Reduced amylin release is a characteristic of impaired glucose tolerance and type 2 diabetes in Japanese Americans.
Islet amyloid is a characteristic feature of type 2 diabetes. Its major component is the normal beta-cell secretory product amylin, or islet amyloid polypeptide (IAPP). To determine whether increased or disproportionate release of amylin may explain the propensity for amyloid deposition in type 2 diabetes, we measured plasma amylin-like immunoreactivity (ALI) and immunoreactive insulin (IRI) release in response to an oral glucose load in 94 Japanese-American subjects with normal glucose tolerance (NGT; n=56), impaired glucose tolerance (IGT; n=10), and type 2 diabetes (n=28) as defined by World Health Organization criteria. The incremental increase in ALI, IRI, and glucose (G) at 30 min after oral glucose ingestion was used to calculate deltaALI/deltaG and deltaIRI/deltaG as measures of beta-cell function. Overall glucose metabolism was assessed as the incremental glucose area (glucose AUC) during the 2 h of the oral glucose tolerance test. As expected, plasma glucose concentrations at both fasting (NGT, 5.0+/-0.4; IGT, 5.5+/-0.1; type 2 diabetes, 6.2+/-0.3 mmol/l; P < 0.0001) and 2 h (NGT, 6.7+/-0.1; IGT, 9.4+/-0.3; type 2 diabetes, 13.2 +/-0.5 mmol/l; P < 0.0001) were elevated in individuals with IGT and type 2 diabetes. In response to glucose ingestion, plasma IRI and ALI increased in all subjects, but these increments were lower in individuals with reduced glucose tolerance, as reflected in the deltaIRI/deltaG (NGT, 119+/-10.3; IGT, 60.7+/-7.1; type 2 diabetes, 49.7 +/-5.4 pmol/l; P < 0.0001) and deltaALI/deltaG (NGT, 2.6+/-0.2; IGT, 1.8+/-0.3; type 2 diabetes, 1.2+/-0.1 pmol/l; P < 0.0001). Moreover, these reductions in the 30-min incremental ALI and IRI responses were proportionate such that the molar ratio of ALI to IRI was not different among the three groups (NGT, 2.6+/-0.2; IGT, 2.9 +/-0.3; type 2 diabetes, 2.9+/-0.3%; NS). Further, the relationship between beta-cell function, measured as either deltaIRI/deltaG or deltaALI/deltaG, and glucose metabolism, assessed as glucose AUC, was nonlinear and inverse in nature, with r2 values of 0.38 (P < 0.0001) and 0.33 (P < 0.0001), respectively. We conclude that the reduced beta-cell function of IGT and type 2 diabetes includes proportionate reductions in both IRI and ALI release. Thus, it is unlikely that the development of islet amyloid in type 2 diabetes is the result of increased release of ALI.


Purification and characterisation of the yeast plasma membrane ATP binding cassette transporter Pdr11p.
The ATP binding cassette (ABC) transporters Pdr11p and its paralog Aus1p are expressed under anaerobic growth conditions at the plasma membrane of the yeast Saccharomyces cerevisiae and are required for sterol uptake. However, the precise mechanism by which these ABC transporters facilitate sterol movement is unknown. In this study, an overexpression and purification procedure was developed with the aim to characterise the Pdr11p transporter. Engineering of Pdr11p variants fused at the C terminus with green fluorescent protein (Pdr11p-GFP) and containing a FLAG tag at the N terminus facilitated expression analysis and one-step purification, respectively. The detergent-solubilised and purified protein displayed a stable ATPase activity with a broad pH optimum near 7.4. Mutagenesis of the conserved lysine to methionine (K788M) in the Walker A motif abolished ATP hydrolysis. Remarkably, and in contrast to Aus1p, ATPase activity of Pdr11p was insensitive to orthovanadate and not specifically stimulated by phosphatidylserine upon reconstitution into liposomes. Our results highlight distinct differences between Pdr11p and Aus1p and create an experimental basis for further biochemical studies of both ABC transporters to elucidate their function.


