Exploring the potential of natural and synthetic neuroprotective steroids against neurodegenerative disorders: A literature review.
Neurodegeneration is a complex process, which leads to progressive brain damage due to loss of neurons. Despite exhaustive research, the cause of neuronal loss in various degenerative disorders is not entirely understood. Neuroprotective steroids constitute an important line of attack, which could play a major role against the common mechanisms associated with various neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Natural endogenous steroids induce the neuroprotection by protecting the nerve cells from neuronal injury through multiple mechanisms, therefore the structural modifications of the endogenous steroids could be helpful in the generation of new therapeutically useful neuroprotective agents. The review article will keep the readers apprised of the detailed description of natural as well as synthetic neuroprotective steroids from the medicinal chemistry point of view, which would be helpful in drug discovery efforts aimed toward neurodegenerative diseases.


Ambulatory treatment with intravenous norepinephrine in a patient with end stage renal disease and generalized AA amyloidosis.
A 35-year-old man with juvenile rheumatoid arthritis and generalized AA amyloidosis of 10 years duration developed end stage renal failure. Following appendectomy, the patient experienced progressive circulatory failure which required IV treatment with norepinephrine. All attempts to discontinue IV norepinephrine failed, each leading to recurrent life-threatening hypotension. Finally, a central venous port with a portable mechanical infusion pump system was implanted supplying a continuous norepinephrine infusion. The patient then became independently mobile and could be discharged. For three months, the patient was monitored as an outpatient and treated by ambulatory intermittent hemofiltration. Finally, the patient suffered from a hemorrhagic infarction of the small bowel due to postoperative adhesions and died shortly after surgery. At autopsy, advanced generalized AA amyloidosis was found. Amyloid deposits had almost entirely replaced the cortex and the medulla of the adrenal glands. It can be speculated that the requirement of exogenous norepinephrine may be in part due to an adrenal insufficiency whereas it was initially considered as being only related to cardiac involvement. A continuous ambulatory treatment with catecholamines could be a possible treatment - at least temporarily - in amyloid cases in which all other attempts have failed to prevent chronic life-threatening hypotension.


Interplay Between Gemcitabine and Erlotinib Over Pancreatic Adenocarcinoma Cells.
Pancreatic ductal adenocarcinoma remains as a chemoresistant disease with the poorest prognosis. Gemcitabine has been the standard treatment during the last decade. Erlotinib, a tyrosine kinase inhibitor, in combination with gemcitabine produces a small increase in survival. However, these results remain insufficient. The aim of this study was to investigate the molecular interplay in vitro between them regarding their effects over cytotoxicity, proliferation, apoptosis, and invasion. Using the human pancreatic cancer cell lines Panc-1 and BxPC-3 in vitro, the effects of gemcitabine and erlotinib therapy on growth, proliferation, and invasion were tested by cytotoxicity, cell cycle, and Annexin V-Fluorescein Isothiocyanate analysis, reverse transcription polymerase chain reaction, protein expression, and Chip assays. Therapy decreased cell proliferation causing G0/G1 phase cell cycle arrest with induction of apoptosis in the Panc-1 cell line. This blockade was associated with increased p27 expression. Besides, treatments enhanced the nuclear factor-κB (NF-κB) pathway and the binding of NF-κB to the promoters of genes related to the proliferation and the evasion of apoptosis. Our data suggest that, although gemcitabine and erlotinib exert antiproliferative effects over pancreatic cancer cell lines, the gemcitabine-induced activation of NF-κB expression and its DNA-binding activities are important drawbacks of this treatment against pancreatic cancer.


Systemic fungal infections: diagnosis and treatment. I. Therapeutic agents.
The story of antifungal agents has not been a stately procession from one development to another. For many years there was no agent of value for systemic mycoses. Then, with the advent of amphotericin B, we have had for over two decades essentially one effective agent, but a difficult drug to manipulate. The appearance of ketoconazole, the first systemic drug with relatively little toxicity, along with the appearance of ominous new forms of mycotic diseases, sharply stimulated interest in development of antifungal agents, initially in the azole classes, but now including a variety of other classes as well. We have very little idea how all of these drugs will act independently, and much less how they may interact together. Indeed, one of the most exciting developments is the return to amphotericin B, with repackaging in liposomes having created a markedly less toxic, and possibly much more potent, antifungal agent than "traditional" amphotericin B. There are indeed so many developments under way that the only safe conclusion that can be made is that within a few years current recommendations will be replaced by very different ones for most if not all of the major fungal pathogens.


Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of FTDP-17 transgenic mice.
Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau.


Preparation of gradient surfaces by using a simple chemical reaction and investigation of cell adhesion on a two-component gradient.
This article describes a simple method for the generation of multicomponent gradient surfaces on self-assembled monolayers (SAMs) on gold in a precise and predictable manner, by harnessing a chemical reaction on the monolayer, and their applications. A quinone derivative on a monolayer was converted to an amine through spontaneous intramolecular cyclization following first-order reaction kinetics. An amine gradient on the surface on a scale of centimeters was realized by modulating the exposure time of the quinone-presenting monolayer to the chemical reagent. The resulting amine was used as a chemical handle to attach various molecules to the monolayer with formation of multicomponent gradient surfaces. The effectiveness of this strategy was verified by cyclic voltammetry (CV), matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS), MS imaging, and contact-angle measurements. As a practical application, cell adhesion was investigated on RGD/PHSRN peptide/peptide gradient surfaces. Peptide PHSRN was found to synergistically enhance cell adhesion at the position where these two ligands are presented in equal amounts, while these peptide ligands were competitively involved in cell adhesion at other positions. This strategy of generating a gradient may be further expandable to the development of functional gradient surfaces of various molecules and materials, such as DNA, proteins, growth factors, and nanoparticles, and could therefore be useful in many fields of research and practical applications.


Application of arteether-loaded polyurethane nanomicelles to induce immune response in breast cancer model.
To concentrate a potent anticancer drug (Arteether) in tumor microenvironment, we encapsulated it in biodegradable and pH sensitive polyurethane (PU) nanomicelles (NMs). The nanocomplex was characterized by Fourier transform infrared (FTIR), dynamic light scattering (DLS). The loading capacity and release profile in pH of 5.4 and 7.4 were considered. The cytotoxicity effect was evaluated in vitro and in vivo settings. The level of IFN-γ and IL-4 cytokines of mice splenocytes were assessed by enzyme-linked immunosorbent assay (ELISA). The nanocomplex showed negative zeta charge of -26.2 mV, size of 42.30 nm and high loading capacity (92%). Release profile showed a faster rate of drug liberation at pH 5.4 as compared to that of pH 7.4. It indicated significant inhibitory effect on the growth of 4T1 cell line and increased IFN-γ level.


Evaluation of a point-of-care anticoagulant rodenticide test for dogs.
To evaluate a point-of-care anticoagulant rodenticide lateral flow analyzer for the detection of various rodenticide compounds. Prospective, laboratory study. University teaching hospital. The study utilized a serum sample from one healthy canine donor. Samples were centrifuged and serum samples were aliquoted and either used within 4 hours or frozen at -70°C for further quantitative analysis. Samples were spiked with clinically relevant concentrations of 1 of 6 rodenticide compounds (warfarin, pindone, chlorphacinone, brodifacoum, bromethalin, and its metabolite desmethylbromethalin). Seventy-five microliters of spiked serum (or unaltered serum) was introduced into the lateral flow test. Three readers who were blinded to the sample preparation interpreted the lateral flow test as either positive or negative for the presence of anticoagulant rodenticide. All readers were in agreement for the results of each serum sample. The point-of-care test kit was able to detect a single anticoagulant rodenticide (warfarin) at concentrations below the manufacturer's recommended limit of detection, but was unable to detect any other anticoagulant rodenticide. The results of this test and therapeutic interventions must be considered in light of history, physical examination, and other clinical data. Based on results from this study, the test kit only detects warfarin and not other more common second-generation anticoagulant rodenticides.


Differences in initial stroke severity between Mexican Americans and non-Hispanic whites vary by age: the Brain Attack Surveillance in Corpus Christi (BASIC) project.
A wide variety of racial and ethnic disparities in stroke epidemiology and treatment have been reported. Race-ethnic differences in initial stroke severity may be one important determinant of differences in the outcome after stroke. The overall goal of this study was to move beyond ethnic comparisons in the mean or median severity, and instead investigate ethnic differences in the entire distribution of initial stroke severity. Additionally, we investigated whether age modifies the relationship between ethnicity and initial stroke severity as this may be an important determinant of racial differences in the outcome after stroke. Ischemic stroke cases were identified from the population-based Brain Attack Surveillance in Corpus Christi (BASIC) project. National Institutes of Health Stroke Scale (NIHSS) was determined from the medical record or abstracted from the chart. Ethnicity was reported as Mexican American (MA) or non-Hispanic white (NHW). Quantile regression was used to model the distribution of NIHSS score by age category (45-59, 60-74, 75+) to test whether ethnic differences exist over different quantiles of NIHSS (5 percentile increments). Crude models examined the interaction between age category and ethnicity; models were then adjusted for history of stroke/transient ischemic attack, hypertension, atrial fibrillation, coronary artery disease, and diabetes. RESULTS were adjusted for multiple comparisons. There were 4,366 ischemic strokes, with median age 72 (IQR: 61-81), 55% MA, and median NIHSS of 4 (IQR: 2-8). MAs were younger, more likely to have a history of hypertension and diabetes, but less likely to have atrial fibrillation compared to NHWs. In the crude model, the ethnicity-age interaction was not statistically significant. After adjustment, the ethnicity-age interaction became significant at the 85th and 95th percentiles of NIHSS distribution. MAs in the younger age category (45-59) were significantly less severe by 3 and 6 points on the initial NIHSS than NHWs, at the 85th and 95th percentiles, respectively. However, in the older age category (75+), there was a reversal of this pattern; MAs had more severe strokes than NHWs by about 2 points, though not reaching statistical significance. There was no overall ethnic difference in stroke severity by age in our crude model. However, several potentially important ethnic differences among individuals with the most severe strokes were seen in younger and older stroke patients that were not explained by traditional risk factors. Age should be considered in future studies when looking at the complex distributional relationship between ethnicity and stroke severity.


