Title IX and Pregnancy Discrimination in Higher Education: The New Frontier.
Pregnancy discrimination is a little known area covered by Title IX. According to the Title IX regulations, areas of prohibited discrimination include: admissions; hiring; coursework accommodations and completion; pregnancy leave policies and status protection upon return from leave; and health insurance coverage. These regulations will soon get more attention as the Obama Administration insists on Title IX dissemination and compliance in an effort to stop the leaky pipeline for women in the STEM fields. Research shows that pregnancy and childbirth are the major reasons why women drop out of research science in much greater numbers than men; this dropout is most likely to occur among graduate students and postdoctoral fellows who are in their peak childbearing years. A similar pattern of dropout can be seen in all fields, including related professional schools. Research also reveals that there are currently few established policies in higher education which adequately address pregnancy and childbirth in formal policies for students. This article will address new efforts by the United States Department of Education and the federal agencies to begin to seek compliance relating to Title IX and pregnancy discrimination in educational institutions. It will discuss the recent successful efforts of the U.S. Department of Education's Office for Civil Rights in investigating and settling pregnancy discrimination claims as well as the lessons learned in private action lawsuits under Title IX. Title IX private action suits have transformed athletics for women, and more recently Title IX has been applied in sexual harassment cases. Pregnancy discrimination is now the new frontier.


PilM/N/O/P proteins form an inner membrane complex that affects the stability of the Pseudomonas aeruginosa type IV pilus secretin.
The highly conserved pilM/N/O/P/Q gene cluster is among the core set of genes required for cell surface expression of type IV pili and associated twitching motility. With the exception of the outer membrane secretin, a multimer of PilQ subunits, the specific functions of the products encoded by this gene cluster are poorly characterized. Orthologous proteins in the related bacterial type II secretion system have been shown to interact to form an inner membrane complex required for protein secretion. In this study, we provide evidence that the PilM/N/O/P proteins form a functionally equivalent type IVa pilus complex. Using Pseudomonas aeruginosa as model organism, we found that all four proteins, including the nominally cytoplasmic PilM, colocalized to the inner membrane. Stability studies via Western blot analyses revealed that loss of one component has a negative impact on the levels of other members of the putative complex. Furthermore, complementation studies revealed that the stoichiometry of the components is important for the correct formation of a stable complex in vivo. We provide evidence that an intact inner membrane complex is required for optimal formation of the outer membrane complex of the type IVa pilus system in P. aeruginosa, as PilQ stability is negatively affected in its absence. Finally, we show that, in the absence of the pilin subunit, the levels of membrane-bound components of the inner membrane complex are negatively regulated by the PilR/S two-component system, suggesting a role for PilR/S in sensing the piliation status of the cell.


High-throughput screening of metal-organic frameworks for kinetic separation of propane and propene.
We apply molecular simulations to screen a database of reported metal-organic framework structures from the computation-ready, experimental (CoRE) MOF database to identify materials potentially capable of separating propane and propene by diffusion. We report a screening workflow that uses descriptor analysis, conventional molecular dynamics (MD), and Nudged Elastic Band (NEB) energy barrier calculations at both classical force field and Density Functional Theory (DFT) levels. For the first time, the effects of framework flexibility on guest transport properties were fully considered in a screening process and led to the identification of candidate MOFs. The hits identified by this proof-of-concept workflow include ZIF-8 and ZIF-67 previously shown to have large differences in propane and propene diffusivities as well as two other materials that have not been tested experimentally yet. This work emphasises the importance of taking into account framework flexibility when studying guest transport in porous materials, demonstrates the potential of the data-driven identification of high-performance materials and highlights the ways of improving the predictive power of the screening workflow.


Secretoneurin in the peripheral ocular innervation.
To evaluate whether secretoneurin represents a sensory neuropeptide innervating the anterior segment of the eye. The presence and distribution of secretoneurin was investigated in human eyes by radioimmunoassay and immunofluorescence and compared with that of the rat eye. The source of secretoneurin-positive nerves in the eye was established by measuring the concentration in eye tissues, the trigeminal and superior cervical ganglia both in control rats and in rats treated with capsaicin, and by performing immunofluorescence in one rat subjected to sympathectomy. In the rat trigeminal ganglion, the corresponding mRNA was verified by in situ hybridization and the processing of secretogranin II into secretoneurin by gel filtration chromatography. In human eyes, the highest levels of the peptide were found in the choroid. Nerve fibers were visualized in both species in the upper corneal and limbal stroma; in the trabecular meshwork; in the ciliary muscle, the ciliary body stroma, and processes; and in clear association with the dilator muscle, which disappeared after sympathetic denervation in rats; and also innervating the sphincter muscle in the iris and the choroidal stroma and surrounding blood vessels. Significant amounts of secretoneurin were present in the rat trigeminal ganglion and rat eye tissues. Capsaicin pretreatment led to a 57.0% +/- 4.3% and 59.1% +/- 11.9% decrease of the concentration in the trigeminal ganglion and the iris/ciliary body complex, respectively. Despite high levels in the rat superior cervical ganglion, sympathetic denervation failed to lower the concentration in eye tissues. The secretogranin II probe labeled numerous small-sized ganglion cells within the rat trigeminal ganglion, and the precursor of the peptide was found to become completely processed into secretoneurin. Apart from the sympathetically innervated dilator muscle, there is unequivocal evidence that secretoneurin represents a constituent of capsaicin-sensitive sensory neurons in the rat trigeminal ganglion and of unmyelinated C-fibers in the rat iris/ciliary body complex, which indicates a participation of this peptide in the ocular irritative response, a model for neurogenic inflammation in lower mammals. Because of the association of nerves with blood vessels and potent angiogenic properties, secretoneurin may be involved in neovascularization processes.


Abnormal retinal vascular function and lipid levels in a sample of healthy UK South Asians.
To investigate ethnic differences in retinal vascular function and their relationship to traditional risk indicators for cardiovascular disease (CVD). A total of 90 normoglycaemic subjects (45 South Asian (SA) and 45 age- and gender-matched white Europeans (WEs)) were recruited for the present study. Retinal vessel reactivity to flickering light was assessed by means of the dynamic retinal vessel analyser according to a modified protocol. Fasting plasma glucose, triglycerides (TG), total, LDL and HDL cholesterol were also measured in all individuals. SA individuals showed higher fasting triglyceride (p=0.001) and lower HDL levels (p=0.007), leading to a higher TG:HDL-C ratio (p=0.001) than age-matched WE subjects. Additionally, in SAs, the retinal arterial reaction time in response to flicker stimulation was significantly longer in the last flicker cycle than in the WEs (p=0.039), and this change correlated positively with measured plasma TG levels (r=0.60; p=0.01). No such relationship was observed in the WEs (p>0.05). Even in the absence of overt vascular disease, in otherwise healthy SAs there are potential signs of retinal vascular function impairment that correlates with established plasma markers for CVD risk.


Tooth wear: when to treat, why, and how. Part two.
Tooth wear has been described in the literature as physiologic--that is, normal, expected over the life span of an individual, and not creating a pathologic condition. It has also been described in pathologic terms as caused by stress, corrosion, and friction, utilizing a variety of mechanisms and affected by a host of endogenous and exogenous factors. From a clinician's point of view, when should we decide to restore a tooth or change the conditions in the mouth to protect the teeth; and what should we consider using to either prevent or restore abnormal--i.e, pathologic--tooth wear? This review in Part One (Northwest Dentistry, September-October 2009) looked at what is normal, non-pathologic tooth wear and etiologies associated with all forms of tooth wear. Part Two will discuss the effects of tooth wear in enamel and dentin, when it may be advisable to intervene in the wear processes diagnosed on specific patients, and what methods of prevention and restoration can be utilized to restore or maintain the dentition. This review will not look at the need for full mouth reconstruction due to wear.


Weight regain after a diet-induced loss is predicted by higher baseline leptin and lower ghrelin plasma levels.
Appetite-related hormones may play an important role in weight regain after obesity therapy. Our objective was to investigate the potential involvement of ghrelin, leptin, and insulin plasma levels in weight regain after a therapeutic hypocaloric diet. A group of obese/overweight volunteers (49 women and 55 men; 35 ± 7 yr; 30.7 ± 2.4 kg/m(2)) followed an 8-wk hypocaloric diet (-30% energy expenditure) and were evaluated again 32 wk after treatment. Body weight as well as plasma fasting ghrelin, leptin, and insulin concentrations were measured at three points (wk 0, 8, and 32). After the 8-wk hypocaloric diet, the average weight loss was -5.0 ± 2.2% (P < 0.001). Plasma leptin and insulin concentrations decreased significantly, whereas ghrelin levels did not markedly change. In the group regaining more than 10% of the weight loss, leptin levels were higher (P < 0.01), whereas ghrelin levels were lower (P < 0.05). No differences were observed in insulin levels. Weight regain at wk 32 was negatively correlated with ghrelin and positively associated with leptin levels at baseline (wk 0) and endpoint (wk 8). These outcomes showed a gender-specific influence, being statistically significant among men for ghrelin and between women for leptin. Moreover, a decrease in ghrelin after an 8-wk hypocaloric diet was related to an increased risk for weight regain (odds ratio = 3.109; P = 0.008) whereas a greater reduction in leptin (odds ratio = 0.141; P = 0.001) was related to weight-loss maintenance. Subjects with higher plasma leptin and lower ghrelin levels at baseline could be more prone to regain lost weight, and hormones levels could be proposed as biomarkers for predicting obesity-treatment outcomes.


The native architecture of a photosynthetic membrane.
In photosynthesis, the harvesting of solar energy and its subsequent conversion into a stable charge separation are dependent upon an interconnected macromolecular network of membrane-associated chlorophyll-protein complexes. Although the detailed structure of each complex has been determined, the size and organization of this network are unknown. Here we show the use of atomic force microscopy to directly reveal a native bacterial photosynthetic membrane. This first view of any multi-component membrane shows the relative positions and associations of the photosynthetic complexes and reveals crucial new features of the organization of the network: we found that the membrane is divided into specialized domains each with a different network organization and in which one type of complex predominates. Two types of organization were found for the peripheral light-harvesting LH2 complex. In the first, groups of 10-20 molecules of LH2 form light-capture domains that interconnect linear arrays of dimers of core reaction centre (RC)-light-harvesting 1 (RC-LH1-PufX) complexes; in the second they were found outside these arrays in larger clusters. The LH1 complex is ideally positioned to function as an energy collection hub, temporarily storing it before transfer to the RC where photochemistry occurs: the elegant economy of the photosynthetic membrane is demonstrated by the close packing of these linear arrays, which are often only separated by narrow 'energy conduits' of LH2 just two or three complexes wide.


