is reported. Treatment of sodium tetraphenylimidodiphosphinate (NaTPIP) and its related counterpart with peripheral isopropyl groups (NaTIPIP) with [NBu4]2[PuIV(NO3)6] yields the respective PuIV complexes [Pu(TPIP)3(NO3)] and [Pu(TIPIP)2(NO3)2] + [PuIV(TIPIP)3(NO3)]. Similarly, the reactions of NaTPIP and NaTIPIP with a Pu(VI) nitrate solution lead to the formation of [PuO2(HTIPIP)2(H2O)][NO3]2, which incorporates a protonated bidentate TIPIP- ligand, and [PuO2(TPIP)(HTPIP)(NO3)], where the protonated HTPIP ligand is bound in a monodentate fashion. Finally, a mixed U(VI)/Pu(VI) compound, [(UO2/PuO2)(TPIP)(HTPIP)(NO3)], is reported. All these actinyl complexes remain in the +VI oxidation state in solution over several weeks. The resultant complexes have been characterized using a combination of X-ray structural studies, NMR, optical, vibrational spectroscopies, and electrospray ionization mass spectrometry. The influence of the R-group (R = phenyl or iPr) on the nature of the complex is discussed with the help of DFT studies.


Palladium-catalyzed regioselective C-H alkynylation of indoles with haloalkynes: access to functionalized 7-alkynylindoles.
A palladium-catalyzed uniquely regioselective C-H alkynylation of indoles has been described. In this protocol, simple and readily available haloalkynes are employed as efficient alkynylating reagents, affording a series of functionalized 7-alkynylindoles in moderate to good yields. Moreover, further transformations of 7-alkynylated products were performed, which demonstrated the potential application of this method in organic synthesis.


Natural antibody recognition of v-H-ras-induced 10T1/2 transformation.
An increasing body of evidence supports a role for natural antitumor antibodies acting against tumors in vivo. However, a role for natural antibodies (NAb) in tumor surveillance would imply that sensitivity to NAb should increase following events associated with cellular transformation. To test this prediction we examined by flow cytometry the effect on serum NAb binding of v-H-ras expression and integration in 10T1/2. The co-introduction of v-H-ras and the neomycin resistance (neor) gene into 10T1/2 followed by G418 selection resulted in a marked and heterogeneous increase in NAb binding. Clonal analysis of this population demonstrated that the increased NAb binding was associated with tumorigenic conversion and ras-p21 expression. The results provide the first evidence for a NAb-susceptible phase of ras-induced transformation.


Role of p53 serine 46 in p53 target gene regulation.
The tumor suppressor p53 plays a crucial role in cellular growth control inducing a plethora of different response pathways. The molecular mechanisms that discriminate between the distinct p53-responses have remained largely elusive. Here, we have analyzed the p53-regulated pathways induced by Actinomycin D and Etoposide treatment resulting in more growth arrested versus apoptotic cells respectively. We found that the genome-wide p53 DNA-binding patterns are almost identical upon both treatments notwithstanding transcriptional differences that we observed in global transcriptome analysis. To assess the role of post-translational modifications in target gene choice and activation we investigated the genome-wide level of phosphorylation of Serine 46 of p53 bound to DNA (p53-pS46) and of Serine 15 (p53-pS15). Interestingly, the extent of S46 phosphorylation of p53 bound to DNA is considerably higher in cells directed towards apoptosis while the degree of phosphorylation at S15 remains highly similar. Moreover, our data suggest that following different chemotherapeutical treatments, the amount of chromatin-associated p53 phosphorylated at S46 but not at pS15 is higher on certain apoptosis related target genes. Our data provide evidence that cell fate decisions are not made primarily on the level of general p53 DNA-binding and that post-translationally modified p53 can have distinct DNA-binding characteristics.