An Item Response Theory-Informed Strategy to Model Total Score Data from Composite Scales.
Composite scale data is widely used in many therapeutic areas and consists of several categorical questions/items that are usually summarized into a total score (TS). Such data is discrete and bounded by nature. The gold standard to analyse composite scale data is item response theory (IRT) models. However, IRT models require item-level data while sometimes only TS is available. This work investigates models for TS. When an IRT model exists, it can be used to derive the information as well as expected mean and variability of TS at any point, which can inform TS-analyses. We propose a new method: IRT-informed functions of expected values and standard deviation in TS-analyses. The most common models for TS-analyses are continuous variable (CV) models, while bounded integer (BI) models offer an alternative that respects scale boundaries and the nature of TS data. We investigate the method in CV and BI models on both simulated and real data. Both CV and BI models were improved in fit by IRT-informed disease progression, which allows modellers to precisely and accurately find the corresponding latent variable parameters, and IRT-informed SD, which allows deviations from homoscedasticity. The methodology provides a formal way to link IRT models and TS models, and to compare the relative information of different model types. Also, joint analyses of item-level data and TS data are made possible. Thus, IRT-informed functions can facilitate total score analysis and allow a quantitative analysis of relative merits of different analysis methods.


Nationwide survey on the use of horse antithymocyte globulins (ATGAM) in patients with acquired aplastic anemia: A report on behalf of the French Reference Center for Aplastic Anemia.
Antithymocyte globulins (ATG) plus cyclosporine (CSA) is the gold standard immunosuppressive treatment (IST) for patients with aplastic anemia. A prospective randomized trial showed in 2011 that hATG was superior to rabbit ATG for first-line treatment of severe AA. The French Health Agency (ANSM) permitted a patient-named authorization for temporary use (ATU) program of hATG (ATGAM, Pfizer) in patients with AA in 2011 since commercial access to hATG is not approved. We took advantage of this program to analyze the outcomes of 465 patients who received antithymocyte globulins (ATGAM) plus CSA as first line treatment (n = 379; 81.5%), or for refractory (n = 26) or relapsed disease (n = 33), from September 2011 to March 2017. In the entire cohort one year, 72% of the patients had partial and 13% had complete response, with worse response for patients with severe AA and a longer interval between diagnosis and IST (more than 6 months). Severe adverse events were mainly linked to infections (24%), hemorrhages (6%), and elevated liver function tests (5%). Overall at 12 months, 9.7% of patients required second line IST and 15.6% received transplantation. Fifty-five patients died during the study mainly because of infections (53%). Factors predicting independently worse survival were age over 40 years, neutrophils less than 0.5 × 109 /L, male gender and longer delay between diagnosis and hATG (>6 months period). This study does illustrate the results of ATGAM with CSA in a true-life perspective and confirms ATGAM as standard of care IST to treat patients with AA not eligible for HSCT.


Parity-related changes in bovine follicle and oocyte populations, oocyte quality, and hormones to 90 days postpartum.
Ultrasound-guided transvaginal follicular aspiration was used to obtain oocytes from Holstein cows to study follicular development and oocyte morphology during early lactation. A single aspiration was conducted on each of the 120 cows during wk 1 to 12 postpartum. On the day of aspiration, the number of follicles and their sizes were recorded. The collected oocytes were morphologically classified into four grades. Blood and follicular fluid samples were collected for hormone and metabolite assays. Greater serum nonesterified fatty acids concentrations for first- and second-parity cattle on d 7 implied a more negative energy balance status than for third-parity cattle. The numbers of follicles and oocytes retrieved were affected by linear days postpartum x parity interactions, with second-parity cattle having increases compared with decreases for third-parity cattle. Oocyte quality score was affected by the quadratic days postpartum x parity interaction. First- and second-parity cattle had greater oocyte quality scores from d 20 to 70 postpartum compared with third-parity cattle, but third-parity cattle had greater quality oocytes near the end of the 12-wk period. In contrast to cattle subjected to multiple aspirations, first- and second-parity cattle had higher estradiol and insulin-like growth factor I concentrations in follicular fluid associated with greater numbers of oocytes retrieved than third-parity cattle. This study demonstrated that conditions related to early lactation have a negative effect on oocyte quality and endocrine measures of dairy cattle and that animals of various parities may be differentially affected.


Inter-fraction variations in respiratory motion models.
Respiratory motion can vary dramatically between the planning stage and the different fractions of radiotherapy treatment. Motion predictions used when constructing the radiotherapy plan may be unsuitable for later fractions of treatment. This paper presents a methodology for constructing patient-specific respiratory motion models and uses these models to evaluate and analyse the inter-fraction variations in the respiratory motion. The internal respiratory motion is determined from the deformable registration of Cine CT data and related to a respiratory surrogate signal derived from 3D skin surface data. Three different models for relating the internal motion to the surrogate signal have been investigated in this work. Data were acquired from six lung cancer patients. Two full datasets were acquired for each patient, one before the course of radiotherapy treatment and one at the end (approximately 6 weeks later). Separate models were built for each dataset. All models could accurately predict the respiratory motion in the same dataset, but had large errors when predicting the motion in the other dataset. Analysis of the inter-fraction variations revealed that most variations were spatially varying base-line shifts, but changes to the anatomy and the motion trajectories were also observed.


Infarct-kidney hypertension in the rat mutant nude.
Infarct-kidney hypertension was induced in congenital athymic nude rats, and in their immunologically normal haired littermates. In both groups a significant initial increase in blood pressure was seen in the course of the first 30 days. In the remainder of the observation period of 120 days the mean blood pressure in the nude rats decreased to a significantly lower level where-as in the haired rats the mean blood pressure remained unchanged at the high level. Although a high mortality weakened the results, it is hypothesized that the failing ability to maintain the elevated blood pressure into the late phase in the nude rats could be due to impaired thymus function. Nine of 14 haired rats had increased numbers of lymphocytes around intrarenal arteries, in contrast to only 1 of 10 nude rats. A periarteritis nodosa like picture was observed around mesenterial arteries of 3 nude and 2 haired rats. The level of plasma renin was similar preoperatively in nude and haired rats. Infarction of the kidney was followed by a significant decrease in the plasma renin level in both nude and haired rats, which at 10 days was significantly lower in haired than in nude rats, despite a higher blood pressure in the latter.


Concentrated-acid triggered superfast generation of porous amorphous cobalt oxide toward efficient water oxidation catalysis in alkaline solution.
Amorphous transition-metal (hydr)oxides have proven to be the most promising oxygen evolution reaction (OER) electrocatalysts. Here, a facile and novel strategy for the generation of porous amorphous cobalt oxide through one-step treatment of the cobalt carbonate hydroxide precursor with concentrated sulfuric acid has been reported. Benefiting from the optimized amorphous structure, the prepared catalyst exhibits an excellent water-oxidation activity in an alkaline electrolyte with the demand of 50 mV less overpotential at 10 mA cm-2 compared to that of highly-crystallized Co3O4. Compared with the 400 °C annealing process for Co3O4, the ultrafast acid treatment process within 10 seconds at room-temperature for achieving such amorphous cobalt oxide demonstrates tremendous convenience. More impressively, after continuous testing for 60 h at an overpotential of 370 mV, it still maintains a porous configuration as well as ∼92% of the original current density. Our findings not only present a high-efficiency OER electrocatalyst, but also provide a methodology with broad applicability toward the systematic study of other non-crystal oxides for green energy applications.


Finding motifs using random projections.
The DNA motif discovery problem abstracts the task of discovering short, conserved sites in genomic DNA. Pevzner and Sze recently described a precise combinatorial formulation of motif discovery that motivates the following algorithmic challenge: find twenty planted occurrences of a motif of length fifteen in roughly twelve kilobases of genomic sequence, where each occurrence of the motif differs from its consensus in four randomly chosen positions. Such "subtle" motifs, though statistically highly significant, expose a weakness in existing motif-finding algorithms, which typically fail to discover them. Pevzner and Sze introduced new algorithms to solve their (15,4)-motif challenge, but these methods do not scale efficiently to more difficult problems in the same family, such as the (14,4)-, (16,5)-, and (18,6)-motif problems. We introduce a novel motif-discovery algorithm, PROJECTION, designed to enhance the performance of existing motif finders using random projections of the input's substrings. Experiments on synthetic data demonstrate that PROJECTION remedies the weakness observed in existing algorithms, typically solving the difficult (14,4)-, (16,5)-, and (18,6)-motif problems. Our algorithm is robust to nonuniform background sequence distributions and scales to larger amounts of sequence than that specified in the original challenge. A probabilistic estimate suggests that related motif-finding problems that PROJECTION fails to solve are in all likelihood inherently intractable. We also test the performance of our algorithm on realistic biological examples, including transcription factor binding sites in eukaryotes and ribosome binding sites in prokaryotes.


Impact of dissociation and interpersonal functioning on inpatient treatment for early sexually abused adults.
Little is known about the possible predictors of treatment outcome in early chronically sexually abused adults. The current study aimed to investigate what impact initial levels of dissociation and pre-treatment negative change in interpersonal functioning have on treatment response after 3 months of first-phase trauma inpatient treatment as well as after a period of 1 year the patients returned to their usual lives. The sample comprised 48 inpatients with childhood sexual abuse histories and mixed trauma-related disorders who were examined at discharge and prospectively followed up for a period of 1 year under naturalistic conditions. Outcome variables were general psychiatric symptoms and interpersonal problems as measured with the Symptom Check List-Revised (SCL-R) and the Inventory of Interpersonal Problems (IIP) Circumplex. The central findings were that pathological dissociation and deterioration in interpersonal functioning prior to admittance predicted general psychiatric symptom levels and interpersonal problems at the end of treatment and at 1-year follow-up. Pathological dissociation, involving memory and identity problems, alone predicted negative outcome at the end of treatment. The findings at 1-year follow-up indicate that it is not pathological dissociation in isolation that affects outcomes, but rather the interaction between dissociation and change in interpersonal functioning prior to treatment. These findings indicate the need of addressing dissociation and interpersonal problems in treatment planning and favor an integrated treatment approach for complex trauma patients. Future research should investigate whether and how this leads to better outcome, including long-term maintenance of gains after the end of treatment.