Use of antioxidant nutrients in the prevention and treatment of type 2 diabetes.
Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), is increasingly common throughout the world. The World Health Organization has predicted that between 1997 and 2025, the number of diabetics will double from 143 million to about 300 million. The incidence of NIDDM is highest in economically developed nations, particularly the U.S., where approximately 6.5% of the population (17 million people) have either diagnosed or undiagnosed diabetes. The two most important factors contributing to the development of NIDDM are obesity and physical inactivity. The leading cause of mortality and morbidity in people with NIDDM is cardiovascular disease caused by macro- and microvascular degeneration. Current therapies for NIDDM focus primarily on weight reduction. Indeed, several investigations indicate that 65% to 75% of cases of diabetes in Caucasians could be avoided if individuals in this subgroup did not exceed their ideal weight. The success of this approach has been, at best, modest. An alternate approach to the control of Type 2 diabetes is to arrest the progress of the pathology until a cure has been found. To this end, some investigators suggest that dietary antioxidants may be of value. Several studies in humans and laboratory animals with NIDDM indicate that vitamin E and lipoic acid supplements lessen the impact of oxidative damage caused by dysregulation of glucose metabolism. In this brief review, we discuss the incidence, etiology, and current therapies for NIDDM and further explore the usefulness of dietary antioxidants in treating this disorder.


Control of aurophilic interaction: conformations and electronic structures of one-dimensional supramolecular architectures.
Gold(i) chloride complexes with the diarsenic ligands cis-1,4-dihydro-1,4-diarsinines (cis-DHDAs) were synthesized. X-ray diffraction revealed that they formed one-dimensional polymeric structures through aurophilic interactions. Their higher-ordered structures are controlled by the ligand structure; methyl- and t-butyl substituted ligands offered transoid-transoid and transoid-cisoid conformations, respectively. Density functional theory (DFT) calculations indicated that the electronic structure of the aurophilic network was highly dependent on the conformations. This is the first study on the relationship between the chain conformation and 5d-orbital structures of gold complexes.


Randomized Sham-Controlled Trial of Navigated Repetitive Transcranial Magnetic Stimulation for Motor Recovery in Stroke.
Background and Purpose- We aimed to determine whether low-frequency electric field navigated repetitive transcranial magnetic stimulation to noninjured motor cortex versus sham repetitive transcranial magnetic stimulation avoiding motor cortex could improve arm motor function in hemiplegic stroke patients when combined with motor training. Methods- Twelve outpatient US rehabilitation centers enrolled participants between May 2014 and December 2015. We delivered 1 Hz active or sham repetitive transcranial magnetic stimulation to noninjured motor cortex before each of eighteen 60-minute therapy sessions over a 6-week period, with outcomes measured at 1 week and 1, 3, and 6 months after end of treatment. The primary end point was the percentage of participants improving ≥5 points on upper extremity Fugl-Meyer score 6 months after end of treatment. Secondary analyses assessed changes on the upper extremity Fugl-Meyer and Action Research Arm Test and Wolf Motor Function Test and safety. Results- Of 199 participants, 167 completed treatment and follow-up because of early discontinuation of data collection. Upper extremity Fugl-Meyer gains were significant for experimental ( P<0.001) and sham groups ( P<0.001). Sixty-seven percent of the experimental group (95% CI, 58%-75%) and 65% of sham group (95% CI, 52%-76%) improved ≥5 points on 6-month upper extremity Fugl-Meyer ( P=0.76). There was also no difference between experimental and sham groups in the Action Research Arm Test ( P=0.80) or the Wolf Motor Function Test ( P=0.55). A total of 26 serious adverse events occurred in 18 participants, with none related to the study or device, and with no difference between groups. Conclusions- Among patients 3 to 12 months poststroke, goal-oriented motor rehabilitation improved motor function 6 months after end of treatment. There was no difference between the active and sham repetitive transcranial magnetic stimulation trial arms. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02089464.


Fat oxidation, body composition and insulin sensitivity in diabetic and normoglycaemic obese adults 5 years after weight loss.
To investigate whether normal glucose-tolerant and type II diabetic overweight adults differ in response to weight regain with regard to substrate oxidation and metabolic parameters. A total of 15 overweight-obese subjects: seven normal glucose tolerant (NGT) and eight with type II diabetes (DM) were restudied 5 y after significant weight loss. Prediet, after 28 days calorie restriction and at 5 y, subjects were characterised for weight, height, waist-to-hip ratio (WHR) and body composition by dual-energy X-ray absorptiometry. Fasting glucose, insulin, leptin and lipid levels were measured and subjects underwent euglycaemic-hyperinsulinaemic clamp (insulin 0.25 U/kg/h for 150 min). Indirect calorimetry was performed resting and in the final 30 min of the clamp. Dietary assessment was by 4-day diet-diary. Both NGT and DM groups regained weight at 5 y and were not different to prediet. Total body fat (%) and WHR were higher at 5 y compared to prediet in both groups. Fasting glucose was increased in NGT subjects at 5 y, and fasting insulin was higher in both groups at 5 y compared to prediet. Insulin sensitivity (GIR) was similar at 5 y compared to prediet, but at 5 y DM subjects were more insulin resistant than NGT subjects. At 5 y, both DM and NGT groups had significantly reduced basal fat oxidation and no significant suppression of fat oxidation with insulin. Clamp respiratory quotient levels at 5 y were significantly higher in NGT compared to DM subjects. Reduced basal fat oxidation, and reduced variation in substrate oxidation in response to insulin develop with fat regain and fasting hyperinsulinaemia in both NGT and DM obese adults.


Detecting cardiac contractile activity in the early mouse embryo using multiple modalities.
The heart is one of the first organs to develop during mammalian embryogenesis. In the mouse, it starts to form shortly after gastrulation, and is derived primarily from embryonic mesoderm. The embryonic heart is unique in having to perform a mechanical contractile function while undergoing complex morphogenetic remodeling. Approaches to imaging the morphogenesis and contractile activity of the developing heart are important in understanding not only how this remodeling is controlled but also the origin of congenital heart defects (CHDs). Here, we describe approaches for visualizing contractile activity in the developing mouse embryo, using brightfield time lapse microscopy and confocal microscopy of calcium transients. We describe an algorithm for enhancing this image data and quantifying contractile activity from it. Finally we describe how atomic force microscopy can be used to record contractile activity prior to it being microscopically visible.


Clarity™ digital PCR system: a novel platform for absolute quantification of nucleic acids.
In recent years, digital polymerase chain reaction (dPCR) has gained recognition in biomedical research as it provides a platform for precise and accurate quantification of nucleic acids without the need for a standard curve. However, this technology has not yet been widely adopted as compared to real-time quantitative PCR due to its more cumbersome workflow arising from the need to sub-divide a PCR sample into a large number of smaller partitions prior to thermal cycling to achieve zero or at least one copy of the target RNA/DNA per partition. A recently launched platform, the Clarity™ system from JN Medsys, simplifies dPCR workflow through the use of a novel chip-in-a-tube technology for sample partitioning. In this study, the performance of Clarity™ was evaluated through quantification of the single-copy human RNase P gene. The system demonstrated high precision and accuracy and also excellent linearity across a range of over 4 orders of magnitude for the absolute quantification of the target gene. Moreover, consistent DNA copy measurements were also attained using a panel of different probe- and dye-based master mixes, demonstrating the system's compatibility with commercial master mixes. The Clarity™ was then compared to the QX100™ droplet dPCR system from Bio-Rad using a set of DNA reference materials, and the copy number concentrations derived from both systems were found to be closely associated. Collectively, the results showed that Clarity™ is a reliable, robust and flexible platform for next-generation genetic analysis.


Perceptions of Nigerian women on domestic violence: evidence from 2003 Nigeria Demographic and Health Survey.
To facilitate the design of effective programmes to eliminate violence against women in Nigeria, this paper examined women's perceptions of wife beating. The data were derived from the 2003 Nigeria Demographic and Health Survey (NDHS). Both descriptive and analytical methods were used to assess the net effects of socio-demographic factors on women's perceptions of domestic violence. The study demonstrates that a large percentage of Nigerian women agreed that a man is justified in beating or hitting his wife; 66.4% and 50.4% of ever-married and unmarried women respectively expressed consent for wife beating. Respondents' approval of wife beating or abuse varied by personal attributes. Ethnic affiliation, level of education, place of residence, wealth index and frequency of listening to radio were significantly related to concurrence with wife beating. This paper highlights the cultural factors responsible for, and negative effects of, domestic violence against women in Nigeria and makes a case for raising public consciousness against it.


Causes of re-hospitalization in different post kidney transplantation periods.
Post kidney transplantation Re-admissions are focused because they are costly and cause morbidity, or may end with unsatisfactory endpoints namely graft loss or death. We compared the pattern, outcome and cost of re-admissions in different post-kidney transplantation periods. In a retrospective study, 562 consecutive re-admissions of kidney recipients categorized to early (during first 6 months; n=278); intermediate (6-24 months; n=115); and late (24 months and afterwards, n=169) hospitalizations. Primary outcome measures included hospitalization pattern (cause and length of hospital stay), and secondary outcome measure were assessed (mortality and graft loss during hospitalization) and costs. The causes of rehospitalization were surgical complication (84 percent), infection (51 percent), graft rejection (45 percent), and malignancy (0.6 percent), in early phase, graft rejection (44 percent), infection (42 percent), surgical complication (13 percent), and malignancy (5 percent), in intermediate phase, and graft rejection (45 percent), infection (39 percent), surgical complication (3 percent), and malignancy (0.06 percent), in late phase. So, infections and surgical complications showed a decreasing trend from early to late post transplant phase, while malignancies showed a peak in intermediate phase. The length of hospital stay (12+/-11, 10+/-10, 9+/-7, p=0.001) and hospitalization charges (708+/-36, 468+/-333, 413+/-262 united states Dollars, p=0.035) were significantly higher in the early post transplant phase. Mortality (p=0.755) and graft loss during hospitalization (p=0.246) remained the same in all time intervals. Early post-kidney transplantation phase, with a higher risk of infections and surgical complications, health care system experience longer and more costly hospitalizations.