Reversible interconversion of two forms of a valyl-tRNA synthetase-containing protein complex.
When an enzyme-containing complex from yeast was incubated in a buffered solution at room temperature, the valyl-transfer RNA synthetase activity and total protein oscillated synchronously between two physical states. This observation suggests a regulatory process that controls a number of enzymes as a group, an integrated function of a kind not heretofore recognized. The two forms of the complex were separated by ammonium sulfate precipitation of one of them in samples withdrawn from the incubated solution every 30 seconds. Glutathione and dithiothreitol in high concentrations (50 mM) enhance formation of the 50% saturated ammonium sulfate-soluble form. Oxidized glutathione, diphosphopyridine nucleotide, triphosphopyridine nucleotide, and a mercurial thiol binding agent in moderate concentrations (0.1 to 1.0 mM) shift the distribution toward the precipitable form. It is suggested that the two forms represent functional and nonfunctional complex-bound enzymes which are interconverted in response to oxidoreductive signals.


Nuclear genomes distinguish cryptic species suggested by their DNA barcodes and ecology.
DNA sequencing brings another dimension to exploration of biodiversity, and large-scale mitochondrial DNA cytochrome oxidase I barcoding has exposed many potential new cryptic species. Here, we add complete nuclear genome sequencing to DNA barcoding, ecological distribution, natural history, and subtleties of adult color pattern and size to show that a widespread neotropical skipper butterfly known as Udranomia kikkawai (Weeks) comprises three different species in Costa Rica. Full-length barcodes obtained from all three century-old Venezuelan syntypes of U. kikkawai show that it is a rainforest species occurring from Costa Rica to Brazil. The two new species are Udranomia sallydaleyae Burns, a dry forest denizen occurring from Costa Rica to Mexico, and Udranomia tomdaleyi Burns, which occupies the junction between the rainforest and dry forest and currently is known only from Costa Rica. Whereas the three species are cryptic, differing but slightly in appearance, their complete nuclear genomes totaling 15 million aligned positions reveal significant differences consistent with their 0.00065-Mbp (million base pair) mitochondrial barcodes and their ecological diversification. DNA barcoding of tropical insects reared by a massive inventory suggests that the presence of cryptic species is a widespread phenomenon and that further studies will substantially increase current estimates of insect species richness.


Enantiodiscrimination of chiral molecules via quantum correlation function.
We propose a method to realize enantiodiscrimination of chiral molecules based on quantum correlation function in a driven cavity-molecule system, where the chiral molecule is coupled with a quantized cavity field and two classical light fields to form a cyclic three-level model. According to the inherent properties of electric-dipole transition moments of chiral molecules, there is a π-phase difference in the overall phase of the cyclic three-level model for the left- and right-handed chiral molecules. Thus, the correlation function depends on this overall phase and is chirality-dependent. The analytical and numerical results indicate that the left- and right-handed chiral molecules can be discriminated by detecting quantum correlation function. Our work opens up a promising route to discriminate molecular chirality, which is an extremely important task in pharmacology and biochemistry.


Human endothelial cell-lymphocyte interaction. Endothelial cells function as accessory cells necessary for mitogen-induced human T lymphocyte activation in vitro.
Mitogen-stimulated human T cell activation is absolutely dependent on the participation of a nonresponding accessory cell. In populations of human peripheral blood mononuclear cells, monocytes function as the requisite accessory cells. The possibility that cultured endothelial cells (EC) might also function as accessory cells was studied by examining the potential of endothelial cells to restore mitogen responsiveness to monocyte-depleted human T cells. Highly purified T cells were prepared by isolating cells rosetting with sheep erythrocytes and removing monocyte contamination by glass adherence and nylon wool column passage. When cultured at low cell density, T cells failed to respond to stimulation with various mitogenic lectins, whereas co-culture with monocytes restored responsiveness. Similarly, EC obtained from umbilical vein, pulmonary artery, and ovarian vein restored the capacity of T cells to respond to mitogens. Mitogen-stimulated T cell activation required viable endothelial cells. Moreover, effective endothelial T cell cooperation appeared to involve the establishment of cell-to-cell contact between EC and responding T cells. Accessory cell function was not a nonspecific property of all tissue culture cells as evidenced by the finding that human foreskin fibroblasts, lung fibroblasts, and HeLa cells were unable to restore responsiveness to monocyte-depleted T cells. These observations indicate that endothelial cells can support the induction of mitogen-induced T cell activation and suggest that cells lining blood vessels may play an active role in the initiation of immune responses in vivo.