How to Choose between the Implant Materials Steel and Titanium in Orthopedic Trauma Surgery: Part 1 - Mechanical Aspects.
When choosing between metal implants of different materials the surgeon mainly needs to balance the pros and cons of steel and titanium. Economic constraints often do not permit both to be kept in stock and it is necessary to decide beforehand which to choose. The arguments for the use of the "preferred metal" vary. The present paper elucidates the practical aspects based on the complex scientific background that has identified the differences between the two metals in their mechanical, electrochemical, biological and application behavior. The data presented here are intended to help the surgeon when he is confronted with different and often complex clinical situations and problems. The following is an overview of different aspects to help with selection of the proper material for the clinical application. The first part concerns mechanical aspects the second part the biological aspects. Both aspects are discussed with the practical application in mind. Nonmetallic implant materials have seen an increasing interest in the recent past. Plastic materials needed improvement to achieve good strength and avoid creep with loss of e.g. compression and minimizing leakage of chemicals.


Rejection sensitivity as a mediator of the impact of childhood exposure to family violence on adult attachment behavior.
Substantial evidence indicates a link between exposure to family violence in childhood and troubled social relationships. We draw on attachment and social-cognitive theory to formulate a model of the mechanisms underlying this association. The model proposes that early experiences of overt rejection (e.g., physical maltreatment) or covert rejection (e.g., emotional neglect) are internalized as sensitivity to rejection. In this study, we operationalize sensitivity to rejection in social-cognitive terms as a tendency to expect and be concerned about rejection across a range of social situations. We hypothesize that rejection sensitivity mediates the link between exposure to family violence and adult attachment behavior. Data from a survey of 212 undergraduates support this hypothesis and also provide evidence that indicates sensitivity to rejection underlies both avoidant and ambivalent patterns of insecure adult attachment behavior. Overall, the results illustrate the power of a process approach to explaining the developmental sequelae of maltreatment.


Metabolic activation of 2,6-xylidine in the nasal olfactory mucosa and the mucosa of the upper alimentary and respiratory tracts in rats.
Whole-body low-temperature radioluminography of (3)H-2,6-xylidine in rats indicates that the nonmetabolized substance, which is a volatile and fat-soluble compound, is distributed throughout the body and accumulates in adipose tissues, e.g., in the abdominal and subcutaneous regions. Whole-body autoradiography with freeze-dried or solvent-extracted tissue sections as well as microautoradiography, which were used to trace tissues in the rats accumulating 2,6-xylidine metabolites, showed presence of tissue-bound 2,6-xylidine metabolites in the nasal olfactory mucosa and the mucosa of the upper alimentary and respiratory tracts. These tissues were found to have an in vitro capacity to bioactivate 2,6-xylidine. Our data indicate that 2,6-xylidine in vivo undergoes an in situ bioactivation in these extrahepatic tissues. Our results showed that the nasal olfactory mucosa had a much higher capacity than the other examined tissues to bioactivate 2,6-xylidine. Thus, the carcinogenic effect of 2,6-xylidine toward the nasal mucosa in rats is correlated with a high capacity of this tissue to bioactivate the compound.


Effect of dietary lipids on saliva composition.
The effects of feeding two different dietary fats on saliva composition were studied in monkeys. Two groups of adult monkeys (M. fascicularis) were fed diets containing 10% corn oil (CO) or 10% hydrogenated coconut oil (HCO). Pilocarpine-stimulated parotid and submandibular saliva samples were obtained at 0, 17, 26 and 29 weeks. These, along with blood plasma, were extracted for lipids, and the fatty acid composition of total lipids was determined by gas chromatography. The levels of linoleic acid in saliva were significantly lower in monkeys fed a diet containing HCO as compared to the other group. Total protein and alpha-amylase activity of saliva showed no difference between the two groups. The results show that nature of the dietary fats can affect the fatty acid composition of parotid and submandibular saliva.


Regenerative Electrode Interfaces for Neural Prostheses.
Neural prostheses are electrode arrays implanted in the nervous system that record or stimulate electrical activity in neurons. Rapid growth in the use of neural prostheses in research and clinical applications has occurred in recent years, but instability and poor patency in the tissue-electrode interface undermines the longevity and performance of these devices. The application of tissue engineering strategies to the device interface is a promising approach to improve connectivity and communication between implanted electrodes and local neurons, and several research groups have developed new and innovative modifications to neural prostheses with the goal of seamless device-tissue integration. These approaches can be broadly categorized based on the strategy used to maintain and regenerate neurons at the device interface: (1) redesign of the prosthesis architecture to include finer-scale geometries and/or provide topographical cues to guide regenerating neural outgrowth, (2) incorporation of material coatings and bioactive molecules on the prosthesis to improve neuronal growth, viability, and adhesion, and (3) inclusion of cellular grafts to replenish the local neuron population or provide a target site for reinnervation (biohybrid devices). In addition to stabilizing the contact between neurons and electrodes, the potential to selectively interface specific subpopulations of neurons with individual electrode sites is a key advantage of regenerative interfaces. In this study, we review the development of regenerative interfaces for applications in both the peripheral and central nervous system. Current and future development of regenerative interfaces has the potential to improve the stability and selectivity of neural prostheses, improving the patency and resolution of information transfer between neurons and implanted electrodes.


Influence of increment of gantry angle and number of arcs on esophageal volumetric modulated arc therapy planning in Monaco planning system: A planning study.
The objective of this study was to analyze the influence of the increment of gantry angle and the number of arcs on esophageal volumetric modulated arc therapy plan. All plans were done in Monaco planning system for Elekta Synergy linear accelerator with 80 multileaf collimator (MLC). Volumetric modulated arc therapy (VMAT) plans were done with different increment of gantry angle like 15°, 20°, 30° and 40°. The remaining parameters were similar for all the plans. The results were compared. To compare the plan quality with number of arcs, VMAT plans were done with single and dual arc with increment of gantry angle of 20°. The dose to gross tumor volume (GTV) for 60 Gy and planning target volume (PTV) for 48 Gy was compared. The dosimetric parameters D98%, D95%, D50% and Dmax of GTV were analyzed. The homogeneity index (HI) and conformity index (CI) of GTV were studied and the dose to 98% and 95% of PTV was analyzed. Maximum dose to spinal cord and planning risk volume of cord (PRV cord) was compared. The Volume of lung receiving 10 Gy, 20 Gy and mean dose was analyzed. The volume of heart receiving 30 Gy and 45 Gy was compared. The volume of normal tissue receiving greater than 2 Gy and 5 Gy was compared. The number of monitor units (MU) required to deliver the plans were compared. The plan with larger increment of gantry angle proved to be superior to smaller increment of gantry angle plans in terms of dose coverage, HI, CI and normal tissue sparing. The number of arcs did not make any difference in the quality of the plan.


Fetal growth: a comparison of growth curves with mathematical modeling.
This study compared the use of fetal growth curves with the Rossavik mathematical model in predicting third trimester fetal growth in 27 Hispanic patients. The parameters tested were BPD, HC, AC, and FL. The growth curve method of predicting third trimester fetal growth was significantly more accurate than the mathematical model for three of the four fetal parameters tested: BPD, HC, and FL. We conclude that the mathematical model method offered no advantage over the more commonly used growth curve method for predicting third trimester fetal growth. In addition, growth curves do not require complex calculations and are conceptually simpler and easier to use.


Anemone rivularis inhibits pyruvate dehydrogenase kinase activity and tumor growth.
Anemone rivularis Buch.-Ham. ex DC. (Ranunculaceae) have been used as a traditional remedy for treatment of inflammation and cancer. However, there is no report demonstrating experimental evidence on anti-tumor action of A. rivularis. The Warburg's effect, preference of aerobic glycolysis rather than oxidative phosphorylation (OXPHOS) even in oxygen rich condition, is focused as one of major characteristics of malignant tumor. Thus, we investigated the effect of A. rivularis on the Pyruvate dehydrogenase (PDH) kinases (PDHKs), a major molecular targets for reducing aerobic glycolysis. The ethanol extract of whole plant of A. rivularis (ARE), fingerprinted by high performance liquid chromatography (HPLC), was applied to in vitro and cell-based PDHK activity assays. The effect of ARE on cell viabilities of several tumor cells was estimated by MTT assay. The expression of phosphor-PDH, PDH and PDHK1 were measured by Western blot analysis. The production of reactive oxygen species (ROS) and apoptosis was measured by fluorescence-activated cell sorting analysis, using 5-(and-6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate (carboxy-H2DCFDA) and Annexin V/propidium iodide (PI) staining, respectively. Mitochondrial membrane potential was examined by tetramethylrhodamine methyl ester (TMRM) staining. In vivo anti-tumor efficacy of ARE was estimated by means of tumor volume and weight using allograft injection of murine Lewis lung carcinoma (LLC) cells to dorsa of C57BL/6 mice. ARE inhibited the viabilities of several cancer cells, including MDA-MB321, K562, HT29, Hep3B, DLD-1, and LLC. ARE suppressed PDHK activity in in vitro kinase assay, and also inhibited aerobic glycolysis by reducing phosphorylation of PDHA in human DLD-1 colon cancer and murine LLC cells. The expression of PDHK1, a major isoform of PDHKs in cancer, was not affected by ARE treatment. Moreover, ARE increased the both ROS production and mitochondrial damage. In addition, ARE suppressed the in vitro tumor growth through mitochondria-mediated apoptosis. The growth rates of allograft LLC cells were also reduced by ARE treatment. Here, we firstly report that ARE inhibits PDHK activity and growth of tumor in both in vitro and in vivo experiments. Therefore, we suggest ARE as a potential candidate for developing anti-cancer drugs.