Lipopolysaccharide-induced activation of beta2-integrin function in macrophages requires Irak kinase activity, p38 mitogen- activated protein kinase, and the Rap1 GTPase.
Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, is a potent activator of macrophages. Besides inducing many transcriptional pathways, LPS also elicits rapid morphological changes such as cell spreading. Here we have investigated the signaling pathway that controls macrophage beta2-integrin-dependent spreading in response to LPS. We show that inhibition of the adapter protein MyD88, the interleukin-1 receptor-associated kinase Irak, the p38 mitogen-activated protein kinase, or the Ras-like GTPase Rap1 blocks LPS-induced spreading. In addition, Irak activates p38 and stimulates p38-dependent spreading. The activation of p38 by Irak requires Irak's kinase activity. We find that p38 controls spreading independently of its role in transcription but rather through activation of Rap1. Together, our results suggest that beta2-integrin-dependent spreading of macrophages in response to LPS is controlled by a linear signaling pathway via MyD88, Irak, p38, and Rap1.


Urinary acylcarnitines are altered in human kidney cancer.
Kidney cancer often diagnosed at late stages when treatment options are severely limited. Thus, greater understanding of tumor metabolism leading ultimately to novel approaches to diagnosis is needed. Our laboratory has been utilizing metabolomics to evaluate compounds appearing in kidney cancer patients' biofluids at concentrations different from control patients. Here, we collected urine samples from kidney cancer patients and analyzed them by chromatography coupled to mass spectrometry. Once normalized to control for urinary concentration, samples were analyzed by two independent laboratories. After technical validation, we now show differential urinary concentrations of several acylcarnitines as a function of both cancer status and kidney cancer grade, with most acylcarnitines being increased in the urine of cancer patients and in those patients with high cancer grades. This finding was validated in a mouse xenograft model of human kidney cancer. Biological validation shows carbon chain length-dependent effects of the acylcarnitines on cytotoxicity in vitro, and higher chain length acylcarnitines demonstrated inhibitory effects on NF-κB activation, suggesting an immune modulatory effect of these compounds. Thus, acylcarnitines in the kidney cancer urine may reflect alterations in metabolism, cell component synthesis and/or immune surveillance, and may help explain the profound chemotherapy resistance seen with this cancer. This study shows for the first time the value of a novel class of metabolites which may lead to new therapeutic approaches for cancer and may prove useful in cancer biomarker studies. Furthermore, these findings open up a new area of investigation into the metabolic basis of kidney cancer.


Flexible structured illumination microscope with a programmable illumination array.
Structured illumination microscopy (SIM) has grown into a family of methods which achieve optical sectioning, resolution beyond the Abbe limit, or a combination of both effects in optical microscopy. SIM techniques rely on illumination of a sample with patterns of light which must be shifted between each acquired image. The patterns are typically created with physical gratings or masks, and the final optically sectioned or high resolution image is obtained computationally after data acquisition. We used a flexible, high speed ferroelectric liquid crystal microdisplay for definition of the illumination pattern coupled with widefield detection. Focusing on optical sectioning, we developed a unique and highly accurate calibration approach which allowed us to determine a mathematical model describing the mapping of the illumination pattern from the microdisplay to the camera sensor. This is important for higher performance image processing methods such as scaled subtraction of the out of focus light, which require knowledge of the illumination pattern position in the acquired data. We evaluated the signal to noise ratio and the sectioning ability of the reconstructed images for several data processing methods and illumination patterns with a wide range of spatial frequencies. We present our results on a thin fluorescent layer sample and also on biological samples, where we achieved thinner optical sections than either confocal laser scanning or spinning disk microscopes.


The relationship between waist circumference and the risk of stroke and myocardial infarction in a Japanese urban cohort: the Suita study.
Body mass index is most commonly used as the obesity index. Recently, waist circumference (WC) has been shown to be associated with the risk of cardiovascular disease (CVD). However, no studies have observed an association between WC and CVD in Japan. We examined the relationships of WC and body mass index with CVD in a Japanese urban population. We studied 5474 Japanese individuals (aged 30 to 79 years without CVD at baseline) who completed a baseline survey and received follow-up through December 2005. WC was measured at the umbilical level of participants in the standing position to the nearest 1 cm. The Cox proportional hazard ratios for CVD according to the quartiles of WC were calculated after adjustment for age, smoking, and drinking status. During a mean follow-up of 11.7 years, 207 strokes and 133 myocardial infarctions were documented. In women, compared with the lowest quartile (WC <70 cm), the hazard ratio (95% CIs) after adjusting for age, smoking, and drinking in the highest quartile (WC >or=84 cm) were 1.85 (1.03 to 3.31) for CVD and 2.64 (1.16 to 6.03) for stroke. However, no such relationships of WC with CVD or stroke risk were observed in men. After further adjustment of hypertension, diabetes, and hypercholesterolemia, all of the mentioned relationships were not statistically significant. No associations of body mass index with CVD or strokes were observed. WC may be a better predictor for CVD or stroke in Japanese women.


Enhanced glutamatergic and decreased GABAergic synaptic appositions to GnRH neurons on proestrus in the rat: modulatory effect of aging.
Previous work by our lab and others has implicated glutamate as a major excitatory signal to gonadotropin hormone releasing hormone (GnRH) neurons, with gamma amino butyric acid (GABA) serving as a potential major inhibitory signal. However, it is unknown whether GABAergic and/or glutamatergic synaptic appositions to GnRH neurons changes on the day of the proestrous LH surge or is affected by aging. To examine this question, synaptic terminal appositions on GnRH neurons for VGAT (vesicular GABA transporter) and VGLUT2 (vesicular glutamate transporter-2), markers of GABAergic and glutamatergic synaptic terminals, respectively, was examined by immunohistochemistry and confocal microscopic analysis in young and middle-aged diestrous and proestrous rats. The results show that in young proestrous rats at the time of LH surge, we observed reciprocal changes in the VGAT and VGLUT2 positive terminals apposing GnRH neurons, where VGAT terminal appositions were decreased and VGLUT2 terminal appositions were significantly increased, as compared to young diestrus control animals. Interestingly, in middle-aged cycling animals this divergent modulation of VGAT and VGLUT2 terminal apposition was greatly impaired, as no significant differences were observed between VGAT and VGLUT2 terminals apposing GnRH neurons at proestrous. However, the density of VGAT and VGLUT2 terminals apposing GnRH neurons were both significantly increased in the middle-aged animals. In conclusion, there is an increase in glutamatergic and decrease in GABAergic synaptic terminal appositions on GnRH neurons on proestrus in young animals, which may serve to facilitate activation of GnRH neurons. In contrast, middle-aged diestrous and proestrous animals show a significant increase in both VGAT and VGLUT synaptic terminal appositions on GnRH neurons as compared to young animals, and the cycle-related change in these appositions between diestrus and proestrus that is observed in young animals is lost.


An extensive investigation into the prevalence and the genetic and serological diversity of toxigenic Vibrio parahaemolyticus in Italian marine coastal waters.
The relationship between Vibrio parahaemolyticus strains isolated from the aquatic environment and those isolated from cases of infection in humans is poorly understood due to the low prevalence of tdh- and/or trh-positive strains in the environment. To address this concern, it would be useful to analyse the genetic relationships among environmental and food strains and with reference to clinical isolates, also applying molecular typing methods. The aim of this study was to evaluate the prevalence of toxigenic V.parahaemolyticus in Italian coastal waters and seafood, to examine intra-species variability and to identify, using serotyping and pulsed-field gel electrophoresis (PFGE), relationships among strains from different sources, geographical origin and period of isolation. Of the 192 V.parahaemolyticus strains isolated in different Italian areas and examined in this study, 25 (13.0%) proved to carry the trh gene while none of the strains proved positive to the search by PCR for tdh and Group-Specific-toxRS genes. The prevalence of toxigenic strains in the Tyrrhenian Sea was significantly lower than that calculated for the Ligurian coasts. Regarding the sources of isolation, the higher prevalence of trh-positive V.parahaemolyticus was revealed in fish, followed by clams, plankton, oysters, mussels and lastly seawater. Within the toxigenic strains, 16 serotypes and 20 distinct PFGE patterns were identified. Two clusters, which included a total of 8 V.parahaemolyticus strains, were specifically associated with the North Adriatic Sea area and were stable over time. Our results demonstrate that trh-positive V.parahaemolyticus strains circulated in Italy in the period 2002-2009 with a prevalence higher than that reported from other European and extra-European countries, confirming that toxigenic V.parahaemolyticus is an emerging public health concern in Italy, regardless of its pandemic potential.


The development of a performance indicator to objectively monitor the quality of care provided by an acute pain team.
Quality assurance procedures are essential in the maintenance of clinical standards in medicine. Conventional analysis techniques have difficulty in detecting gradual changes over time. Cumulative sum techniques monitor the frequency with which an event occurs and can detect changes in its frequency as soon as they become statistically significant. This study explores the use of cumulative sum techniques to monitor the performance of an acute pain team in a teaching hospital. It shows that periods of suboptimal performance can be readily identified. The prospective use of these techniques in clinical audit may allow the earlier identification and correction of technical or organisational problems. These should lead to improvements in patient care and satisfaction.


Venous thromboembolism: Past, present and future.
Venous thromboembolism (VTE), the third most frequent acute cardiovascular syndrome, is associated with a considerable disease burden which continues to grow along with the longer life expectancy of the population worldwide. In the past century, parenteral heparin prophylaxis was established for hospitalised patients at elevated risk of VTE. More recently, non-vitamin K antagonist oral anticoagulants (NOACs) with a direct inhibiting effect on factor Xa or thrombin, underwent extensive testing in clinical trials and have been approved for patients undergoing hip or knee replacement. Clinical investigation is ongoing in further areas of thromboprophylaxis, including medical prophylaxis in patients and high-risk situations in the outpatient setting. The diagnostic approach to suspected VTE is now based on advanced imaging techniques and robust diagnostic algorithms which ensure high sensitivity and specificity. Nevertheless, the role of clinical, or pre-test, probability assessment remains crucial to avoid overdiagnosis and treatment errors. Advances in reperfusion strategies, along progressive establishment of the NOACs as the new standard of anticoagulation treatment, have simplified the management of VTE, improving outcomes and particularly safety. While new molecular targets for anticoagulation are being investigated in the quest to further reduce bleeding risk, adjusting the initial regimen to the patient's risk and finding the optimal duration of anticoagulation after an index VTE event will be some of the top priorities in the years to come. Importantly, and in parallel to new drugs and technical advances in imaging, incentives such as hospital accreditation and funding based on evidence-based practice need to be implemented to increase guideline adherence.