Evidence-Based Discriminant Analysis: A New Insight into Iron Profile for the Diagnosis of Parkinson's Disease.
Parkinson's disease is the second most common neurodegenerative disorder. Neurochemical studies have implicated metals in pathogenesis of PD. To examine the association of serum iron, transferrin, ferritin, transferrin saturation and UIBC in PD patients and to derive the Discrimination Function with scores of these variables to correctly classify PD cases and healthy controls. In the present study, identification of biomarker pool in case-control study involving 79 PD cases and 80 healthy controls were performed. The results of independent t-test analysis showed that PD cases presented significantly higher (P < 0.01) level of transferrin, total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC) and urea than controls. As only one-third of transferrin is saturated with iron, so the transferrin present in serum has the extra binding capacity (67%), this is called UIBC. Discriminant analysis was performed to determine the factors that best discriminate between the categories of an outcome variables (Disease status = PD and Control) and total of five biochemical independent variables (UIBC, transferrin, iron, transferrin saturation, and copper) were taken into consideration. UIBC has emerged out to be highest discriminating, powerful and independent variable among considered independent variables, which indicates iron deficiency. After development of Discriminant Function (Z) and calculation of discriminant function cut points, a cross-validation analysis of PD cases and controls were conducted. The sensitivity of the developed model was 98.73% and specificity 83.75%. Receiver operating characteristics (ROC) was plotted, and the findings of ROC curve corroborated with the results obtained from discriminant function analysis. Prospective validation of Discriminant model in large cohort is warranted in future studies.


Highly air stable passivation of graphene based field effect devices.
The sensitivity of graphene based devices to surface adsorbates and charge traps at the graphene/dielectric interface requires proper device passivation in order to operate them reproducibly under ambient conditions. Here we report on the use of atomic layer deposited aluminum oxide as passivation layer on graphene field effect devices (GFETs). We show that successful passivation produce hysteresis free DC characteristics, low doping level GFETs stable over weeks though operated and stored in ambient atmosphere. This is achieved by selecting proper seed layer prior to deposition of encapsulation layer. The passivated devices are also demonstrated to be robust towards the exposure to chemicals and heat treatments, typically used during device fabrication. Additionally, the passivation of high stability and reproducible characteristics is also shown for functional devices like integrated graphene based inverters.


Pex/PEX tissue distribution and evidence for a deletion in the 3' region of the Pex gene in X-linked hypophosphatemic mice.
PEX, a phosphate-regulating gene with homology to endopeptidases on the X chromosome, was recently identified as the candidate gene for X-linked hypophosphatemia. In the present study, we cloned mouse and human Pex/PEX cDNAs encoding part of the 5' untranslated region, the protein coding region, and the entire 3' untranslated region, determined the tissue distribution of Pex/PEX mRNA, and characterized the Pex mutation in the murine Hyp homologue of the human disease. Using the reverse transcriptase/polymerase chain reaction (RT/PCR) and ribonuclease protection assays, we found that Pex/PEX mRNA is expressed predominantly in human fetal and adult mouse calvaria and long bone. With RNA from Hyp mouse bone, an RT/PCR product was generated with 5' but not 3' Pex primer pairs and a protected Pex mRNA fragment was detected with 5' but not 3' Pex riboprobes by ribonuclease protection assay. Analysis of the RT/PCR product derived from Hyp bone RNA revealed an aberrant Pex transcript with retention of intron sequence downstream from nucleotide 1302 of the Pex cDNA. Pex mRNA was not detected on Northern blots of poly (A)+ RNA from Hyp bone, while a low-abundance Pex transcript of approximately 7 kb was apparent in normal bone. Southern analysis of genomic DNA from Hyp mice revealed the absence of hybridizing bands with cDNA probes from the 3' region of the Pex cDNA. We conclude that Pex/PEX is a low-abundance transcript that is expressed predominantly in bone of mice and humans and that a large deletion in the 3' region of the Pex gene is present in the murine Hyp homologue of X-linked hypophosphatemia.


Short-term afferent axotomy increases both strength and depression at Ia-motoneuron synapses in Rat.
Synaptic efficacy at the rat Ia-motoneuron synapse has been reported to increase in vivo, within 3 d of sectioning a single muscle nerve (). We provide an indirect test of the hypothesis that this increase is caused by altered probability of transmitter release of axotomized afferents. Experiments consisted of in vivo recording of maximal composite group I EPSPs evoked in intact rat medial gastrocnemius (MG) motoneurons by stimulation of the lateral gastrocnemius-soleus nerve (LG-S). We compared the maximal LG-S EPSP amplitude and the response to high-frequency stimulation (modulation) recorded in untreated rats, with the same measures recorded in rats that had the LG-S nerve axotomized 3 d before data collection. In confirmation of previous work, the mean amplitude of LG-S EPSPs evoked by stimulation of axotomized afferents was significantly larger than that measured in untreated rats (3.9 +/- 0. 34 and 2.3 +/- 0.19 mV, respectively). The increase in EPSP amplitude was accompanied by significantly greater negative modulation (depression) of EPSP amplitude during high-frequency stimulation (-39 +/- 4% and -53 +/- 4%, untreated and treated, respectively). Modulation would not be expected to change if the increase in EPSP amplitude was attributable solely to a greater number of afferent connections (). Therefore, the present results are consistent with the hypothesis that the initial axotomy-induced increase in synaptic efficacy occurs because of an increase in the probability of transmitter release. Furthermore, these results suggest that the probability of transmitter release at this synapse is regulated by either afferent activity and/or trophic communication with the target muscle.