The Dolly case, the Polly drug, and the morality of human cloning.
The year 1996 witnessed the cloning of the lamb Dolly, based on the revolutionary somatic cell nuclear transfer (SCNT) technique, developed by researchers from the Roslin Institute in Edinburgh, Scotland. This fact marked a relevant biotechnoscientific innovation, with probable significant consequences in the field of public health, since in principle it allows for expanding possibilities for the reproductive autonomy of infertile couples and carriers of diseases of mitochondrial origin. This article expounds on 1) the experiment's technical data and the theoretical implications for the biological sciences; 2) the public's perception thereof and the main international documents aimed at the legal and moral regulation of the technique; and 3) the moral arguments for and against cloning, from the point of view of consequentialist moral theory. We conclude that in the current stage of the debate on the morality of cloning, in which there are no cogent deontological arguments either for or against, weighing the probability of risks and benefits is the only reasonable way of dealing with the issue in societies that consider themselves democratic, pluralistic, and tolerant.


The relative contribution of band number to phylogenetic accuracy in AFLP data sets.
We examined the effect of increasing the number of sampled amplified fragment length polymorphism (AFLP) bands to reconstruct an accurate and well-supported AFLP-based phylogeny. In silico AFLP was performed using simulated DNA sequences evolving along balanced and unbalanced model trees with recent, uniform and ancient radiations and average branch lengths (from the most internal node to the tip) ranging from 0.02 to 0.05 substitutions per site. Trees were estimated by minimum evolution (ME) and maximum parsimony (MP) methods from both DNA sequences and virtual AFLP fingerprints. The comparison of the true tree with the estimated AFLP trees suggests that moderate numbers of AFLP bands are necessary to recover the correct topology with high bootstrap support values (i.e. >70%). Fewer numbers of bands are necessary for shorter tree lengths and for balanced than for unbalanced tree topologies. However, branch length estimation was rather unreliable and did not improve substantially after a certain number of bands were sampled. These results hold for different levels of genome coverage and number of taxa analysed. In silico AFLP using bacterial genomic DNA sequences recovered a well-supported tree topology that mirrored an empirical phylogeny based on a set of 31 orthologous gene sequences when as few as 263 AFLP bands were scored. These results suggest that AFLPs may be an efficient alternative to traditional DNA sequencing for accurate topology reconstruction of shallow trees when not very short ancestral branches exist.


Tips for efficiently maintaining pET expression plasmids.
pET expression plasmids are widely used for producing recombinant proteins in Escherichia coli. Selection and maintenance of cells harboring a pET plasmid are possible using either a Tn3.1-type genetic fragment (which encodes a ß-lactamase and confers resistance to ß-lactam antibiotics) or a Tn903.1-type genetic fragment (which encodes an aminoglycoside-3'-phosphotransferase and confers resistance aminoglycoside antibiotics). Herein we have investigated how efficiently pET plasmids are maintained using these two fragments. The study reveals that pET plasmids are efficiently maintained with both Tn3.1 and Tn903.1 genetic fragments prior to the induction of recombinant protein production, and over short induction times (i.e., 2 h). However, over longer induction times (i.e., 20 h), the efficiency of plasmid maintenance depends on the host strain used, and the type of antibiotic selection cassette used. Based on our collective observations, we have 2 general tips for efficiently maintaining pET plasmids during recombinant production experiments. Tip #1: Use a strain with lowered levels of the T7 RNA polymerase, such as C41(DE3). pET plasmids will be efficiently maintained over long induction times with both the Tn3.1 and Tn903.1 genetic fragments, regardless of whether antibiotics are present during cultivation. Tip #2: If a strain with higher levels of T7 RNA polymerase strain is necessary, such as BL21(DE3)), keep induction times short or use a plasmid containing a Tn903.1-type fragment and select with kanamycin.