MicroRNA-34a is a potent tumor suppressor molecule in vivo in neuroblastoma.
Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system and accounts for 15% of childhood cancer mortalities. With regards to the role of miRNAs in neuroblastoma, miR-34a, mapping to a chromosome 1p36 region that is commonly deleted, has been found to act as a tumor suppressor through targeting of numerous genes associated with cell proliferation and apoptosis. A synthetic miR-34a (or negative control) precursor molecule was transfected into NB1691luc and SK-N-ASluc neuroblastoma cells. Quantitative PCR was used to verify increased miR-34a levels in NB1691luc and SK-N-ASluc cell lines prior to in vitro and in vivo analysis. In vitro analysis of the effects of miR-34a over expression on cell growth, cell cycle and phosphoprotein activation in signal transduction pathways was performed. Neuroblastoma cells over expressing miR-34a were injected retroperitoneally into immunocompromised CB17-SCID mice and tumor burden was assessed over a 21 day period by measuring bioluminescence (photons/sec/cm²). Over expression of miR-34a in both NB1691luc and SK-N-ASluc neuroblastoma cell lines led to a significant decrease in cell number relative to premiR-negative control treated cells over a 72 hour period. Flow cytometry results indicated that miR-34a induced cell cycle arrest and subsequent apoptosis activation. Phosphoprotein analysis highlighted key elements involved in signal transduction, whose activation was dysregulated as a result of miR-34a introduction into cells. As a potential mechanism of miR-34a action on phosphoprotein levels, we demonstrate that miR-34a over-expression results in a significant reduction of MAP3K9 mRNA and protein levels. Although MAP3K9 is a predicted target of miR-34a, direct targeting could not be validated with luciferase reporter assays. Despite this fact, any functional effects of reduced MAP3K9 expression as a result of miR-34a would be expected to be similar regardless of the mechanism involved. Most notably, in vivo studies showed that tumor growth was significantly repressed after exogenous miR-34a administration in retroperitoneal neuroblastoma tumors. We demonstrate for the first time that miR-34a significantly reduces tumor growth in an in vivo orthotopic murine model of neuroblastoma and identified novel effects that miR-34a has on phospho-activation of key proteins involved with apoptosis.


Mechanistic understanding of alkyne cyclotrimerization on mononuclear and dinuclear scaffolds: [4 + 2] cycloaddition of the third alkyne onto metallacyclopentadienes and dimetallacyclopentadienes.
Cyclotrimerization of alkynes catalyzed by transition metal complexes is a straightforward synthetic method for constructing a benzene skeleton in organic synthesis. Not only mononuclear complexes, but also multinuclear complexes act as catalysts for alkyne cyclotrimerization, and their reaction mechanisms have been intensively investigated toward developing highly efficient and regio- and chemo-selective catalysts. In this review, we summarize stoichiometric and catalytic alkyne coupling reactions on mononuclear and dinuclear scaffolds in relation to the reaction mechanism of alkyne cyclotrimerization, including our recent mechanistic approaches using dinuclear tantalum motifs.


Lateral gene transfer and ancient paralogy of operons containing redundant copies of tryptophan-pathway genes in Xylella species and in heterocystous cyanobacteria.
Tryptophan-pathway genes that exist within an apparent operon-like organization were evaluated as examples of multi-genic genomic regions that contain phylogenetically incongruous genes and coexist with genes outside the operon that are congruous. A seven-gene cluster in Xylella fastidiosa includes genes encoding the two subunits of anthranilate synthase, an aryl-CoA synthetase, and trpR. A second gene block, present in the Anabaena/Nostoc lineage, but not in other cyanobacteria, contains a near-complete tryptophan operon nested within an apparent supraoperon containing other aromatic-pathway genes. The gene block in X. fastidiosa exhibits a sharply delineated low-GC content. This, as well as bias of codon usage and 3:1 dinucleotide analysis, strongly implicates lateral gene transfer (LGT). In contrast, parametric studies and protein tree phylogenies did not support the origination of the Anabaena/Nostoc gene block by LGT. Judging from the apparent minimal amelioration, the low-GC gene block in X. fastidiosa probably originated by LGT at a relatively recent time. The surprising inability to pinpoint a donor lineage still leaves room for alternative, albeit less likely, explanations other than LGT. On the other hand, the large Anabaena/Nostoc gene block does not seem to have arisen by LGT. We suggest that the contemporary Anabaena/Nostoc array of divergent paralogs represents an ancient ancestral state of paralog divergence, with extensive streamlining by gene loss occurring in the lineage of descent representing other (unicellular) cyanobacteria.


Resilience of Biocontrol for Aflatoxin Minimization Strategies: Climate Change Abiotic Factors May Affect Control in Non-GM and GM-Maize Cultivars.
There has been significant interest in the development of formulations of non-toxigenic strains of Aspergillus flavus for control of toxigenic strains to reduce the aflatoxin B1 (AFB1) contamination of maize. In the future, climate change (CC) abiotic conditions of temperature (+2-4°C), CO2 (existing levels of 400 vs. 800-1,200 ppb), and drought stress will impact on the agronomy and control of pests and diseases. This study has examined (1) the effect of two-way interacting factors of water activity × temperature on colonization and AFB1 contamination of maize cobs of different ripening ages; (2) the effect of non-toxigenic strains of A. flavus (50:50 inoculum ratio) on relative control of toxigenic A. flavus and AFB1 contamination of ripening cobs; (3) post-harvest control of AFB1 by non-toxigenic strains of A. flavus in non-GM and isogenic GM maize cultivars using the same inoculum ratio; and (4) the impact of three-way interacting CC factors on relative control of AFB1 in maize cobs pre-harvest and in stored non-GM/GM cultivars. Pre-harvest colonization and AFB1 production by a toxigenic A. flavus strain was conserved at 37°C when compared with 30°C, at the three ripening stages of cob development examined: milk ripe (R3), dough (R4), and dent (R5). However, pre-harvest biocontrol with a non-toxigenic strain was only effective at the R3 and R4 stages and not at the R5 stage. This was supported by relative expression of the aflR regulatory biosynthetic gene in the different treatments. When exposed to three-way interacting CC factors for control of AFB1 pre-harvest, the non-toxigenic A. flavus strain was effective at R3 and £4 stages but not at the R5 stage. Post-harvest storage of non-GM and GM cultivars showed that control was achievable at 30°C, with slightly better control in GM-cultivars in terms of the overall inhibition of AFB1 production. However, in stored maize, the non-toxigenic strains of A. flavus had conserved biocontrol of AFB1 contamination, especially in the GM-maize cultivars under three-way interacting CC conditions (37°C × 1,000 ppm CO2 and drought stress). This was supported by the relative expression of the aflR gene in these treatments. This study suggests that the choice of the biocontrol strains, for pre- or post-harvest control, needs to take into account their resilience in CC-related abiotic conditions to ensure that control of AFB1 contamination can be conserved.


[Public Participation and Mental Health: the contrasted and unfinished response of mental health users].
The objective of this article is show the way that mental health users in Quebec responded to the last Mental Health Action Plan Directive (2005-2010): the strength of the links which were labelled as follows: 'The MSSS, The Health and Social Service Agencies, as well as the Centers of Health and Service Agencies must be sure to obtain the participation of mental health users (and those close to them), in all mental health and planning organizational services.' (MSSS, 2005: p.16) METHOD: The results presented in this article are based on the qualitative exploratory study conducted in the 11 regions of Quebec. In total 35 persons participated in the study, 13 service users, 11 persons coming from institutional environments (interveners and administrators) and 11 key players. The PASM's directive gave rise to a major mobilization of service users who drew up social groupings to engage in the participation activities. As well, it has permitted a generalization and regionalization of participation activities. However, the imprecision regarding the organization of the participants relative to the means required to implement the long-awaited results, has given rise to multiple interpretations, and therefore, to uneven results according to the regions, including the interior of the main region. The participation of service users will remain a principle whose effects will be contingent, as long as the ministerial willingness will not be accompanied by precise targets to reach, a planned process of rendering of accounts and adequate financing.


Systematic review of the literature on the effectiveness of product reformulation measures to reduce the sugar content of food and drink on the population's sugar consumption and health: a study protocol.
Obesity, type 2 diabetes and dental caries are all major public health problems in the UK, with significant costs to the healthcare service. We aim to conduct a systematic review to summarise the evidence on the effectiveness of product reformulation measures to reduce the sugar content of food and drink on the population's sugar consumption and health. Electronic database will be systematically searched using a combination of terms, tailored to optimise sensitivity, specificity, and the syntax and functionality of each database. The databases searched will include the Cochrane Library, EMBASE, MEDLINE (Ovid) and Scopus. The bibliographies of those papers that match inclusion criteria will be searched by hand to identify any further, relevant references, which will be subject to the same screening and selection process. The database search results will be supplemented by hand searches. In addition to the peer-reviewed literature, a number of grey literature searches will be undertaken using the broad search terms 'sugar' and 'food' or 'drink' and 'reduction', these searches will include key government and organisation websites as well as general searches in Google. The selection of the studies, data collection and quality appraisal will be performed independently by 2 reviewers. Data will be initially analysed through a narrative synthesis method. If a subset of data we analyse appears comparable, we will investigate the possibility of performing a meta-analysis. Ethics approval will not be required as this is a protocol for a systematic review. The findings will be disseminated widely through conference presentations and published in a peer-reviewed journal. CRD42016034022.


Soliton fusion and steering by the simultaneous launch of two different-color solitons.
Two optical solitons with different center frequencies simultaneously launched into an optical fiber are considered. By numerical simulation and by experiment, it is shown that if their frequency separation is small, they will either merge into a single pulse (fusion) or form two pulses with different velocities (steering), depending on their phase difference. With a 400-m fiber and ~2.5-ps solitons at 1457.7 and 1460.7 nm, fusion and steering of as much as 7 ps are demonstrated.