The test-retest reliability of the Peyronie's disease questionnaire.
The Peyronie's Disease Questionnaire (PDQ) is a disease-specific, patient-reported outcome instrument designed to measure the psychosexual consequences and treatment outcomes of Peyronie's disease (PD). The aim of this study was to evaluate the test-retest reliability of the PDQ. Adult men with PD were recruited through eight clinical sites across the United States. Participants completed the PDQ during two study visits scheduled 7 (± 3) days apart. At Visit 1, participants completed a sociodemographic questionnaire, the PDQ, and the International Index of Erectile Function (IIEF). At Visit 2, participants repeated the PDQ and completed an Overall Treatment Effect (OTE) scale. Test-retest reliability of the PDQ was assessed in a stable subsample (as determined by responses to the OTE). Intraclass correlation coefficients (ICCs) were calculated to evaluate the degree of association between the three PDQ subscale scores at Visits 1 and 2. Internal consistency of the subscales was also evaluated using Cronbach's alpha. The main outcome measure was the PDQ. Of the 61 PD patients (mean age 59.3) who took part in the study, the majority were not receiving treatment for their PD (n=35, 57.4%). The sample's mean score on the erectile function domain of IIEF was 19.7 (± 8.2), indicating mild-moderate dysfunction. Nearly two-thirds reported penile pain at baseline (n=37, 63.8%). Of the participants with baseline PDQ data and who had engaged in vaginal intercourse in the past 3 months, 57 completed both study visits. The PDQ demonstrated excellent test-retest reliability in 53 stable patients. The ICC was 0.85 for the Psychological and Physical Symptom subscale, 0.89 for the Peyronie's Symptom Bother subscale, and 0.88 for the Penile Pain subscale. The Cronbach's alpha estimates for all three subscales were acceptable at the >0.70 level. The PDQ is a highly reproducible measure of PD and can be an effective end point in clinical trials evaluating treatments for PD.


Behavioral and Ovipositional Response of Diaeretiella rapae (Hymenoptera: Braconidae) to Rhopalosiphum padi and Brevicoryne brassicae in Winter Wheat and Winter Canola.
Winter canola Brassica napus L. (Brassicales: Brassicaceae) was introduced to U.S. Southern Great Plains (Kansas, Oklahoma, Texas) growers to manage some difficult-to-control grassy weeds in winter wheat Triticum aestivum L. (Poales: Poaceae). Two braconid parasitoids, Diaeretiella rapae (M'Intosh) and Lysiphlebus testaceipes (Cresson) (Hymenoptera: Braconidae) are active in this cropping landscape. Both wasps move between crops but D. rapae has a limited ability to develop in the main wheat aphid hosts, so L. testaceipes could influence D. rapae's ability to maintain itself when canola is absent in the landscape. We compared behavioral responses of naturally emerged D. rapae and wasps that were excised before emergence to odor volatiles of host plant, aphid host and aphid-infested plants using two plant/aphid combinations (wheat/Rhopalosiphum padi (L.) and canola/Brevocoryne brassicae L. (Hemiptera: Aphididae). We also compared parasitism rates of D. rapae that were naturally emerged and excised from R. padi or B. brassicae on subsequent parasitism rates of R. padi or B. brassicae hosts. Naturally emerged wasps responded more strongly to host plant and host plant + aphid odors compared to excised wasps regardless of the host origin. Neither wasp group responded to odors from aphids alone. Both wasp groups were most attracted to odors from aphid-infested host plants, regardless of the combination. D. rapae parasitism rates on canola-reared aphids were higher than on wheat-reared aphids. D. rapae parasitism rates were lower when switched from its original host to the alternate host. Results suggest that D. rapae faces challenges to maintain significant populations in the wheat/canola landscape of the Southern Great Plains, especially in years when canola is not locally present.


Richness and density of aquatic benthic macroinvertebrates after exposure to fungicides and insecticides in rice paddy fields.
The objective of this study was to verify the richness and density of aquatic benthic macroinvertebrates after exposure to fungicides and insecticides of the rice paddy fields. In the crop seasons of 2012/13 and 2013/14, field experiments were performed, which consisted of single-dose applications of the fungicides trifloxystrobin + tebuconazole and tricyclazole, and the insecticides lambda-cyhalothrin + thiamethoxam and diflubenzuron, in 10 m2 experimental plots, over rice plants in the R3 stage. Control plots with and without rice plants were maintained in order to simulate a natural environment. Soil samples were collected during rice cultivation for assessment of the macroinvertebrate fauna. Chemical-physical parameters assessed in the experiments included temperature, pH and oxygen dissolved in the water and pesticide persistence in the water and in the soil. The application of a single dose of the pesticides and fungicides in the recommended period does not cause significant negative effects over the richness and density of the macroinvertebrates. Tebuconazole, tricyclazole and thiamethoxam showed high persistence in the irrigation water of rice paddy fields. Thus, the doses and number of applications of these products in crops should be carefully handled in order to avoid contamination of the environment.


Mesencephalic lesions followed by normophagia but decreased body weight.
Twenty mature male Sprague-Dawley rats were lesioned in the area of the ascending ventral noradrenergic bundle in the mesencephalon. Nine sham-operated animals served as controls. Food intake between the lesioned and nonlesioned groups was not significantly different except for the first day post surgery. However, body weight of the lesioned group was significantly below that of the controls when measured 15 days after the operation. The lesioned animals weighed significantly less than the controls throughout the rest of the experiment. They also were hypoactive when compared to the sham-operated rats. Control rats and lesioned rats did not differ significantly in deep rectal temperature. It is suggested that the significant decrease in body weight of the lesioned rats in the presence of normophagia may be caused by alterations in the animal's metabolism.


Automatic assessment of stent neointimal coverage by intravascular optical coherence tomography.
This study aimed to validate automatic intravascular optical coherence tomography (IVOCT) analysis for the evaluation of neointimal coverage in response to stent implantation. Fourteen stented segments in common iliac arteries, acquired from a total of seven adult male New Zealand White rabbits, were interrogated in vivo by IVOCT. Durable polymer everolimus-eluting stents (EES; Xience V, Abbott Vascular, Santa Clara, CA, USA) were used exclusively. Comparison with histology was made in a total of 63 pairs of images, where neointimal thickness over corresponding individual stent struts was assessed. A high correlation coefficient (R = 0.85, P < 0.001) was obtained by comparing automatic IVOCT analysis with histology. Moreover, Bland-Altman statistics showed good limits of agreement (LOAs) of ±45 µm, with an average difference of -10 µm. In addition, manual IVOCT assessment presented very similar results when compared with histology (R = 0.83, P < 0.001 and LOA = ±48 µm with an average difference of -8 µm). Therefore, a very high correlation value was found, comparing manual to automatic IVOCT measurements (R = 0.95, P < 0.001) together with good LOAs (±27 µm) and an average difference of -2 µm. The results of the study suggest that automatic IVOCT analysis is a reliable and accurate tool able to speed up current IVOCT analysis procedures. This would potentially allow for a better integration of IVOCT in clinical practice and clinical studies assessing vascular response to stent implantation in a large series of patients.


In Vitro Models for Neurogenesis.
The process of generating new neurons of different phenotype and function from undifferentiated stem and progenitor cells starts at very early stages of development and continues in discrete regions of the mammalian nervous system throughout life. Understanding mechanisms underlying neuronal cell development, biology, function, and interaction with other cells, especially in the neurogenic niche of fully developed adults, is important in defining and developing new therapeutic regimes in regenerative neuroscience. Studying these complex and dynamic processes in vivo is challenging because of the complexity of the nervous system and the presence of many known and unknown confounding variables. However, the challenges could be overcome with simple and robust in vitro models that more or less recapitulate the in vivo events. In this work, we will present an overview of present available in vitro cell-based models of neurogenesis.


Excision and Reimplantation of the Proximal Humerus After Fracture-Dislocation.
Fractures of the proximal humerus are common and the treatment for both displaced and comminuted variants remains controversial. Treatment options initially consisted of closed reduction, traction, casting, and abduction splints. In the early 1930s, operative treatment for displaced fractures gained popularity, which continued in the 1940s and 1950s. Humeral head replacement for severely displaced fractures of the proximal humerus was introduced in the 1950s. In the 1970s, the Association for Osteosynthesis/Association for the Study of Internal Fixation popularized plates and screws for fracture fixation, and humeral head prostheses were redesigned. The traditional management of severely displaced proximal humerus fractures has been with arthroplasty because of the significant risk of osteonecrosis of the humeral head following open reduction and internal fixation. The authors present a case of a 51-year-old right-hand-dominant man who sustained a seizure along with a posteriorly displaced proximal humerus fracture-dislocation of the right upper extremity. This was treated with surgical extrusion of the entire humeral head and subsequent open reduction and internal fixation. During the surgical procedure, the patient's humeral head was completely extruded from the body through a posterior incision and then reduced back to the proximal humerus through the standard anterior deltopectoral approach. After 4 years of follow-up, the patient remains pain free, has functional range of motion, and is without signs of osteonecrosis on plain radiographs. This case illustrates that even with complete disruption of the vascular supply to the humeral head, revascularization after osteosynthesis is possible. [Orthopedics. 2016; 39(4):e779-e782.].


Inclusion of Lesbian, Gay, Bisexual, Transgender, Queer, and Intersex Health in Australian and New Zealand Medical Education.
This study aims at establishing the scope of lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI) health in Australian and New Zealand medical curricula. We sent medical school curriculum administrators an online cross-sectional survey. The response rate was 15 medical schools (71%): 14 Australian schools and 1 New Zealand school. Respondents included program directors (n = 5; 33%), course coordinators (n = 4; 27%), Heads of School (n = 2; 13%), one Dean (7%), and three others (20%). Most schools (n = 9; 60%) reported 0-5 hours dedicated to teaching LGBTQI content during the required pre-clinical phase; nine schools (60%) reported access to a clinical rotation site where LGBTQI patient care is common. In most schools (n = 9; 60%), LGBTQI-specific content is interspersed throughout the curriculum, but five schools (33%) have dedicated modules. The most commonly used teaching modalities include lectures (n = 12; 80%) and small-group sessions (n = 9; 60%). LGBTQI content covered in curricula is varied, with the most common topics being how to obtain information about same-sex sexual activity (80%) and the difference between sexual behavior and identity (67%). Teaching about gender and gender identity is more varied across schools, with seven respondents (47%) unsure about what is taught. Eight respondents (53%) described the coverage of LGBTQI content at their institution as "fair," two (13%) as "good," and two (13%) as "poor," with one respondent (7%) describing the coverage as "very poor." None of the respondents described the coverage as "very good." Currently, medical schools include limited content on LGBTQI health, most of which focuses on sexuality. There is a need for further inclusion of curriculum related to transgender, gender diverse, and intersex people.