On-Site Classification of Pansteatitis in Mozambique Tilapia (Oreochromis mossambicus) using a Portable Lipid-Based Analyzer.
While no pansteatitis-related large-scale mortality events have occurred since 2008, the current status of pansteatitis (presence and pervasiveness) in the Olifants River system and other regions of South Africa remain largely unknown. In part, this is due to both a lack of known biological markers of pansteatitis and a lack of suitable non-invasive assays capable of rapidly classifying the disease. Here, we propose the application of a point-of-care (POC) device using lipid-based test strips (total cholesterol (TC) and total triglyceride (TG)), for classifying pansteatitis status in the whole blood of pre-spawning Mozambique tilapia (Oreochromis mossambicus). Using the TC strips, the POC device was able to non-lethally classify the tilapia as either healthy or pansteatitis-affected; the sexes were examined independently because sexual dimorphism was observed for TC (males p = 0.0364, females χ2 = 0.0007). No significant difference between diseased and pansteatitis-affected tilapia was observed using the TG strips. This is one of the first described applications of using POC devices for on-site environmental disease state testing. A discussion on the merits of using portable lipid-based analyzers as an in-field disease-state diagnostic tool is provided.


A comparison of male sex workers in Prague: Internet escorts versus men who work in specialized bars and clubs.
Prague, the Czech Republic, is a popular sex tourism destination where sex work is decriminalized and young men offer sexual services at low prices relative to countries in Western Europe. This quantitative survey aimed to identify some of the demographic characteristics of these young men and their experiences in the sex industry. Internet escorts (N = 20) and sex workers in bars and clubs (N = 20) completed the survey anonymously in spring 2011. The results showed that sex workers in clubs often had troubled pasts and were forced into sex work to survive. They also reported incidents of violence, serious alcohol and drug use, as well as frequent gambling. The larger group of sex workers in Prague is made up of Internet escorts who have backgrounds that are not atypical for the average Czech youth. They had fewer problems with drugs and alcohol but were twice as likely as sex workers in bars and clubs to be victims of violent crime. Plans for interventions to help those who would change their line of work, as well as the importance of sociocultural context in understanding sex workers, are discussed.


PPAR{gamma} regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-{kappa}B.
NADPH oxidases are a major source of superoxide production in the vasculature. The constitutively active Nox4 subunit, which is selectively upregulated in the lungs of human subjects and experimental animals with pulmonary hypertension, is highly expressed in vascular wall cells. We demonstrated that rosiglitazone, a synthetic agonist of the peroxisome proliferator-activated receptor-γ (PPARγ), attenuated hypoxia-induced pulmonary hypertension, vascular remodeling, Nox4 induction, and reactive oxygen species generation in the mouse lung. The current study examined the molecular mechanisms involved in PPARγ-regulated, hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells (HPASMC). Exposing HPASMC to 1% oxygen for 72 h increased Nox4 gene expression and H(2)O(2) production, both of which were reduced by treatment with rosiglitazone during the last 24 h of hypoxia exposure or by treatment with small interfering RNA (siRNA) to Nox4. Hypoxia also increased HPASMC proliferation as well as the activity of a Nox4 promoter luciferase reporter, and these increases were attenuated by rosiglitazone. Chromatin immunoprecipitation assays demonstrated that hypoxia increased binding of the NF-κB subunit, p65, to the Nox4 promoter and that binding was attenuated by rosiglitazone treatment. The role of NF-κB in Nox4 regulation was further supported by demonstrating that overexpression of p65 stimulated Nox4 promoter activity, whereas siRNA to p50 or p65 attenuated hypoxic stimulation of Nox4 promoter activity. These results provide novel evidence for NF-κB-mediated stimulation of Nox4 expression in HPASMC that can be negatively regulated by PPARγ. These data provide new insights into potential mechanisms by which PPARγ activation inhibits Nox4 upregulation and the proliferation of cells in the pulmonary vascular wall to ameliorate pulmonary hypertension and vascular remodeling in response to hypoxia.