Delirium accelerates cognitive decline in Alzheimer disease.
To examine the impact of delirium on the trajectory of cognitive function in a cohort of patients with Alzheimer disease (AD). A secondary analysis of data collected from a large prospective cohort, the Massachusetts Alzheimer's Disease Research Center's patient registry, examined cognitive performance over time in patients who developed (n = 72) or did not develop (n = 336) delirium during the course of their illnesses. Cognitive performance was measured by change in score on the Information-Memory-Concentration (IMC) subtest of the Blessed Dementia Rating Scale. Delirium was identified using a previously validated chart review method. Using linear mixed regression models, rates of cognitive change were calculated, controlling for age, sex, education, comorbid medical diagnoses, family history of dementia, dementia severity score, and duration of symptoms before diagnosis. A significant acceleration in the slope of cognitive decline occurs following an episode of delirium. Among patients who developed delirium, the average decline at baseline for performance on the IMC was 2.5 points per year, but after an episode of delirium there was further decline to an average of 4.9 points per year (p = 0.001). Across groups, the rate of change in IMC score occurred about three times faster in those who had delirium compared to those who did not. Delirium can accelerate the trajectory of cognitive decline in patients with Alzheimer disease (AD). The information from this study provides the foundation for future randomized intervention studies to determine whether prevention of delirium might ameliorate or delay cognitive decline in patients with AD.


Intrinsically disordered and pliable Starmaker-like protein from medaka (Oryzias latipes) controls the formation of calcium carbonate crystals.
Fish otoliths, biominerals composed of calcium carbonate with a small amount of organic matrix, are involved in the functioning of the inner ear. Starmaker (Stm) from zebrafish (Danio rerio) was the first protein found to be capable of controlling the formation of otoliths. Recently, a gene was identified encoding the Starmaker-like (Stm-l) protein from medaka (Oryzias latipes), a putative homologue of Stm and human dentine sialophosphoprotein. Although there is no sequence similarity between Stm-l and Stm, Stm-l was suggested to be involved in the biomineralization of otoliths, as had been observed for Stm even before. The molecular properties and functioning of Stm-l as a putative regulatory protein in otolith formation have not been characterized yet. A comprehensive biochemical and biophysical analysis of recombinant Stm-l, along with in silico examinations, indicated that Stm-l exhibits properties of a coil-like intrinsically disordered protein. Stm-l possesses an elongated and pliable structure that is able to adopt a more ordered and rigid conformation under the influence of different factors. An in vitro assay of the biomineralization activity of Stm-l indicated that Stm-l affected the size, shape and number of calcium carbonate crystals. The functional significance of intrinsically disordered properties of Stm-l and the possible role of this protein in controlling the formation of calcium carbonate crystals is discussed.


Transcatheter aortic valve implantation vs. surgical aortic valve replacement for treatment of severe aortic stenosis: a meta-analysis of randomized trials.
In view of the currently available evidence from randomized trials, we aimed to compare the collective safety and efficacy of transcatheter aortic valve implantation (TAVI) vs. surgical aortic valve replacement (SAVR) across the spectrum of risk and in important subgroups. Trials comparing TAVI vs. SAVR were identified through Medline, Embase, and Cochrane databases. The primary outcome was death from any cause at 2 years. We performed random-effects meta-analyses to combine the available evidence and to evaluate the effect in different subgroups. This systematic review and meta-analysis is registered with PROSPERO (CRD42016037273). We identified four eligible trials including 3806 participants, who were randomly assigned to undergo TAVI (n = 1898) or SAVR (n = 1908). For the primary outcome of death from any cause, TAVI when compared with SAVR was associated with a significant 13% relative risk reduction [hazard ratio (95% CI): 0.87 (0.76-0.99); P = 0.038] with homogeneity across all trials irrespective of TAVI device (Pinteraction = 0.306) and baseline risk (Pinteraction = 0.610). In subgroup analyses, TAVI showed a robust survival benefit over SAVR for patients undergoing transfemoral access [0.80 (0.69-0.93); P = 0.004], but not transthoracic access [1.17 (0.88-1.56); P = 0.293] (Pinteraction = 0.024) and in female [0.68 (0.50-0.91); P = 0.010], but not male patients [0.99 (0.77-1.28); P = 0.952] (Pinteraction = 0.050). Secondary outcomes of kidney injury, new-onset atrial fibrillation, and major bleeding favoured TAVI, while major vascular complications, incidence of permanent pacemaker implantation, and paravalvular regurgitation favoured SAVR. Compared with SAVR, TAVI is associated with a significant survival benefit throughout 2 years of follow-up. Importantly, this superiority is observed irrespective of the TAVI device across the spectrum of intermediate and high-risk patients, and is particularly pronounced among patients undergoing transfemoral TAVI and in females.


Resource utilization and work or school loss reported by patients with diabetes: experience in diabetes training programs.
Diabetes exerts a major economic impact on healthcare in the United States both in terms of direct and indirect costs. Diabetes management and education programs designed to assist patients in achieving more optimal glycemic control represent a potential mechanism for reducing the morbidity and costs associated with diabetes. The relationship between HbA1c and patient hospitalizations and between HbA1c and days lost from work or school related to diabetes within the past year were evaluated. A cohort of 2359 patients with diabetes (188 type I, 2171 type II) referred to a comprehensive diabetes self-management training program was included in the analyses. Overall, 350 (14.8%) patients reported hospitalization, and 212 (9.0%) reported days lost from work or school. Patients with type I diabetes reported more hospitalizations (26.1% vs 13.9% and days lost (19.2% vs 8.1%) than type II patients. For the hospitalization outcome, the multivariate analyses indicated that younger age, the number of co-morbidities, and the duration of diabetes exerted a greater influence on the reported numbers of hospitalization than glycemic control. For the days lost outcome, the multivariate analyses indicated that there was a marginally significant association between patients with poor glycemic control and reported work or school loss related to diabetes (odds ratio = 1.5; 95% confidence interval, 1.0-2.2). These data suggest that interventions that improve glycemic control may decrease indirect costs related to diabetes.


Biodiesel production from seed oil of Cleome viscosa L.
Edible oil seed crops, such as rapeseed, sunflower, soyabean and safflower and non-edible seed oil plantation crops Jatropha and Pongamia have proved to be internationally viable commercial sources of vegetable oils for biodiesel production. Considering the paucity of edible oils and unsustainability of arable land under perennial plantation of Jatropha and Pongamia in countries such as India, the prospects of seed oil producing Cleome viscosa, an annual wild short duration plant species of the Indogangetic plains, were evaluated for it to serve as a resource for biodiesel. The seeds of C. viscosa resourced from its natural populations growing in Rajasthan, Haryana and Delhi areas of Aravali range were solvent extracted to obtain the seed oil. The oil was observed to be similar in fatty acid composition to the non-edible oils of rubber, Jatropha and Pongamia plantation crops and soybean, sunflower, safflower, linseed and rapeseed edible oil plants in richness of unsaturated fatty acids. The Cleome oil shared the properties of viscosity, density, saponification and calorific values with the Jatropha and Pongamia oils, except that it was comparatively acidic. The C. viscosa biodiesel had the properties of standard biodiesel specified by ASTM and Indian Standard Bureau, except that it had low oxidation stability. It proved to be similar to Jatropha biodiesel except in cloud point, pour point, cold filter plugging point and oxidation stability. In view of the annual habit of species and biodiesel quality, it can be concluded that C. viscosa has prospects to be developed into a short-duration biodiesel crop.


Minimally Invasive Saliva Testing to Monitor Norovirus Infection in Community Settings.
Norovirus is a leading cause of acute gastroenteritis worldwide. Routine norovirus diagnosis requires stool collection. The goal of this study was to develop and validate a noninvasive method to diagnose norovirus to complement stool diagnostics and to facilitate studies on transmission. A multiplex immunoassay to measure salivary immunoglobulin G (IgG) responses to 5 common norovirus genotypes (GI.1, GII.2, GII.4, GII.6, and GII.17) was developed. The assay was validated using acute and convalescent saliva samples collected from Peruvian children <5 years of age with polymerase chain reaction (PCR)-diagnosed norovirus infections (n = 175) and controls (n = 32). The assay sensitivity and specificity were calculated to determine infection status based on fold rise of salivary norovirus genotype-specific IgG using norovirus genotype from stool as reference. The salivary assay detected recent norovirus infections and correctly assigned the infecting genotype. Sensitivity was 71% and specificity was 96% across the evaluated genotypes compared to PCR-diagnosed norovirus infection. This saliva-based assay will be a useful tool to monitor norovirus transmission in high-risk settings such as daycare centers or hospitals. Cross-reactivity is limited between the tested genotypes, which represent the most commonly circulating genotypes.


Effects of 2,2,2-trifluoroethyl methacrylate on properties of autopolymerized hard direct denture reline resins.
This study evaluated the effects of the fluorinated monomer of 2,2,2-trifluoroethyl methacrylate (TFEMA) on the properties of autopolymerized hard direct denture reline resins. Iso-butyl methacrylate (i-BMA) and 2-hydroxyethyl methacrylate (2-HEMA) containing 30% TFEMA by weight were used as monomers, while poly(ethyl methacrylate) was used as a powder. Setting characteristics, dynamic mechanical properties, and changes over time, as well as wettability were determined by use of an oscillating rheometer, dynamic viscoelastometer, and contact angle meter. Water absorption and solubility were also measured according to ISO specifications. The reline resin based on i-BMA had greater elasticity and stiffness properties, while that based on 2-HEMA showed fewer dynamic mechanical property changes over time with the addition of TFEMA. Furthermore, water absorption and solubility tended to be reduced and contact angle increased. The results of this study suggest that TFEMA improves mechanical properties and durability of reline resins over time.