Fungal endophytes attune withanolide biosynthesis in Withania somnifera, prime to enhanced withanolide A content in leaves and roots.
Endophytes have been reported from all plant species from different parts of tissue including root, stem and leaves. Here we report, three fungal endophytes, Aspergillus terreus strain 2aWF (2aWF), Penicillium oxalicum strain 5aWF (5aWF), and Sarocladium kiliense strain 10aWF (10aWF) from Withania somnifera, which could enhance withanolides content in leaf and root. Upon treatment with the above endophytes to 4 weeks old plants in field conditions, W. somnifera elicited withanolide A content (97 to 100%) in leaves without considerable changes in withaferin A content. Furthermore, withanolide A content in roots of 5aWF and 10aWF endophyte treated W. somnifera plants increased up to 52% and 65% respectively. Incidentally, expression profile of withanolide and sterol biosynthetic pathway genes HMGR, DXR, FPPS, SQS, SQE, CAS, SMT1, STE1 and CYP710A1 were significantly upregulated in 2aWF, 5aWF and 10aWF fungal endophyte treated plants. Besides, modulation of withanolide biosynthetic pathway genes, fungal endophytes also induce a host resistant related gene, NPR1 resulting in 2, 4 and 16 fold expression levels in 2aWF, 10aWF and 5aWF endophyte treatments respectively, compared to control plants. Overall, our results illustrate that application of native-fungal endophytes 2aWF (96.60%), 5aWF (95%) and 10aWF (147%) enhances plant biomass in addition to withanolide content.


Validation of daily microincrement deposition in otoliths of juvenile and adult Peruvian anchovy Engraulis ringens.
Wild adult specimens of the Peruvian anchovy Engraulis ringens were captured and reared to validate the daily periodicity of otolith microincrement formation. The postcapture stress generated spontaneous spawning, making it possible to conduct a rearing trial on larvae first in an artificial nutrient-enriched system (ANES) for 52 days followed by an artificial feeding regime in a culture tank until day 115 post-hatch. Microincrements of the sagittal otoliths of sacrificed juveniles [mean ± S.D. total length (LT ) = 5·13 ± 0·37 cm, range 5-6 cm; c.v. = 7·5%] showed very distinct light and dark zones. The slope of the relationship between the total number of increments after the hatch check and days elapsed after hatching was not significantly different from 1. The transfer from ANES to the artificial feeding regime induced a mark in the sagittal otoliths. The number of microincrements after this induced mark coincided with the number of days elapsed after the transfer date. In parallel experiments, adult E. ringens (mean ± S.D. LT = 14·92 ± 0·55 cm, range 13-16 cm) were exposed to one of two fluorescent marking immersion treatments with either alizarin red S (ARS; 25 mg l(-1) per 6 h) or oxytetracycline hydrochloride (OTC; 200 mg l(-1) per 10 h). The microincrements between fluorescent bands were distinct, ranging from 0·89 to 2·75 µm (mean ± S.D. =1·43 ± 0·28 µm; c.v. = 32%) and from 0·71 to 2·89 µm (1·53 ± 0·27 µm; c.v. = 35%) for ARS and OTC, respectively. The relationship between the number of microincrements between marks and the number of elapsed days for ARS and OCT treatments indicated that there was a significant correspondence between the number of increases observed and the number of days. Hence, daily microincrements of otoliths of E. ringens are likely to be formed in juveniles and adults under natural conditions.


Frequency of Borrelia in Morphea Lesion by Polymerase Chain Reaction in Northeast of Iran.
The etiology of morphea is still unknown. Borrelia spp. as a causative agent of morphea has been discussed since 1985, but the relationship remains uncertain. We aimed to find the frequency of Borrelia in morphea lesions by polymerase chain reaction (PCR) in northeast of Iran. Sixty six patients with morphea were prospectively included in the present study. For each patient, formalin-fixed, paraffin-embedded tissue blocks of skin lesion biopsies were examined for Borrelia spp. DNA using PCR. No Borrelia DNA was detected by PCR in skin lesions of patients with morphea. The result of this study showed no relationship between Borrelia infection and morphea lesions and in other word indicated that morphea, at least in Iran, is not caused by Borrelia spp.


The Role of Wrist Fusion and Wrist Arthroplasty in Rheumatoid Arthritis.
Rheumatoid arthritis is the most common form of inflammatory arthritis with a predilection for the hand and wrist. The aggressive nature of the disease can lead to severe joint destruction causing significant disability. Surgical options for pan-carpal arthritis include total wrist arthroplasty and total wrist fusion both with varying outcomes, yet both have a role in the carefully selected patients. Fusion remains a popular procedure with consistent reliable results with few complications. We present a review of current evidence, indications and guidance for both fusion and arthroplasty in rheumatoid arthritis.


Can we measure out a life in coffee spoons?
Public policy decisions in medicine and other fields necessitate careful weighing of choices and consequences. Cost-benefit analyses have been offered as one way to facilitate such decisions. In "Quantifying the value of human life," L. Eugene Arnold asserts that mathematical models such as his offer greater clarity in making public policy decisions than is possible with the "intuitive" or "emotional" approach. In our opinion, problems associated with this quantitative analysis demonstrate a need for caution in applying such mathematical models to public policy decisions....


Bioinspired Tannic Acid-Modified Coffee Grounds as Sustainable Fillers: Effect on the Properties of Polybutylene Adipate Terephthalate Composites.
Preparing composites from gricultural waste with biodegradable polymers is one of the strategies used to ensure the long-term sustainability of such materials. However, due to the differences in their chemical properties, biomass fillers often exhibit poor interfacial adhesion with polymer matrices. Inspired by mussel foot silk, this work focused on the surface modification of coffee grounds (CGs) using a combination of tannic acid (TA) and alkali treatment. CGs were used as a biomass filler to prepare polybutylene adipate terephthalate (PBAT)/CG composites. The modification of CGs was demonstrated by Fourier transform infrared spectroscopy (FTIR), the water contact angle, and scanning electron microscopy (SEM). The effect of CGs on the rheological, tensile, and thermal properties of the PBAT/CG composites was investigated. The results showed that the addition of CGs increased the complex viscosity, and the surface modification enhanced the matrix-filler adhesion. Compared with unmodified CG composites, the tensile strength and the elongation at break of the composite with TA-modified alkali-treated CGs increased by 47.0% and 53.6%, respectively. Although the addition of CGs slightly decreased the thermal stability of PBAT composites, this did not affect the melting processing of PBAT, which often occurs under 200 °C. This approach could provide a novel method for effectively using biomass waste, such as coffee grounds, as fillers for the preparation of polymer composites.


Selection of noise level in strategy adoption for spatial social dilemmas.
We studied spatial Prisoner's Dilemma and Stag Hunt games where both the strategy distribution and the players' individual noise level could evolve to reach higher individual payoff. Players are located on the sites of different two-dimensional lattices and gain their payoff from games with their neighbors by choosing unconditional cooperation or defection. The way of strategy adoption can be characterized by a single K (temperaturelike) parameter describing how strongly adoptions depend on the payoff difference. If we start the system from a random strategy distribution with many different player specific K parameters, the simultaneous evolution of strategies and K parameters drives the system to a final stationary state where only one K value remains. In the coexistence phase of cooperator and defector strategies the surviving K parameter is in good agreement with the noise level that ensures the highest cooperation level if uniform K is supposed for all players. In this paper we give a thorough overview about the properties of this evolutionary process.


Midazolam combined with paracervical blockade compared to general anaesthesia for curettage of the uterus.
Two anaesthetic techniques were compared in a randomized trial of 60 ASA I and II women admitted for diagnostic dilatation and curettage of the uterus. Group I had fentanyl 2.5 micrograms/kg and thiopentone 2 mg/kg i.v. Supplementary thiopentone 50 mg was given every 15 s until loss of the eyelid reflex. Anaesthesia was maintained with nitrous oxide in oxygen 2/1 together with supplementary thiopentone 50 mg as required. Group II had midazolam 0.1 mg/kg i.v. and a supplementary 0.025 mg/kg every second min until sleep or dysarthria, followed by paracervical blockade with 1% mepivacaine 10 ml on each side of the portio. There was no significant depression of the cardiovascular system. The working conditions for the gynaecologist were good in both groups. The midazolam technique gave just as good amnesia as did general anaesthesia, and there was a high degree of patient satisfaction in both groups. In the thiopentone group there was a significant depression of the respiratory rate and a significantly higher frequency of adverse effects (nausea and vomiting) as compared to the midazolam group. It is concluded that paracervical blockade combined with midazolam, titrated i.v., until sleep or dysarthria, is a recommendable anaesthetic technique for diagnostic dilatation and curettage.