Intermediate-term outcomes of 350-mm(2) Baerveldt glaucoma implants.
To determine the intermediate-term outcome of 350-mm(2) Baerveldt glaucoma implants. Retrospective, noncomparative case series. Sixty-five patients (65 eyes). Implantation of 350-mm(2) Baerveldt glaucoma drainage device. Intraocular pressure, number of glaucoma medications, best-corrected Snellen visual acuity, length of follow-up, risk factors for failure, and complications. Mean intraocular pressure was reduced from a preoperative value of 32 mmHg to a 2-year postoperative value of 14 mmHg (56% reduction, P < 0.001). Success rates at 2-year follow-up were 71%, 81%, 78%, 60%, and 47% for the overall group, primary open-angle glaucoma group, neovascular group, uveitic group, and other group, respectively. After accounting for the effect of diagnosis group, significant risk factors in the overall group for failure at 2 years included younger age, high preoperative intraocular pressure, and more prior incisional surgeries. Glaucoma medication use in our overall study population was reduced from 2.5 mean preoperative medications to 0.8 postoperative medications (68%). Median change in Snellen visual acuity between preoperative and 2-year postoperative visits was not significant in the overall group. Postoperative complications included choroidal effusion in 15 patients (23%), tube obstruction by blood or vitreous in five patients (8%), phthisis in four patients (6%), aqueous misdirection in two patients (3%), strabismus in two patients (3%), tube-cornea touch in two patients (3%), endophthalmitis in two patients (3%), and retinal detachment in two patients (3%). No patients had suprachoroidal hemorrhage. The 350-mm(2) Baerveldt glaucoma implants are a safe and effective treatment for intermediate-term intraocular pressure control in patients with refractory glaucoma.


Galectin-3 in heart failure with preserved ejection fraction. A RELAX trial substudy (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure).
This study hypothesized that elevated galectin-3 (Gal-3) levels would identify patients with more advanced heart failure (HF) with preserved ejection fraction (HFpEF) as assessed by key pathophysiological domains. Gal-3 is implicated in the pathogenesis of cardiac fibrosis but is also increased with normal aging and renal dysfunction. Cardiac fibrosis may contribute to cardiac dysfunction, exercise intolerance, and congestion in HFpEF. Two hundred eight patients from the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure) trial of sildenafil in HFpEF had Gal-3 measured at enrollment. Pathophysiological domains assessed included biomarkers of neurohumoral activation, fibrosis, inflammation and myocardial necrosis, congestion severity and quality of life, cardiac structure and function, and exercise performance. Analysis adjusted for age, sex, and/or cystatin-C levels. Potential interaction between baseline Gal-3 and treatment (sildenafil) effect on the RELAX study primary endpoint (change in peak oxygen consumption) was tested. Gal-3 levels were associated with age and severity of renal dysfunction. Adjusting for age, sex, and/or cystatin-C, Gal-3 was not associated with biomarkers of neurohumoral activation, fibrosis, inflammation or myocardial necrosis, congestion or quality-of-life impairment, cardiac remodeling or dysfunction, or exercise intolerance. Gal-3 did not identify patients who responded to phosphodiesterase type 5 (PDE-5) inhibitors (interaction p = 0.53). In overt HFpEF, Gal-3 was related to severity of renal dysfunction and accounting for this, was not independently associated with severity of pathophysiological derangements or response PDE-5 inhibition. These findings underscore the need to adjust for renal function when interpreting Gal-3 levels, and call into question the value of Gal-3 to quantify disease severity in overt HFpEF.


Patient selection for trials.
The last several decades have witnessed considerable progress in our understanding of the pathogenesis, refining diagnostic criteria, and identifying therapies of value for modifying the course of relapsing forms of multiple sclerosis. While the pace of progress has lagged for those with progressive phase disease, this now seems to be changing. This review considers those characteristics of patients with primary progressive multiple sclerosis that may contribute to phase 3 trial success and identifies some of the thorny issues that remain ahead. The larger of the studies conducted thus far have sequentially informed our understanding of "pure" primary progressive disease, and also challenge both phase 3 and especially phase 2 trial designs and participant selection for investigations going forward. This may have particular relevance for testing therapeutics directed at neuroprotection and repair in the face of ongoing progression regardless of trial participant categorization using current conventional disease phenotypes.