Cognitive flexibility correlates with gambling severity in young adults.
Although gambling disorder (GD) is often characterized as a problem of impulsivity, compulsivity has recently been proposed as a potentially important feature of addictive disorders. The present analysis assessed the neurocognitive and clinical relationship between compulsivity on gambling behavior. A sample of 552 non-treatment seeking gamblers age 18-29 was recruited from the community for a study on gambling in young adults. Gambling severity levels included both casual and disordered gamblers. All participants completed the Intra/Extra-Dimensional Set Shift (IED) task, from which the total adjusted errors were correlated with gambling severity measures, and linear regression modeling was used to assess three error measures from the task. The present analysis found significant positive correlations between problems with cognitive flexibility and gambling severity (reflected by the number of DSM-5 criteria, gambling frequency, amount of money lost in the past year, and gambling urge/behavior severity). IED errors also showed a positive correlation with self-reported compulsive behavior scores. A significant correlation was also found between IED errors and non-planning impulsivity from the BIS. Linear regression models based on total IED errors, extra-dimensional (ED) shift errors, or pre-ED shift errors indicated that these factors accounted for a significant portion of the variance noted in several variables. These findings suggest that cognitive flexibility may be an important consideration in the assessment of gamblers. Results from correlational and linear regression analyses support this possibility, but the exact contributions of both impulsivity and cognitive flexibility remain entangled. Future studies will ideally be able to assess the longitudinal relationships between gambling, compulsivity, and impulsivity, helping to clarify the relative contributions of both impulsive and compulsive features.


Elucidating stream bacteria utilizing terrestrial dissolved organic matter.
Terrestrial dissolved organic matter (tDOM) is susceptible to microbiological and photolytic oxidations and contributes significantly to the energy flow in aquatic ecosystems. However, bacterial species actively utilizing this tDOM are still not determined. We here elucidated the microbial groups actively utilizing tDOM. We characterized sediment microbial biomass and community structure using phospholipid phosphate and phospholipid fatty acids (PLFAs) analysis, respectively, and identified metabolically active members using PLFA stable-isotope-probing. Prokaryotes comprised 61% of the streambed microbial community consisting of aerobic, facultative anaerobic and anaerobic bacteria while microeukaryotes comprised the remaining 39%. Sediments were incubated in re-circulating mesocosm chambers amended with leachate from composted 13C-labelled tulip poplar (Liriodendron tulipifera L.) tree-tissues and examined for 13C incorporation into microbial PLFAs. The structure of stream sediment microbial communities prior to and after mesocosm incubation, in both the presence and absence of 13C-labeled DOM, showed no significant differences and indicated our mesocosm-based experimental design as sufficiently robust to investigate the utilization of 13C-DOM by sediment microbial communities. After 48 h of incubation, bacterial fatty acids i15:0, a15:0, 16:0, 16:1ω9, 18:1ω9c, 18:1ω7c, 10me16 and cy19:0 showed increased abundance of 13C. This identified the aerobic, facultative anaerobic and anaerobic bacteria as actively utilizing the 13C-labeled DOM. A single dark 48 h incubation showed incorporation into both bacterial and microeukaryotic fatty acids (20:4ω6, 20:5ω3) suggesting that microeukaryotic predators consumed bacteria that utilized 13C-labeled DOM. Hence, our data support the hypothesis that streamwater tDOM is utilized by stream bacteria, and substantially contributes to the energy flow in aquatic ecosystems.


Role of circulating endotoxin and interleukin-6 in the ACTH and corticosterone response to intraperitoneal LPS.
Peripheral administration of lipopolysaccharide (LPS) may activate the hypothalamus-pituitary-adrenal (HPA) axis by way of both neural and humoral mechanisms. We have investigated whether biologically active endotoxin appears in the general circulation after intraperitoneal administration of LPS (5 or 100 micrograms/kg) to rats and whether this is a prerequisite for activation of this HPA axis. Within 15 min, endotoxin appeared in the general circulation, whereas elevations of plasma adrenocorticotropic hormone (ACTH), corticosterone, and interleukin (IL)-6 concentrations were not detected until 90 min after LPS injection. At this time, a marked interindividual variation was observed in plasma concentrations of endotoxin, ACTH, corticosterone, and IL-6. Elevated levels of plasma endotoxin were associated with elevated levels of ACTH, corticosterone, and IL-6. Intravenous administration of the LPS antagonist cationic antimicrobial protein 18 (5 mg/kg), which did not affect cytokine production in the peritoneal cavity, markedly reduced plasma ACTH, corticosterone, and IL-6 levels after 5 micrograms/kg LPS. Our results suggest that circulating endotoxin is required for the activation of the HPA axis. They also favor a role for circulating IL-6 in this response.


Cells of the human intestinal tract mapped across space and time.
The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung's disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.


Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling.
The MHC class I allele HLA-B27 is very strongly associated with development of autoimmune spondyloarthritis, although the disease mechanism remains unknown. Class I molecules classically associate in the endoplasmic reticulum (ER) with beta2-microglobulin (beta(2)m) and antigenic peptides for cell surface expression and presentation to T cells. We have previously shown that HLA-B27 is capable of forming beta(2)m-free disulfide-bonded homodimers in vitro. Here we show that HLA-B27 forms disulfide-bonded homodimers in vivo by two distinct pathways. HLA-B27 homodimers form in the ER but appear unable to egress to the cell surface in human cells. Cell surface HLA-B27 homodimers are abundantly expressed in a variety of lymphoid cell lines. Experiments with inhibitors indicate that HLA-B27 homodimers can arise from cell-surface heterodimers via an endosome-dependent recycling pathway. HLA-B27 homodimer expression on the cell surface of 721.220 is dependent on the unpaired cysteine(67) and is inhibited by restoration of tapasin function or by incubation with peptides that bind strongly to HLA-B27 heterodimers. Cell surface expressed HLA-B27 homodimers are likely to be immunologically reactive ligands for NK family immunoreceptors and, hence, could play a pathogenic role in spondyloarthritis.


Synthesis of multisubstituted phenols by formal [4 + 2] cycloaddition of nucleophilic alkynes with 3-ethoxycyclobutanones.
Nucleophilic alkynes bearing sulfonamide, trimethylsilyl, or p-methoxyphenyl groups at the sp carbon reacted with 3-ethoxycyclobutanones to give formal [4 + 2] cycloadducts by activation with TiCl4. Reactions with 2-monoalkyl and 2-nonsubstituted 3-ethoxycyclobutanones gave phenol derivatives directly by benzannulation, while the use of 2,2-dimethyl-3-ethoxycyclobutanone gave the corresponding dienones, which were converted to pentasubstituted phenols by dienone-phenol rearrangement. Regioselectivity that depended on the activation conditions of dienone-phenol rearrangement is also described.


Strong Southern Ocean carbon uptake evident in airborne observations.
The Southern Ocean plays an important role in determining atmospheric carbon dioxide (CO2), yet estimates of air-sea CO2 flux for the region diverge widely. In this study, we constrained Southern Ocean air-sea CO2 exchange by relating fluxes to horizontal and vertical CO2 gradients in atmospheric transport models and applying atmospheric observations of these gradients to estimate fluxes. Aircraft-based measurements of the vertical atmospheric CO2 gradient provide robust flux constraints. We found an annual mean flux of –0.53 ± 0.23 petagrams of carbon per year (net uptake) south of 45°S during the period 2009–2018. This is consistent with the mean of atmospheric inversion estimates and surface-ocean partial pressure of CO2 (Pco2)–based products, but our data indicate stronger annual mean uptake than suggested by recent interpretations of profiling float observations.


Development of Predictive Classification Models for Whole Cell Antimycobacterial Activity of Benzothiazinones.
Nitrobenzothiazinones (BTZs) are a very potent class of antibiotics against Mycobacterium tuberculosis. However, relationships between their structural properties and whole cell activity remain poorly predictable. Herein, we present the synthesis and antimycobacterial evaluation of a diverse set of BTZs. High potency was predominantly achieved by piperidine and piperazine substitutions, whereupon three compounds were identified as promising candidates, showing preferable metabolic stability. Lack of correlation between potency and calculated binding energies suggested that target inhibition is not the only requirement to obtain suitable antimycobacterial agents. In contrast, prediction of whole cell activity class was successfully accomplished by extensively validated machine learning models. The performance of the superior model was further verified by >70% correct class predictions for a large set of reported BTZs. Our generated model is thus a key prerequisite to streamline lead optimization endeavors, particularly regarding the improvement of overall hit rates in whole cell antimycobacterial assays.


Validation of Demographics, Etiology, and Risk Factors for Chronic Pancreatitis in the USA: A Report of the North American Pancreas Study (NAPS) Group.
Our aim was to validate recent epidemiologic trends and describe the distribution of TIGAR-O risk factors in chronic pancreatitis (CP) patients. The NAPS-2 Continuation and Validation (NAPS2-CV) study prospectively enrolled 521 CP patients from 13 US centers from 2008 to 2012. CP was defined by definitive changes in imaging, endoscopy, or histology. Data were analyzed after stratification by demographic factors, physician-defined etiology, participating center, and TIGAR-O risk factors. Demographics and physician-defined etiology in the NAPS2-CV study were similar to the original NAPS2 study. Mean age was 53 years (IQR 43, 62) with 55% males and 87% white. Overall, alcohol was the single most common etiology (46%) followed by idiopathic etiology (24%). Alcohol etiology was significantly more common in males, middle-aged (35-65 years), and non-whites. Females and elderly (≥65 years) were more likely to have idiopathic etiology, while younger patients (<35 years) to have genetic etiology. Variability in etiology was noted by participating centers (e.g., alcohol etiology ranged from 27 to 67% among centers enrolling ≥25 patients). Smoking was the most commonly identified (59%) risk factor followed by alcohol (53%), idiopathic (30%), obstructive (19%), and hyperlipidemia (13%). The presence of multiple TIGAR-O risk factors was common, with 1, 2, ≥3 risk factors observed in 27.6, 47.6, and 23.6% of the cohort, respectively. Our data validate the current epidemiologic trends in CP. Alcohol remains the most common physician-defined etiology, while smoking was the most commonly identified TIGAR-O risk factor. Identification of multiple risk factors suggests CP to be a complex disease.


Cardiac autonomic imaging with SPECT tracers.
Radionuclide cardiac imaging has potential to assess underlying molecular, electrophysiologic, and pathophysiologic processes of cardiac disease. An area of current interest is cardiac autonomic innervation imaging with a radiotracer such as (123)I-meta-iodobenzylguanidine ((123)I-mIBG), a norepinephrine analogue. Cardiac (123)I-mIBG uptake can be assessed by planar and SPECT techniques, involving determination of global uptake by a heart-to-mediastinal ratio, tracer washout between early and delayed images, and focal defects on tomographic images. Cardiac (123)I-mIBG findings have consistently been shown to correlate strongly with heart failure severity, pre-disposition to cardiac arrhythmias, and poor prognosis independent of conventional clinical, laboratory, and image parameters. (123)I-mIBG imaging promises to help monitor a patient's clinical course and response to therapy, showing potential to help select patients for an ICD and other advanced therapies better than current methods. Autonomic imaging also appears to help diagnose ischemic heart disease and identify higher risk, as well as risk-stratify patients with diabetes. Although more investigations in larger populations are needed to strengthen prior findings and influence modifications of clinical guidelines, cardiac (123)I-mIBG imaging shows promise as an emerging technique for recognizing and following potentially life-threatening conditions, as well as improving our understanding of the pathophysiology of various diseases.