A microfluidic bioreactor for increased active retrovirus output.
Retroviruses are one of the most commonly used vectors in ongoing gene therapy clinical trials. To evaluate and advance virus production on the microscale platform, we have created a novel microfluidic bioreactor for continuous retrovirus production. We investigated the growth kinetics of a retroviral packaging cell line in microfluidic bioreactors for several compartment sizes, and packaging cells perfused in the microdevices showed similar growth kinetics to those cultured in conventional static conditions. To evaluate the efficiency of retrovirus production, virus titers from the microdevices were compared to those obtained from static tissue culture. When retrovirus production and collection were maintained at 37 degrees C, virus production levels were comparable for the microdevices and static tissue culture conditions. However, immediate cold storage downstream of the packaging cells in the microdevices resulted in 1.4- to 3.7-fold greater active virus production levels with the microdevices compared to the conventional static conditions over a 5 day period. Lastly, the use of microfluidics for virus production provides a continuous supply of virus supernatant for immediate infection of target cells or for preservation and storage. Such devices will be valuable for the optimization of production and evaluation of retroviruses and other viral vectors for gene therapy applications.


A mixed-methods feasibility trial of protein kinase C iota inhibition with auranofin in asymptomatic ovarian cancer patients.
This trial was undertaken (1) to determine the feasibility of enrolling asymptomatic ovarian cancer patients with CA-125 elevation in a trial with the protein kinase C iota (PKCι) inhibitor auranofin and (2) to understand patients' perceptions of CA-125 monitoring. Asymptomatic ovarian cancer patients with CA-125 elevation received 3 mg auranofin orally twice per day and were evaluated. The patients participated in interviews about CA-125 monitoring. Ten patients were enrolled in slightly over 6 months, exceeding our anticipated accrual rate. Four manifested stable CA-125 levels for 1 month or longer. The median progression-free survival was 2.8 months (95% CI: 1.3-3.8); auranofin was well tolerated. One patient had baseline and monthly CA-125 levels of 5,570, 6,085, 3,511, and 2,230 U/ml, respectively, stopped auranofin because of radiographic progression at 3 months, and manifested an increase in CA-125 to 7,168 U/ml approximately 3 months later. Patient interviews revealed (1) the important role of CA-125 in cancer monitoring, (2) ardent advocacy of CA-125 testing, and (3) an evolution toward CA-125 assuming a life of its own. This study showed the feasibility of enrolling asymptomatic ovarian cancer patients with CA-125 elevation in a trial with auranofin. One patient had a decline in CA-125, suggesting that PKCι inhibition merits further study in ovarian cancer.


AP2/ERF Family Transcription Factors ORA59 and RAP2.3 Interact in the Nucleus and Function Together in Ethylene Responses.
The gaseous plant hormone ethylene is a key signaling molecule regulating plant growth, development, and defense against pathogens. Octadecanoid-responsive arabidopsis 59 (ORA59) is an ethylene response factor (ERF) transcription factor and has been suggested to integrate ethylene and jasmonic acid signaling and regulate resistance to necrotrophic pathogens. Here we screened for ORA59 interactors using the yeast two-hybrid system to elucidate the molecular function of ORA59. This led to the identification of RELATED TO AP2.3 (RAP2.3), another ERF transcription factor belonging to the group VII ERF family. In binding assays, ORA59 and RAP2.3 interacted in the nucleus and showed ethylene-dependent nuclear localization. ORA59 played a positive role in ethylene-regulated responses, including the triple response, featured by short, thick hypocotyl and root, and exaggerated apical hook in dark-grown seedlings, and resistance to the necrotrophic pathogen Pectobacterium carotovorum, as shown by the increased and decreased ethylene sensitivity and disease resistance in ORA59-overexpressing (ORA59OE) and null mutant (ora59) plants, respectively. In genetic crosses, ORA59OE rap2.3 crossed lines lost ORA59-mediated positive effects and behaved like rap2.3 mutant. These results suggest that ORA59 physically interacts with RAP2.3 and that this interaction is important for the regulatory roles of ORA59 in ethylene responses.