Intravenous short narcoses in geriatric patients, A comparative study of etomidate with various analgesics.
Because of their often complicated pathology, geriatric patients may present special problems to the anesthetist. Whereas the hazards of surgery have been diminished through specific pre- and posttreatment, the so-called short narcosis has failed as yet to fulfill the requirements of maximum safety for the patient. In our study, two potent analgesics, i.e. fentanyl or pentazocine are associated with the narcotic etomidate for short narcosis. The effects either combination has on cardiovascular or respiratory values during unassisted ventilation are studied. Both the fentanyl/etomidate combination and the pentazocine/etomidate combination are characterized by stable cardiovascular conditions. The unfavourable effect on spontaneous respiration is greater after fentanyl as compared with pentazocine. Combined anesthesia of pentazocine and etomidate remains safe an easy to perform when the patient breathes spontaneously. If fentanyl is used, assisted respiration with oxygen is required.


[Cancer and menopause].
After a brief review of menopausal disorders, the author develops three chapters. The first deals with conventional hormonal or replacement therapy, which has beneficial effects on vasomotor disorders, atrophy of the urogenital tract and osteoporosis, but also carries a risk of adenocarcinoma. Next, the author gives the oncologist's point of view, expounding in particular the major contraindications of estrogen therapy. The third chapter develops non-hormonal treatments of menopause, their specific mode of action and advantages, with a reference to veralipride. In his conclusion, the author emphasizes that hormonal and non-hormonal treatments of menopause should not be opposed but are complementary.


Ductal vs. acinar? Recent insights into identifying cell lineage of pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of less than 8%. To date, there are no early detection methods or effective treatments available. Many questions remain to be answered in regards to the pathogenesis of PDAC, among which, the controversy over the cell lineage of PDAC demands more attention. Ductal cells were originally thought to be the cell of origin for PDAC due to the ductal morphology of most cases of PDAC. However, recent studies have demonstrated that acinar cells are more sensitive to KRAS mutation and tend to develop to PanIN and PDAC effectively, very likely by undergoing acinar to ductal metaplasia into a transient state that contributes to PDAC initiation. There is also evidence that both ductal and acinar cells can potentially develop to PDAC when exposed to certain genetic settings and stimuli, suggesting that more scrutiny is required for the identification of the true cell lineage of individual cases of PDAC. In this work, we summarize recent findings in the identification of the cellular origin of PDAC, with the goal of advancing our knowledge on the initiation and progression of the disease. We also discuss various models and techniques for investigating early events of PDAC. Better understanding of these cellular events is crucial to identify new methods for the early diagnosis and treatment of PDAC.


Baseline Results: The Association Between Cardiovascular Risk and Preclinical Alzheimer's Disease Pathology (ASCEND) Study.
The rate of AD for African Americans (AAs) is 64% higher than for non-Hispanic White Americans (Whites). It is hypothesized that poor peripheral vascular function, in combination with genetics, stress, and inflammation may directly contribute to the accumulation of AD pathologic biomarkers. These risk factors may disproportionately affect AAs. Our objective was to determine if in a healthy middle-aged cohort at risk for AD (1) AD biomarkers in CSF differ by race, (2) peripheral vascular dysfunction and cognition are related to a higher burden of CSF AD biomarkers, and (3) these relationships differ by race. We enrolled 82 cognitively normal, middle-aged (45 and older) adults including AAs and Whites at high risk for AD due to parental history. Study procedures included lumbar puncture, vascular ultrasound, and cognitive testing. While participants were in overall good health, AAs exhibited poorer indices of preclinical vascular health, including higher central SBP, central MAP, and EndoPAT AI, a marker of arterial stiffness. AAs also had significantly less cerebrospinal fluid tau burden than Whites. After polynomial regression analysis, adjusted for age, gender, education, and ApoE4 status, race significantly modified the relationship between total tau, phospho-tau, and Trails B, a marker of executive function. Small differences in tau correlated with poorer cognition in AAs. In a healthy middle-aged cohort at risk for AD, AAs had worse peripheral vascular health and worse cognition than Whites. Despite lower tau burden overall, race modified the relationship between tau and cognition, such that small differences in tau between AAs was related to worse cognition when compared to Whites.