An outbreak of fatal fluoride intoxication in a long-term hemodialysis unit.
To determine the cause of an outbreak of acute illness and death in a long-term hemodialysis unit. A retrospective cohort and case-control study of patients receiving hemodialysis and a laboratory study of a model deionization system to purify water for hemodialysis. An outpatient hemodialysis unit of a university hospital. 12 patients who became severely ill after hemodialysis treatment and 20 patients who did not become ill after receiving hemodialysis treatment in the same unit. Medical and dialysis unit records were reviewed to identify and characterize cases. Fluids for dialysis were tested for toxic substances, and fluoride was measured in patients' serum. Resistivity and fluoride were measured in effluent from a model deionization system operated in the same way as the system associated with illness. During five consecutive hemodialysis shifts, 12 of 15 patients receiving dialysis treatment in one room became acutely ill, with severe pruritus, multiple nonspecific symptoms, and/or fatal ventricular fibrillation (3 patients). None of 17 patients treated in the adjacent room became ill (P < 0.0001). Death was associated with longer hemodialysis time and increased age compared with other patients who became ill. Serum concentrations of fluoride in the sick patients were markedly increased to as high as 716 mumol/L, and the source of fluoride was the temporary deionization system used to purify water for hemodialysis only in the affected room. Operation of a model deionization system showed how fluoride was adsorbed and then displaced in a massive efflux. Because deionization systems are used widely in hemodialysis and can cause fatal fluoride intoxication, careful design and monitoring are essential.


Perlecan is essential for cartilage and cephalic development.
Perlecan, a large, multi-domain, heparan sulfate proteoglycan originally identified in basement membrane, interacts with extracellular matrix proteins, growth factors and receptors, and influences cellular signalling. Perlecan is present in a variety of basement membranes and in other extracellular matrix structures. We have disrupted the gene encoding perlecan (Hspg2) in mice. Approximately 40% of Hspg2-/- mice died at embryonic day (E) 10.5 with defective cephalic development. The remaining Hspg2-/- mice died just after birth with skeletal dysplasia characterized by micromelia with broad and bowed long bones, narrow thorax and craniofacial abnormalities. Only 6% of Hspg2-/- mice developed both exencephaly and chondrodysplasia. Hspg2-/- cartilage showed severe disorganization of the columnar structures of chondrocytes and defective endochondral ossification. Hspg2-/- cartilage matrix contained reduced and disorganized collagen fibrils and glycosaminoglycans, suggesting that perlecan has an important role in matrix structure. In Hspg2-/- cartilage, proliferation of chondrocytes was reduced and the prehypertrophic zone was diminished. The abnormal phenotypes of the Hspg2-/- skeleton are similar to those of thanatophoric dysplasia (TD) type I, which is caused by activating mutations in FGFR3 (refs 7, 8, 9), and to those of Fgfr3 gain-of-function mice. Our findings suggest that these molecules affect similar signalling pathways.


Waist circumference predicts clustering of cardiovascular risk factors in older South Africans.
A cross-sectional analytical study to determine the cardiovascular risk factor profile of older residents of fishing villages on the West Coast of South Africa, and to determine which anthropometric measures are associated with risk factors. A convenient community-based sample of 152 subjects of mixed ancestry aged 55 years and over was recruited door-to-door using an address list of age-eligible subjects provided by the local public health care clinics. Cardiovascular relationships were investigated between (i) number of risk factors (hypertension, hypercholesterolaemia, diabetes) and body mass index (BMI), waist-to-hip ratio (WHR), and waist circumference; and (ii) continuous cardiovascular risk factor variables and physical activity, smoking, dietary intake, and 24-hour urinary sodium and potassium concentrations. The prevalence of hypertension ( > or =160/95 mmHg) was 74.3% (95% CI: 67.2 - 81.4%). Neither 24-hour urinary sodium nor potassium concentrations was associated with blood pressure (BP). Past, but not present, moderate-intensity physical activity, particularly that associated with occupation, was negatively associated with systolic BP (r = -0.24, P < 0.05). The prevalence of diabetes and hypercholesterolaemia (serum cholesterol > or = 6.5 mmol/l) was 24.6% (95% CI: 17.2 - 32%) and 40% (95% CI: 31.8 - 48.2%), respectively. The percentage of subjects with 0, 1, or 2 or more cardiovascular risk factors was 13.4%, 44.1% and 42.5%, respectively. Subjects with a waist circumference > or = 92 cm had a significantly higher number of cardiovascular risk factors than those with a waist circumference < 92 cm ( chi(2) = 9.29, P < 0.01), and this association remained significant even after controlling for age, sex and smoking (P < 0.05). Neither BMI tertiles according to sex, nor a BMI cut-point > or =30, was significantly associated with a clustering of risk factors. In a sample of older South Africans of mixed ancestry at high risk of cardiovascular disease, waist circumference measuring > or = 92 cm predicts clustering of risks factors, independently of BMI. This simple, population-specific reference value may provide a useful screening tool to identify at-risk individuals for targeted prevention for coronary heart disease and associated metabolic disorders.


Tobacco industry efforts to erode tobacco advertising controls in Hungary.
To review strategies of transnational tobacco companies (TTCs) at creating a favourable advertising environment for their products in Hungary, with special regard to efforts resulting in the liberalisation of tobacco advertising in 1997. Analysis of internal tobacco industry documents relevant to Hungary available on the World Wide Web. Transcripts of speeches of members of the Parliament during the debate of the 1997 advertising act were also reviewed. The tobacco companies not only entered the Hungarian market by early participation in the privatisation of the former state tobacco monopoly, but also imported theirsophisticated marketing experiences. Evasion and violation of rules in force, creation of new partnerships, establishment and use of front groups, finding effective ways for influencing decision makers were all parts of a well orchestrated industry effort to avoid a strict marketing regulation for tobacco products.


Consequences of Molecular Architecture on the Supramolecular Assembly of Discrete Block Co-oligomers.
Supramolecular block copolymers composed of discrete blocks have promising properties for nanotechnology resulting from their ability to combine well-defined morphologies with good bulk material properties. Here, we present the impact of a well-defined siloxane block in either the main-chain or present as pendant grafts on the properties of supramolecular block copolymers that form ordered nanostructures with sub-5 nm domains. For this, two types of supramolecular block copolymers were synthesized based on the ureidopyrimidinone-urethane (UPy-UT) motif. In the first, oligodimethylsiloxanes (oDMS) of discrete length were end-capped with the UPy-UT motif, affording main-chain UPy-UT-Si n . In the second, the UPy-UT motif was grafted with discrete oDMS affording grafted UPy-UT- g -Si 7 . For the two systems, the compositions are similar; only the molecular architecture differs. In both cases, crystallization of the UPy-UT block is in synergy with phase segregation of the oDMS, resulting in the formation of lamellar morphologies. The grafted UPy-UT- g -Si 7 can form long-range ordered lamellae, resulting in the formation of micrometer-sized 2D sheets of supramolecular polymers which show brittle properties. In contrast, UPy-UT-Si n forms a ductile material. As the compositions of both BCOs are similar, the differences in morphology and mechanical properties are a direct consequence of the molecular architecture. These results showcase how molecular design of the building block capable of forming block copolymers translates into controlled nanostructures and material properties as a result of the supramolecular nature of the interactions.


3,3'-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice.
Studies have linked the consumption of broccoli and other cruciferous vegetables to a reduced risk of breast cancer. The phytochemical indole-3-carbinol (I3C), present in cruciferous vegetables, and its major acid-catalyzed reaction product 3,3'-diindolylmethane (DIM) have bioactivities relevant to the inhibition of carcinogenesis. In this study, the effect of DIM on angiogenesis and tumorigenesis in a rodent model was investigated. We found that DIM produced a concentration-dependent decrease in proliferation, migration, invasion and capillary tube formation of cultured human umbilical vein endothelial cells (HUVECs). Consistent with its antiproliferative effect, which was significant at only 5 microM DIM, this indole caused a G1 cell cycle arrest in actively proliferating HUVECs. Furthermore, DIM downregulated the expression of cyclin-dependent kinases 2 and 6 (CDK2, CDK6), and upregulated the expression of CDK inhibitor, p27(Kip1), in HUVECs. We observed further in a complementary in vivo Matrigel plug angiogenesis assay that, compared with vehicle control, neovascularization was inhibited up to 76% following the administration of 5 mg/kg DIM to female C57BL/6 mice. Finally, this dose of DIM also inhibited the growth of human MCF-7 cell tumor xenografts by up to 64% in female athymic (nu/nu) mice, compared with the vehicle control. This is the first study to show that DIM can strongly inhibit the development of human breast tumor in a xenograft model and to provide evidence for the antiangiogenic properties of this dietary indole.


Synthesis, structure and spectral and electrochemical properties of 3-pyrrolyl BODIPY-metal dipyrrin complexes.
The stable dipyrrin substituted 3-pyrrolyl BODIPY (α-dipyrrin 3-pyrrolyl BODIPY) was synthesized by oxidation of dipyrromethane substituted 3-pyrrolyl BODIPY with 2,3-dichloro-5,6-dicyano-benzoquinone in CH2Cl2 at room temperature. The α-dipyrrin 3-pyrrolyl BODIPY is characterized by using HR-MS, 1D, 2D NMR and absorption spectroscopic techniques. The absorption spectrum of α-dipyrrin 3-pyrrolyl BODIPY showed a characteristic absorption band at 630 nm and a charge transfer band at 717 nm due to intramolecular charge transfer from the dipyrrin unit to the 3-pyrrolyl BODIPY unit. The 3-pyrrolyl BODIPY-metal dipyrrin complexes (Pd(ii), Re(i) and Ru(ii)) were prepared by treating α-dipyrrin 3-pyrrolyl BODIPY with appropriate metal salts in toluene-triethylamine at 100 °C and purified by silica gel column chromatography. The crystal structure obtained for the 3-pyrrolyl BODIPY-Pd(ii) dipyrrin complex showed that the 3-pyrrolyl BODIPY and metal dipyrrin moieties are aligned to each other with an angle of 41.9°. The absorption studies showed a strong band at ∼620 nm corresponding to 3-pyrrolyl BODIPY moiety and a weak band at ∼530 nm corresponding to metal dipyrrin unit with complete disappearance of the charge transfer band at 717 nm. The complexes are electron deficient and exhibited only reversible/quasi-reversible reductions in cyclic voltammetry.