The relationship of pro-inflammatory markers to vascular endothelial function after acute stroke.
Purpose/Aim: Data from chronic stroke studies have reported reduced blood flow and vascular endothelial function in the stroke-affected limb. It is unclear whether these differences are present early after stroke. First, we investigated whether vascular endothelial function in the stroke-affected limb would be different from healthy adults. Second, we examined whether between-limb differences in vascular endothelial function existed in the stroke-affected arm compared to the non-affected arm. Last, we tested whether reduced vascular endothelial function was related to pro-inflammatory markers that are present early after stroke. Vascular endothelial function was assessed by flow-mediated dilation (FMD) in the brachial artery within 72 h post-stroke. All participants withheld medications from midnight until after the procedure. Ultrasound scans and blood draws for pro-inflammatory markers occurred on the same day between 7:30 am and 9:00 am. People with acute stroke had significantly lower FMD (4.2% ± 4.6%) than control participants (8.5% ± 5.2%, p = 0.037). Stroke participants had between-limb differences in FMD (4.2% ± 4.6% stroke-affected vs. 5.3% ± 4.4% non-affected, p = 0.02), whereas, the control participants did not. Of the pro-inflammatory markers, only vascular cell adhesion molecule-1(VCAM-1) had a significant relationship to FMD (stroke-affected limb, r = -0.62, p = 0.03; non-affected limb, r = -0.75, p = 0.005), but not tumor necrosis factor alpha nor interleukin-6. Vascular endothelial function is reduced starting in the early stage of stroke recovery. People with higher levels of VCAM-1 had a lower FMD response.


Clinical and histological predictors of response to medical therapy in collagenous colitis.
Collagenous colitis (CC) is an uncommon form of inflammatory bowel disease. The response to typical medical therapies (antimotility agents, 5-aminosalicylic acid [5-ASA], and corticosteroids) is variable. We aimed to determine if there are clinical or histological variables that can predict response to medical therapy. All cases of CC were identified in three tertiary care medical centers. All charts of included patients were reviewed and clinical variables (age, gender, duration of symptoms, frequency of bowel movements, and the use of nonsteroidal anti-inflammatory drugs [NSAIDs]) were recorded. Available histology slides were reviewed by one GI pathologist. Intraepithelial inflammation, epithelial loss or detachment, inflammation in the lamina propria, presence of eosinophilia, crypt inflammation, Paneth's cell metaplasia, and collagen layer thickness were recorded. Depending on their response to therapy, patients were divided into three groups: 1) spontaneous recovery or response to antidiarrheal agents alone, 2) response to 5-ASA agents, and 3) response to corticosteroids after failure of antidiarrheal agents and 5-ASA. Ninety-four patients with CC were identified. Of these, 62 patients were included. The median age was 58 (range = 20-85), and 88% were female. Among the histological parameters only the degree of inflammation in the lamina propria significantly differed between the three response groups (p = 0.007). Patients who required corticosteroids had greater inflammation. Among the clinical parameters age at presentation and use of NSAIDs significantly differed between groups. In the antidiarrheal group, patients tended to be more elderly, and in the corticosteroid group, more patients were on NSAIDs. 1) The degree of lamina propria inflammation can be used as a histological predictor to guide treatment in patients with CC. 2) Patients who responded to antidiarrheal agents or had spontaneous remissions were significantly older than those patients requiring 5-ASA compounds or corticosteroids. 3) Patients who were taking NSAIDs were more likely to require corticosteroid therapy, presumably reflecting more severe disease.


Processable hybrids of ferrocene-containing poly(phenylacetylene)s and carbon nanotubes: fabrication and properties.
A group of ferrocene-containing poly(phenylacetylene)s (PPAs) with different alkyl spacers were synthesized by using organorhodium complexes [Rh(diene)Cl](2) and Rh (+)(nbd)[C(6)H(5)B (-)(C(6)H(5))(3)] as catalysts. With the aid of pi-pi interactions between the walls of carbon nanotubes (CNTs) and the PPA skeleton together with the ferrocene pendants, the polymer (P 1, P2(5) and P2(10)) chains effectively wrapped round the shells of both single-walled carbon nanotubes (SWNTs) and multiwalled carbon nanotubes (MWNTs). The "additive effect" of the PPA skeleton and the ferrocene pendants in dispersing the SWNTs and MWNTs resulted in the generation of highly soluble hybrids. The solubilities of P 1-functionalized SWNTs and MWNTs in tetrahydrofuran (THF) are up to 633 mg/L and 967 mg/L, respectively. They are much higher than the solubilities of M 1-modified SWNTs and MWNTs, which are only 167 mg/L and 133 mg/L in THF. The results indicate the existence of a powerful polymer effect on dispersing CNTs. The high solubilities of the hybrids in organic solvents allowed us to fabricate high-quality and large-area films. Meanwhile, the desirable loading of ferrocene-containing PPAs onto the CNTs offered polymer/CNTs hybrids with multiple redox centers and ferrocene-featured electrochemical properties. The P 1/MWNT hybrid exhibits evident optical-limiting properties. At high incident laser fluence, the optical-limiting power of P 1/MWNT is higher than that of C(60), a well-known optical limiter. Thermal analyses indicate that the decomposition temperatures ( T(d), the temperature at which a sample loses its 5% weight) for P1 and P1/MWNT are 342 and 346 degrees C, respectively, much higher than that for PPA (225 degrees C). Thus the attachment of a ferrocene pendant to a PPA backbone, followed by hybridization with CNTs, improved the thermal stability. Upon pyrolysis, both the polymer and the polymer/CNTs hybrid gave rise to superparamagnetic ceramics; the saturation magnetizations ( M(s)) of the ceramics derived from P1 and P1/MWNT are 29.9 and 26.9 emu/g, respectively. The latter datum is in the list of the best results reported for the magnetic nanocomposites obtained by the attachment of magnetic nanoparticles onto CNTs.


Flux exclusion superconducting quantum metamaterial: towards quantum-level switching.
Nonlinear and switchable metamaterials achieved by artificial structuring on the subwavelength scale have become a central topic in photonics research. Switching with only a few quanta of excitation per metamolecule, metamaterial's elementary building block, is the ultimate goal, achieving which will open new opportunities for energy efficient signal handling and quantum information processing. Recently, arrays of Josephson junction devices have been proposed as a possible solution. However, they require extremely high levels of nanofabrication. Here we introduce a new quantum superconducting metamaterial which exploits the magnetic flux quantization for switching. It does not contain Josephson junctions, making it simple to fabricate and scale into large arrays. The metamaterial was manufactured from a high-temperature superconductor and characterized in the low intensity regime, providing the first observation of the quantum phenomenon of flux exclusion affecting the far-field electromagnetic properties of the metamaterial.


The central conserved cystine noose of the attachment G protein of human respiratory syncytial virus is not required for efficient viral infection in vitro or in vivo.
The G glycoprotein of human respiratory syncytial virus (RSV) was identified previously as the viral attachment protein. Although we and others recently showed that G is not essential for replication in vitro, it does affect the efficiency of replication in a cell type-dependent fashion and is required for efficient replication in vivo. The ectodomain of G is composed of two heavily glycosylated domains with mucin-like characteristics that are separated by a short central region that is relatively devoid of glycosylation sites. This central region contains a 13-amino acid segment that is conserved in the same form among RSV isolates and is overlapped by a second segment containing four cysteine residues whose spacings are conserved in the same form and which create a cystine noose. The conserved nature of the cystine noose and flanking 13-amino acid segment suggested that this region likely was important for attachment activity. To test this hypothesis, we constructed recombinant RSVs from which the region containing the cysteine residues was deleted together with part or all of the conserved 13-amino acid segment. Surprisingly, each deletion had little or no effect on the intracellular synthesis and processing of the G protein, the kinetics or efficiency of virus replication in vitro, or sensitivity to neutralization by soluble heparin in vitro. In addition, neither deletion had any discernible effect on the ability of RSV to infect the upper respiratory tract of mice and both resulted in a 3- to 10-fold reduction in the lower respiratory tract. Thus, although the G protein is necessary for efficient virus replication in vivo, this activity does not require the central conserved cystine noose region.


Spontaneous massive necrosis of a hepatocellular carcinoma.
A case of hepatocellular carcinoma that underwent total necrosis without previous chemotherapy is described. Histologic examination of the neoplasm revealed massive thrombosis of numerous peritumoral venous vessels in the adjacent normal liver. Although the importance of a newly formed arterial blood supply for the maintenance of the viability of hepatocellular carcinoma is unquestionable, this case suggests a similar importance of the venous drainage of the surrounding liver.


Near infrared spectroscopy for measuring changes in bone hemoglobin content after exercise in individuals with spinal cord injury.
Bone blood perfusion has an essential role in maintaining a healthy bone. However, current methods for measuring bone blood perfusion are expensive and highly invasive. This study presents a custom built near-infrared spectroscopy (NIRS) instrument to measure changes in bone blood perfusion. We demonstrated the efficacy of this device by monitoring oxygenated and deoxygenated hemoglobin changes in the human tibia during and after exercise in able-bodied and in individuals with spinal cord injury (SCI), a population with known impaired peripheral blood perfusion. Nine able-bodied individuals and six volunteers with SCI performed a 10 min rowing exercise (functional electrical stimulation rowing for those with SCI). With exercise, during rowing, able-bodied showed an increase in deoxygenated hemoglobin in the tibia. Post rowing, able-bodied showed an increase in total blood content, characterized by an increase in total hemoglobin content due primarily to an increase in deoxygenated hemoglobin. During rowing and post-rowing, those with SCI showed no change in total blood content in the tibia. The current study demonstrates that NIRS can non-invasively detect changes in hemoglobin concentration in the tibia. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:183-191, 2018.


Hierarchical Porous Intercalation-Type V2 O3 as High-Performance Anode Materials for Li-Ion Batteries.
As intercalation-type anode materials for Li-ion batteries (LIBs), the commercially used graphite and Li4 Ti5 O12 exhibit good cycling and rate properties, but their theoretical specific capacities are too low to meet the ever-growing demands of high-energy applications such as electric vehicles. Therefore, the development of new intercalation-type anode materials with larger capacity is very desirable. Herein, we design and synthesize novel 3 D hierarchical porous V2 O3 @C micro/nanostructures consisting of crumpled nanosheets, through self-reduction under annealing from the structurally similar VO2 (B)@C precursors without the addition of any other reducing reagent or gas. Excitingly, it is found for the first time through ex situ XRD technology that V2 O3 is a new, promising intercalation-type anode material for LIBs with a high capacity. V2 O3 @C micro/nanostructures can deliver a large capacity of 732 mAh g-1 without capacity loss at 100 mA g-1 even after 136 cycles, as well as exhibiting excellent cycling and rate performances. The application of V2 O3 for Na-ion batteries (NIBs) is elaborated for the first time, and excitingly, it is found that V2 O3 @C micro/nanostructures may be promising anode materials for NIBs.