Plasma fibrinolysis, inflammatory markers, and postthrombotic syndrome: preliminary findings from the Kids-DOTT Biobank.
Plasma levels of markers of coagulation and inflammation have been identified as prognostic factors for adult postthrombotic syndrome (PTS). We aimed to determine whether plasma fibrinolytic capacity and cytokine levels during the first 3 months after provoked deep venous thrombosis (DVT) are associated with risk of PTS in young patients. We analyzed plasma biospecimens (6 weeks and 3 months after provoked DVT) and clinical data from a National Heart, Lung, and Blood Institute-sponsored multinational trial of anticoagulation for provoked venous thromboembolism in patients younger than age 21 years (Kids-DOTT). Patients with a provoked extremity DVT who had plasma samples available at both 6-week and 3-month post-DVT time points and PTS assessment at 1 year were included. We measured plasma fibrinolytic capacity using the Clot Formation and Lysis (CloFAL) assay and plasma cytokine levels by multiplex immunoassay. Logistic regression analyses evaluated prognostic associations with PTS. Seventy-nine patients were included (median age, 12.8 years; range, 0.04-20.8 years). PTS developed in 34%. Complete veno-occlusion at 6 weeks after diagnosis of DVT (odds ratio [OR], 3.12; 95% confidence interval [CI], 0.81-11.94; P = .097), low fibrinolytic capacity in plasma at 3 months post-DVT (OR, 2.71; 95% CI, 0.92-7.97; P = .07), and elevated serum amyloid A at 3 months post-DVT (OR, 2.85; 95% CI, 0.98-8.34; P = .055) were identified as putative prognostic factors for development of PTS. In multivariable logistic regression analysis, these factors did not retain a statistically significant independent association with PTS, but these preliminary results warrant further investigation in an independent data set to definitively evaluate these findings and identify additional potential prognostic factors for the development of PTS after a provoked DVT in young patients.


Shoulder isokinetic profile of male handball players of the Brazilian National Team.
Data obtained on an isokinetic dynamometer are useful to characterize muscle status and have been reported in muscle imbalance studies in different types of sport. However, few studies have assessed elite handball players to establish reference values. The purpose of this study was to compare, for the dominant (D) and non-dominant (ND) side, the isokinetic profile of shoulder rotator muscle strength between male handball players (H) and asymptomatic non-athletes (NA). Isokinetic concentric and eccentric strength tests for D upper limbs were performed by the H group (n=20) and the NA group (n=12). Internal and external rotator muscle peak torque in concentric action was assessed at 60°/s and 300°/s and in eccentric action at 300°/s. We also calculated conventional balance (the ratio of external rotator peak torque to internal rotator peak torque in concentric action) and functional balance (the ratio of external rotator peak torque in eccentric action to internal rotator peak torque in concentric action). In the H group, dominant limbs were stronger in concentric action for external rotation at 60 and 300°/s. The conventional balance ratio for the D side was significantly lower at 60 and 300°/s for H compared to NA. The functional ratio for the D side was significantly lower at 300º/s for H compared to NA. Compared to asymptomatic non-athletes, handball players presented significant muscular imbalance resulting from daily sports practice, a known risk factor for shoulder injuries.


The htx and ptx operons of Pseudomonas stutzeri WM88 are new members of the pho regulon.
The htx and ptx operons of Pseudomonas stutzeri WM88 allow for the use of the inorganic reduced phosphorus (P) compounds hypophosphite (P valence, +1) and phosphite (P valence, +3) as sole P sources. To support the proposed in vivo role for the htx and ptx operons, namely the use of phosphite and hypophosphite as alternative P sources, we used reporter gene fusions to examine their expression levels with respect to various P conditions. Expression of the htx and ptx operons was induced up to 17- and 22-fold, respectively, in cultures grown under phosphate starvation conditions relative to expression in medium with excess phosphate (Pi). However, the presence of the reduced P substrate hypophosphite, phosphite, or methylphosphonate, in addition to excess Pi, did not result in an increase in the expression of either operon. To provide further support for a role of the htx and ptx operons in Pi acquisition, we identified P. stutzeri phoBR homologs and constructed deletion mutants. Induction of the htx and ptx reporter gene fusions in response to growth on limiting Pi was abolished in DeltaphoB, DeltaphoR, and DeltaphoBR mutants, demonstrating that htx and ptx expression is phoBR dependent. The putative LysR-type regulator encoded by ptxE has no apparent role in the expression of the htx and ptx operons, as no effect was observed on the level of induction of either operon in a DeltaptxE mutant.