A very low-carbohydrate diet improves gastroesophageal reflux and its symptoms.
Obese patients with gastroesophageal reflux disease (GERD) may experience resolution of symptoms utilizing a very low-carbohydrate diet. The mechanism of this improvement is unknown. This studied aimed to prospectively assess changes in distal esophageal acid exposure and GERD symptoms among obese adults initiating a very low-carbohydrate diet. We studied obese individuals with GERD initiating a diet containing less than 20 g/day of carbohydrates. Symptom severity was assessed using the GERD Symptom Assessment Scale--Distress Subscale (GSAS-ds). Participants underwent 24-hr esophageal pH probe testing and initiated the diet upon its completion. Within 6 days, a second pH probe test was performed. Outcomes included changes in the Johnson-DeMeester score, percentage total time with a pH<4 in the distal esophagus, and GSAS-ds scores. Eight participants were enrolled. Mean Johnson-DeMeester score decreased from 34.7 to 14.0 (P=0.023). Percentage time with pH<4 decreased from 5.1% to 2.5% (P=0.022). Mean GSAS-ds score decreased from 1.28 to 0.72 (P=0.0004). These data suggest that a very low-carbohydrate diet in obese individuals with GERD significantly reduces distal esophageal acid exposure and improves symptoms.


beta-lactam susceptibility of Escherichia coli isolates from urinary tract infections exhibiting different resistance phenotypes.
Susceptibility to beta-lactams was determined in 203 recent Spanish E. coli isolates from urinary tract infections exhibiting different resistance phenotypes: a) susceptible (n = 60); b) quinolone-resistant (n = 45); c) penicillinase (n=64); d) hyperproduction of penicillinase (n=8); e) inhibitor resistant TEM (IRT) (n=18), and f) extended spectrum betalactamase (ESBL) (n=8).Minimum inhibitory concentration (MIC) determination by agar dilution and susceptibility tests for ESBL detection by macrodilution were performed following CLSI recommendations. All the beta-lactams tested showed high activity against susceptible and penicillinase phenotypes, with close to 100 % susceptibility. Hyperproduction of penicillinase increased MIC90 values for all antibiotics except for meropenem, with 100% resistance to cefuroxime and amoxicillin/clavulanic acid, and 100% susceptibility to cefotaxime, piperacillin/tazobactam and meropenem. All the antibiotics, except for amoxicillin/clavulanic acid, exhibited high activity against IRT. Meropenem, cefminox and piperacillin/tazobactam exhibited the highest activity against ESBL, followed by amoxicillin/clavulanic acid. The most active compound among the parenteral antibiotics was meropenem, regardless of the resistance phenotype. Among the oral antibiotics, the most active compound was cefditoren with the exception of ESBL where amoxicillin/clavulanic acid where the MIC90 value was one dilution lower.


Pleomorphic dermal sarcoma: adverse histologic features predict aggressive behavior and allow distinction from atypical fibroxanthoma.
The behavior of atypical fibroxanthoma is benign, if strict diagnostic criteria are applied. Tumors with similar pathologic features but deep subcutaneous invasion, necrosis, and/or lymphovascular or perineural invasion are thought to be associated with adverse outcome and are better regarded as pleomorphic dermal sarcoma or undifferentiated pleomorphic sarcoma of skin. This tumor group is not well documented in the literature, and its characteristics are only poorly defined. To study the clinical and pathologic spectrum more comprehensively, we retrieved 32 pleomorphic dermal sarcomas from our departmental files. The tumors were large (median: 25 mm) and exclusively presented on sun-damaged skin with a strong predilection for the head. Typically, elderly men were affected (median age: 81 y). Histologically, these often ulcerated tumors were poorly marginated, asymmetrical, and deeply invasive into deep subcutaneous, muscular, and/or fascial tissues. The tumors were cellular and composed of pleomorphic epithelioid cells, atypical spindle cells, and multinucleated tumor giant cells in varying proportions. Mitotic count was brisk and often atypical. Tumor necrosis was observed in 53%, lymphovascular invasion in 26%, and perineural infiltration in 29%. The majority of tumors showed a predominance of atypical spindle cells in a fascicular arrangement. A sheet-like growth of pleomorphic epithelioid cells or mixed spindle and epithelioid cell features were less frequently observed. Myxoid and keloidal change, a desmoplastic stromal response, pseudoangiomatous and storiform growth patterns, and admixed osteoclast-like giant cells were additional morphologic features in some cases. No immunoreactivity was noted for multiple cytokeratins, S100, HMB-45, desmin, and CD34. Smooth muscle actin was expressed in 70%, CD31 in 48%, epithelial membrane antigen in 16%, Melan A in 6%, and p63 in 1 case. CD10 was expressed in all cases stained. Follow-up (available for 29 patients; median: 24 mo) showed local recurrence in 28% and a metastatic rate of 10%, mainly in the skin. Progressive metastatic disease was observed in 2 patients. Remission was achieved in 1 patient using systemic chemotherapy. The second patient died in the setting of advanced-stage non-Hodgkin lymphoma. No disease-related mortality was noted. Our data underscore the importance of recognizing adverse histologic features in tumors otherwise resembling atypical fibroxanthoma. Deep subcutaneous invasion, tumor necrosis, and perineural and/or lymphovascular invasion confers at least low-grade malignant potential.


Familial neuroendocrine tumors as a model of hereditary cancer.
Familial neuroendocrine tumors are reviewed. The most dramatic advances have been in the application of molecular genetic techniques to define the affected genes and to develop predictive testing for patients with multiple endocrine neoplasia syndromes. Germline mutations at specific loci of the RET proto-oncogene have been demonstrated in patients with multiple endocrine neoplasia types IIA, IIB, and familial medullary thyroid carcinoma not associated with multiple endocrine neoplasia. This has led to direct DNA testing for these mutations in patients at risk for these syndromes. The approach to predictive testing, diagnosis, and early treatment of these patients is discussed as a model for the approach to hereditary cancers. Linkage testing with DNA markers is still required for patients with multiple endocrine neoplasia type I because the responsible gene has not yet been isolated. Efforts to clarify the etiologies of other familial neuroendocrine tumors not associated with multiple endocrine neoplasia continue. Familial pheochromocytoma, neuroblastoma, and carcinoid also are reviewed. The use of molecular genetic techniques as a powerful tool for the early identification and treatment of susceptible individuals is emphasized.


Characterization of a robust co(II) fluorescent complex deposited intact on HOPG.
The new diimine fluorescent ligand ACRI-1 based on a central acridine yellow core is reported along with its coordination complex [Co2 (ACRI-1)2 ] (1), a fluorescent weak ferromagnet. Due to the strong fluorescence of the acridine yellow fluorophore, it is not completely quenched when the ligand is coordinated to Co(II) . The magnetic properties of bulk complex 1 and its stability in solution have been studied. Complex 1 has been deposited on highly ordered pyrolitic graphite (HOGP) from solution. The thin films prepared have been characterized by AFM, time-of-flight secondary ion mass spectrometry (TOF-SIMS), grazing incidence X-ray diffraction (GIXRD), X-ray absorption spectroscopy (XAS), X-ray magnetic circular dichroism (XMCD) and theoretical calculations. The data show that the complex is robust and remains intact on the surface of graphite.


Molecular typing of Meningiomas by Desorption Electrospray Ionization Mass Spectrometry Imaging for Surgical Decision-Making.
Meningiomas are the most frequent intracranial tumors. The majority is benign slow-growing tumors but they can be difficult to treat depending on their location and size. While meningiomas are well delineated on magnetic resonance imaging by their uptake of contrast, surgical limitations still present themselves from not knowing the extent of invasion of the dura matter by meningioma cells. The development of tools to characterize tumor tissue in real or near real time could prevent recurrence after tumor resection by allowing for more precise surgery, i.e. removal of tumor with preservation of healthy tissue. The development of ambient ionization mass spectrometry for molecular characterization of tissue and its implementation in the surgical decision-making workflow carry the potential to fulfill this need. Here, we present the characterization of meningioma and dura mater by desorption electrospray ionization mass spectrometry to validate the technique for the molecular assessment of surgical margins and diagnosis of meningioma from surgical tissue in real-time. Nine stereotactically resected surgical samples and three autopsy samples were analyzed by standard histopathology and mass spectrometry imaging. All samples indicated a strong correlation between results from both techniques. We then highlight the value of desorption electrospray ionization mass spectrometry for the molecular subtyping/subgrouping of meningiomas from a series of forty genetically characterized specimens. The minimal sample preparation required for desorption electrospray ionization mass spectrometry offers a distinct advantage for applications relying on real-time information such as surgical decision-making. The technology here was tested to distinguish meningioma from dura mater as an approach to precisely define surgical margins. In addition we classify meningiomas into fibroblastic and meningothelial subtypes and more notably recognize meningiomas with NF2 genetic aberrations.


Monstar disclinations in the polarization of singular optical beams.
The control of spatial and polarization modes of optical beams enables the production of topological singularities encoded on the polarization of the light. This allows the study of topological disclinations not easily found in the natural setting. In this article we report on the observation of new features in disclinations realized with singular optical beams. They were prepared using three spatial modes bearing optical vortices in non-separable superpositions with circular polarization states. The disclinations involve asymmetric rotational dislocations, whose optical counterparts in the optical far field are known as C-points, and which are classified as monstars. They have been known to have a singularity index that can be positive, or negative as reported by us recently. Here we report on monstars with an index of zero. Monstars are characterized by having sectors bound by radial lines that involve curved lines radiating from the singularity. We found that kinks in otherwise smooth line patterns of asymmetric disclinations are scars of a separate but related pattern of line-slope discontinuities, carried optically by C-lines in the far field. These scars are indicative of the underlying structure or symmetry of the pattern. We present a general formalism to understand and generate monstars, along with measurements: the experimental results are in excellent agreement with theoretical modelings.