A novel cause of community-acquired pneumonia in a young immunocompetent host.
Diffuse pulmonary infiltrates represent a common problem encountered by pulmonologists. The differential diagnosis is extensive and includes infectious, inflammatory, environmental and malignant conditions. Appropriate evaluation, aside from a thorough history and physical examination, includes serologic, radiographic and procedural elements. We describe a case of a healthy male with diffuse pulmonary infiltrates. Work up revealed a novel infectious etiology. Although this particular microorganism has been described to cause native valve endocarditis, recurrent breast abscesses, osteomyelitis and bacteremia, it has to date not been described as a cause for community acquired pneumonia in immunocompetent hosts.


Sarcopenia is an independent predictor of complications after colorectal cancer surgery.
The significance of sarcopenia after colorectal cancer (CRC) resection has only been discussed with relatively small samples or short follow-up periods. This study aimed to clarify the clinical significance of sarcopenia in a large-sample study. We retrospectively analyzed the relationship between sarcopenia and clinical factors, surgical outcomes, and the survival in 494 patients who underwent CRC surgery between 2004 and 2013. Sarcopenia was defined based on the sex-specific skeletal muscle mass index measured by preoperative computed tomography. Sarcopenia was associated with sex (higher rate of male, P < 0.0001), and low body mass index (P < 0.0001), but not age or tumor stage. Sarcopenia was associated with higher incidence of all postoperative complications (P = 0.02), especially for patients with Clavien-Dindo classification grade ≥2 (CDC; P = 0.0007). Postoperative hospital stays were significantly longer for sarcopenic patients than for non-sarcopenic patients (P = 0.02). In a multivariate analysis, sarcopenia was an independent predictor for postoperative complications (P = 0.01, odds ratio 1.82, 95% confidence interval 1.13-3.00). Among postoperative complications (CDC grade ≥2), sarcopenia was correlated with non-surgical-site infections (P = 0.03). Sarcopenia was not correlated with the overall or recurrence-free survival. Sarcopenia was an independent predictive factor for postoperative complications after CRC surgery.


Large piezoelectric effect in Pb-free ceramics.
We report a non-Pb piezoelectric ceramic system Ba(Ti(0.8)Zr(0.2))O(3)-(Ba(0.7)Ca(0.3))TiO(3) which shows a surprisingly high piezoelectric coefficient of d(33) approximately 620 pC/N at optimal composition. Its phase diagram shows a morphotropic phase boundary (MPB) starting from a tricritical triple point of a cubic paraelectric phase (C), ferroelectric rhombohedral (R), and tetragonal (T) phases. The high piezoelectricity of the MPB compositions stems from the composition proximity of the MPB to the tricritical triple point, which leads to a nearly vanishing polarization anisotropy and thus facilitates polarization rotation between 001T and 111R states. We predict that the single-crystal form of the MPB composition of the present system may reach a giant d(33) = 1500-2000 pC/N. Our work may provide a new recipe for designing highly piezoelectric materials (both Pb-free and Pb-containing) by searching MPBs starting from a TCP.


Long-term analysis of chronic Broca's aphasia: an illustrative single case.
In this article, a longitudinal case study of a client (whose initials are TH) with chronic Broca's aphasia is presented. The language data encompass test and therapy data over a 7-year period, during which TH's language performance and verbal communicative behavior have improved and continue to improve. A carryover from oral to written sentence production and to verbal communication in everyday life has been observed. The long-term provision of therapy has not only lead to improved verbal communication skills, but has also enhanced his quality of life. The case study discussed in this article demonstrates the value of long-term treatment and research on the evolution of language deficits across time. This approach provides a window for examining the dynamic processes of language recovery--the quantitative and qualitative changes that can be achieved when language therapy is provided long term in the chronic phase. Long-term analysis of the manner in which language functions respond to therapeutic intervention also provides detailed basic information required for a realistic characterization of the spectrum of language deficits for each symptom complex and/or aphasia type, not only for a single test time. This will lead to a better understanding of the recovery process and to development of therapy protocols in better accordance with the deficits at a particular point in the recovery process.


Attorney-General (QLD) v. Parents, In re S.
The Family Court of Australia ruled that parents may authorize a hysterectomy for their mentally retarded 12-year old daughter without first seeking court approval. The child resided in a residential facility, although she remained in her parents' legal custody. She functioned at a cognitive level of approximately one year of age, and exhibited behavioral disorders including poor hygiene and fecal smearing. Although the child was well-developed physically, she had not begun menstruating. The Court rejected the provision of contraceptives and assistance with menstrual hygiene as an option, and concluded that involuntary sterilization would be in the best interest of the child because the child would not be able to cope with a pregnancy, nor the responsibilities of rearing a child. The Court traced the development of case law involving involuntary sterilization of minors in Australia and Great Britain.


Immune complex degradation by cultured rat mesangial cells.
The binding and degradation of radiolabelled immune complexes by cultured rat glomerular mesangial cells were measured and compared with the binding and degradation by thioglycollate-elicited rat peritoneal macrophages. Mesangial cells are generally considered to be a modified pericyte with smooth muscle-like properties, but they were able to bind and degrade soluble immune complexes at rates comparable to those of the macrophages. In a second study, the ability of cultured mesangial cells to bind and degrade immune complexes of varying molecular weight was assessed. Very large, insoluble complexes were found to bind to mesangial cells more avidly than small soluble complexes, but unlike the small complexes, the large complexes did not appear to undergo degradation. These findings support a role for the intrinsic mesangial cell in the elimination of small soluble immune complexes as they arrive in the glomerulus. They also provide a possible explanation for the paradox that large immune complexes--i.e., electron-dense deposits--can persist in the mesangium next to the intrinsic mesangial cells without being rapidly destroyed.


Efficient, specific and targeted delivery of genes to the lung.
Many inherited and acquired pulmonary disorders without satisfactory therapies may be amenable to gene therapy. Despite numerous advances, efficient delivery and expression of the therapeutic transgene at physiological levels for phenotypic correction of disease has proved elusive. This article focuses on various strategies aimed at achieving targeted delivery to the lungs. Both physical methods and biological targeting have been successfully applied in various gene delivery systems. Targeting of different cell types has been achieved by pseudotyping of viral vectors with capsids from different serotypes and modification of nonviral vectors with targeting ligands. Both classes of vectors are discussed with respect to their gene delivery and expression efficiencies, longevity of expression and immunogenicity. Moreover, gene therapy clinical trials for different lung diseases are discussed.


Induction of apoptosis by ar-turmerone on various cell lines.
This study investigated the cytotoxic effect of ar-turmerone isolated from turmeric (Curcuma longa L) on the K562, L1210, U937 and RBL-2H3 cell lines by the MTT assay. Ar-turmerone exhibited potent cytotoxicity on these cancer cell lines. The IC50 values of ar-turmerone on these cell lines were 20-50 microg/ml. They showed an increased inhibition ratio on cell viability according to the drug concentration < or = 80 microg/ml in the cell lines tested. The DNA fragmentation that is a characteristic of apoptosis due to ar-turmerone occurred in a concentration- and time-dependent manner in the K562, L1210, U937 and RBL-2H3 cancer cell lines. These results suggest that ar-turmerone can induce the apoptotic activity in the K562, L1210, U937 and RBL-2H3 cells.


[Symptoms: anorexia and emaciation].
Anorexia and emaciation are symptoms which can be found in many diseases either singly or in combination with other unspecific clinical signs such as diarrhea and vomiting. Therefore accurately assessing the medical history, performing a thorough clinical examination and carrying out laboratory tests are all necessary steps in establishing a diagnosis. Further specific examinations such as radiography, ultrasonography or endoscopy may also have to be performed. Since anorexia and emaciation can result in severe consequences for the organism, establishing a definitive diagnosis is important to enable the appropriate therapy to be applied without delay.


Detection of human papillomavirus type 16 early-gene transcription by reverse transcription-PCR is associated with abnormal cervical cytology.
Human papillomavirus type 16 (HPV-16) is associated with abnormal Papanicolou smears, indicative of cervical intraepithelial neoplasia. HPV-16 is the most common genital HPV and is found in up to 40% of young women with normal cervical cytology. In order to investigate whether transcriptionally active HPV-16 infection is associated with abnormal cervical smears, a reverse transcription-nested PCR assay with primers from the E5 open reading frame was developed to detect all HPV-16 early-region mRNA (E-mRNA) transcripts. It was used to study HPV-16-infected women with normal and abnormal cervical cytologies to obtain evidence of active infection. Among HPV-16 DNA-positive women, HPV-16 E-mRNA was detected in 15 of 37 (40.5%) women with abnormal cervical cytology but in only 4 of 35 (11.4%) women with normal cytology (P = 0.007). Thus, HPV-16 E-mRNA transcription is associated with abnormal cervical smears and may have value as a prognostic marker of progressive disease.


A polyoxometalate-based complex with visible-light photochromism as the electrocatalyst for generating hydrogen from water.
Two polyoxometalate (POM)-based complexes formulated as (HL1)2(Mo8O26)·2HL1·11H2O (L1 = 3-(5-(1H-pyrazol-4-yl)-1H-1,2,4-triazol-3-yl)pyridine) (1) and Co2(L2)4[P2Mo(VI)5O23Mo(II)(H2O)2]·3H2O (L2 = 4-(5-(2H-1,2,4-triazol-3-yl)-2H-1,2,4-triazol-3-yl)pyridine) (2) have been synthesized and structurally characterized by single-crystal X-ray diffraction. Complex 1 shows a bi-capped POM with the two Mo centers from the [Mo8O26](4-) moiety coordinated by two HL1 ligands via two Mo-N bonds. Complex 2 consists of a mononuclear unsaturated coordinated Co(ii) unit and a [P2Mo(VI)5O23Mo(II)(H2O)2](4-) moiety, in which [P2Mo(VI)5O23Mo(II)(H2O)2](4-) shows a chain-like structure constructed from edge-sharing or vertex-sharing {MoO6} and {PO4} polyhedra. The two complexes are both soluble in neutral aqueous solution and they can electrocatalyze the H2 evolution reaction (HER) from water with lowered overpotentials and enhanced currents, and complex 1 shows better electrocatalytic activity for the HER than complex 2. Complex 1 shows visible-light photochromism. In the presence of complex 1, the HER current is enhanced with visible-light irradiation in comparison with the current without light irradiation.


Loss of Hif-2α Rescues the Hif-1α Deletion Phenotype of Neonatal Respiratory Distress In Mice.
Hypoxia is a state of decreased oxygen reaching the tissues of the body. During prenatal development, the fetus experiences localized occurrences of hypoxia that are essential for proper organogenesis and survival. The response to decreased oxygen availability is primarily regulated by hypoxia-inducible factors (HIFs), a family of transcription factors that modulate the expression of key genes involved in glycolysis, angiogenesis, and erythropoiesis. HIF-1α and HIF-2α, two key isoforms, are important in embryonic development, and likely are involved in lung morphogenesis. We have recently shown that the inducible loss of Hif-1α in lung epithelium starting at E4.5 leads to death within an hour of parturition, with symptoms similar to neonatal respiratory distress syndrome (RDS). In addition to Hif-1α, Hif-2α is also expressed in the developing lung, although the overlapping roles of Hif-1α and Hif-2α in this context are not fully understood. To further investigate the independent role of Hif-2α in lung epithelium and its ability to alter Hif-1α-mediated lung maturation, we generated two additional lung-specific inducible Hif-α knockout models (Hif-2α and Hif-1α+Hif-2α). The intrauterine loss of Hif-2α in the lungs does not lead to decreased viability or observable phenotypic changes in the lung. More interestingly, survivability observed after the loss of both Hif-1α and Hif-2α suggests that the loss of Hif-2α is capable of rescuing the neonatal RDS phenotype seen in Hif-1α-deficient pups. Microarray analyses of lung tissue from these three genotypes identified several factors, such as Scd1, Retlnγ, and Il-1r2, which are differentially regulated by the two HIF-α isoforms. Moreover, network analysis suggests that modulation of hormone-mediated, NF-κB, C/EBPα, and c-MYC signaling are central to HIF-mediated changes in lung development.


Anticholinergic actions of steroid muscle relaxants.
The chronotropic effects of two new steroid muscle relaxants have been investigated. Each was compared individually with pancuronium bromide, using acetylcholine as an agonist on the isolated perfused rabbit heart. One of the drugs. Organon 6368, was very similar to pancuronium in its degree of antagonism to the bradycardia produced by acetylcholine and may therefore be a useful drug clinically. Dacuronium, on the other hand, would appear to have marked chronotropic effects at dose levels needed for adequate neuromuscular blockade and thus may be less useful.


The many dimensions of germline competence.
Primordial germ cell (PGC) specification is the first step in the development of the germline. Recent work has elucidated human-mouse differences in PGC differentiation and identified cell states with enhanced competency for PGC-like cell (PGCLC) differentiation in vitro in both species. However, it remains a subject of debate how different PGC competent states in vitro relate to each other, to embryonic development, and to the origin of PGCs in vivo. Here we review recent literature on human PGCLC differentiation in the context of mouse and non-human primate models. In contrast to what was previously thought, recent work suggests human pluripotent stem cells (hPSCs) are highly germline competent. We argue that paradoxical observations regarding the origin and signaling requirements of hPGCLCs may be due to local cell interactions. These confound assays of competence by generating endogenous signaling gradients and spatially modulating the ability to receive exogenous inductive signals. Furthermore, combinatorial signaling suggests that there is no unique germline competent state: rather than a one-dimensional spectrum of developmental progression, competence should be considered in a higher dimensional landscape of cell states.


Expression of androgen receptor in primary breast carcinoma and its relation with clinicopathologic features, estrogen, progesterone, and her-2 receptor status.
The role of estrogen/progesterone receptors (ER/PR) is well-established with respect to therapy and prognosis of breast carcinoma. However, the role of androgen receptor (AR) expression is unclear in the Indian context. The objective is to study the following: (a) Expression of AR in resection specimens of ductal carcinomas, (b) Relationship of AR with clinicopathologic features, ER, PR, and Her-2 status. This study included female patients with infiltrating ductal carcinoma with a minimum of 10 axillary lymph nodes, whose hormone receptor status data were available. Demographic and histopathologic details were retrieved. Immunohistochemistry for AR was done and considered positive if ≥10% of tumor cells showed nuclear staining and compared to various clinicopathologic features. A total of 71 cases were included in the study. AR expression was noted in 52% of cases. Of the 35 ER and/or PR expressing tumors, AR was positive in 24 cases. In contrast, of the 36 ER/PR-negative tumors, AR was expressed in only 13 cases (P = 0.006). There was no significant difference in the expression of AR between Her-2 positive and negative cases. AR positivity was noted in 23% of triple-negative tumors. Age did not show an influence on AR status. Among histopathologic parameters, low-grade tumors were significantly associated with AR expression (P = 0.018) while tumor size, lymphovascular emboli, and nodal status were not. Within the follow-up period, four patients from AR-positive group developed distant metastasis. Indian patients with breast carcinoma have a higher AR expression in low-grade and ER/PR-positive tumors, in concordance with Western studies. A good number of triple-negative tumors also express AR, which needs further evaluation.


Gene-Diet Interactions in Type 2 Diabetes: The Chicken and Egg Debate.
Consistent evidence from both experimental and human studies indicates that Type 2 diabetes mellitus (T2DM) is a complex disease resulting from the interaction of genetic, epigenetic, environmental, and lifestyle factors. Nutrients and dietary patterns are important environmental factors to consider in the prevention, development and treatment of this disease. Nutritional genomics focuses on the interaction between bioactive food components and the genome and includes studies of nutrigenetics, nutrigenomics and epigenetic modifications caused by nutrients. There is evidence supporting the existence of nutrient-gene and T2DM interactions coming from animal studies and family-based intervention studies. Moreover, many case-control, cohort, cross-sectional cohort studies and clinical trials have identified relationships between individual genetic load, diet and T2DM. Some of these studies were on a large scale. In addition, studies with animal models and human observational studies, in different countries over periods of time, support a causative relationship between adverse nutritional conditions during in utero development, persistent epigenetic changes and T2DM. This review provides comprehensive information on the current state of nutrient-gene interactions and their role in T2DM pathogenesis, the relationship between individual genetic load and diet, and the importance of epigenetic factors in influencing gene expression and defining the individual risk of T2DM.


[Proposition and evaluation of the educational activities for effective utilization of opioids performed by pharmacists in palliative home care].
Recently, it is required that community pharmacists participate in palliative home care. In this study, we designed educational activities for palliative home care to local residents as a new approach performed by community pharmacists. In addition, we proposed this approach to community pharmacists and discussed its roles to promote palliative home care in the future. We designed and held an educational seminar on palliative home care focusing on safe use of opioids in local residents. After this seminar, we conducted a questionnaire survey of the participants. Then, we made a proposition of this new approach by presentation of a seminar to community pharmacists (members of "Heartfulcare INC"). After the proposition, a questionnaire survey of the seminar on palliative home care was performed. In total, 79 people participated in the educational seminar. Most (87.3%) participants thought that it was informative. Furthermore, about 40% of participants answered "misunderstanding of opioids" or "anxiety regarding side effects of opioids" were removed following the seminar. All participating pharmacists evaluated the seminar as useful. The educational activity in the present study seemed effective to local residents on their misunderstanding of opioids. Furthermore, this approach was appreciated as an important role of community pharmacists in the palliative home care not only by local residents but also by pharmacists themselves. Therefore it seems important to continue such activities so as to improve palliative home care in the future.


Dark matters: black-PDMS nanocomposite for opaque microfluidic systems.
Optically detectable labels and probes are commonly used in bioapplications. Together with the miniaturization of analytical platforms based on microfluidic technology, with tuneable properties, they yield unparalleled opportunities towards faster, cheaper and more efficient biomolecule analysis. This work describes the preparation and testing of uniformly shaded polydimethylsiloxane (PDMS) membranes and microfluidic devices used to enhance or inhibit optical detection of fluorescent labels. The uniformly pigmented black-PDMS nanocomposite mixtures have been prepared by adding a known quantity of black pigment to PDMS, and its optical, spectroscopic and morphological properties have been characterized. The effect of pigment-to-DMS mixing ratio has been investigated by Ultra-Violet/Visible, near infrared and middle infrared spectroscopies; scanning electron microscopy and atomic force microscopy; and contact angle measurements. The results demonstrate that optical and spectroscopic properties of black-PDMS are strongly altered with the progressive inclusion of black pigment while wetting behaviour and morphology are maintained. Surface contact angle decreases more prominently with the decreasing ratio of DMS-to-curing agent than for the inclusion of pigment nanocomposite in the mixture. The ability to tune optical properties of PDMS has been experimentally demonstrated in a Black-PDMS nanocomposite microfluidic chip cast and bonded to glass. The results show double the signal-to-noise in fluorescence images as compared to pure PDMS devices, demonstrating a very promising integrated optical detection strategy for portable microfluidic systems.


The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.
Nutrient availability is a key determinant of tumor cell behavior. While nutrient-rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non-derepressible 2 (GCN2; also known as eIF-2-alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53-mediated apoptosis in patient-derived models of colon adenocarcinoma (COAD). In nutrient-rich conditions, a cell-autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl-tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically stressed COAD cells.


Rhenium-Catalyzed Intramolecular Carboalkoxylation and Carboamination of Alkynes for the Synthesis of C3-Substituted Benzofurans and Indoles.
A rhenium-catalyzed carboalkoxylation and carboamination of alkyne is reported. This reaction provides an efficient route to synthesize de novo C3-substituted benzofurans and indoles under mild conditions in moderate to good yields. Mechanistic studies revealed that the rhenium played the role of a π acid catalyst to activate the alkynes, followed by a charge-accelerated [3,3]-sigmatropic rearrangement.