Understanding the marvels behind liver regeneration.
Tissue regeneration is a process by which the remaining cells of an injured organ regrow to offset the missed cells. This field is relatively a new discipline that has been a focus of intense research by clinicians, surgeons, and scientists for decades. It constitutes the cornerstone of tissue engineering, creation of artificial organs, and generation and utilization of therapeutic stem cells to undergo transformation to different types of mature cells. Many medical experts, scientists, biologists, and bioengineers have dedicated their efforts to deeply comprehend the process of liver regeneration, striving for harnessing it to invent new therapies for liver failure. Liver regeneration after partial hepatectomy in rodents has been extensively studied by researchers for many years. It is divided into three important distinctive phases including (a) Initiation or priming phase which includes an overexpression of specific genes to prepare the liver cells for replication, (b) Proliferation phase in which the liver cells undergo a series of cycles of cell division and expansion and finally, (c) termination phase which acts as brake to stop the regenerative process and prevent the liver tissue overgrowth. These events are well controlled by cytokines, growth factors, and signaling pathways. In this review, we describe the function, embryology, and anatomy of human liver, discuss the molecular basis of liver regeneration, elucidate the hepatocyte and cholangiocyte lineages mediating this process, explain the role of hepatic progenitor cells and elaborate the developmental signaling pathways and regulatory molecules required to procure a complete restoration of hepatic lobule. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Signaling Pathways > Global Signaling Mechanisms Gene Expression and Transcriptional Hierarchies > Cellular Differentiation.


On relating the generalized equivalent uniform dose formalism to the linear-quadratic model.
Two main approaches are commonly used in the literature for computing the equivalent uniform dose (EUD) in radiotherapy. The first approach is based on the cell-survival curve as defined in the linear-quadratic model. The second approach assumes that EUD can be computed as the generalized mean of the dose distribution with an appropriate fitting parameter. We have analyzed the connection between these two formalisms by deriving explicit formulas for the EUD which are applicable to normal distributions. From these formulas we have established an explicit connection between the two formalisms. We found that the EUD parameter has strong dependence on the parameters that characterize the distribution, namely the mean dose and the standard deviation around the mean. By computing the corresponding parameters for clinical dose distributions, which in general do not follow the normal distribution, we have shown that our results are also applicable to actual dose distributions. Our analysis suggests that caution should be used in using generalized EUD approach for reporting and analyzing dose distributions.


Persistent sensitization of depressive-like behavior and thermogenic response during maternal separation in pre- and post-weaning guinea pigs.
Early attachment disruption is thought to promote later onset of depressive illness through a process involving sensitization. Maternal separation in guinea pig pups produces depressive-like behavior and core body temperature fluctuations that appear to be mediated by proinflammatory activity. In pups near the age of weaning (~20 days of age), these responses are increased during repeated separations occurring over several days. Here, enhanced depressive-like behavior and core body temperature responses were observed during repeated separations in guinea pigs from ~10 to 30 days of age. The sensitization lasted for more than a week, with the greatest temperature response occurring during the final separation. These results demonstrate persisting sensitization of behavioral and thermogenic responses to maternal separation over the age range in which these responses are known to occur. The findings are consistent with the hypothesis that proinflammatory activity contributes to the sensitization response and provide further suggestion that the impact of early attachment disruption on susceptibility to depression may involve proinflammatory processes.


Lack of association between mutations in the folate receptor-alpha gene and spina bifida.
Defects of neural tube closure are among the most common of all human malformations. Epidemiological and genetic studies indicate that most of these defects are multifactorial in origin with genetic and environmental causes. Although periconceptional supplementation of the maternal diet with folic acid has been shown to reduce the recurrence and occurrence of neural tube defects (NTDs) by up to 70%, the underlying mechanism remains unknown. Folic acid enters cells of certain tissues via a receptor-mediated process known as potocytosis. The folate receptor alpha (FR-alpha) gene codes for the protein responsible for binding folate, which is the first, and only, folate-dependent step in folate transport. The FR-alpha exons, which code for mature protein and the intron-exon boundaries, were examined for mutations in three separate studies. Initial screening was performed by single-stranded conformational polymorphism (SSCP) analysis in a subset of 1,688 samples obtained from a population-based case-control study of NTDs in California. In the second study, the DNA sequence of exons 5 and 6 was determined in a group of 50 NTD affected individuals. The final experiment involved using dideoxy fingerprinting (ddF) to screen a population-based case-control sample of 219 individuals who were stratified into four sub-groups on the basis of folate intake and pregnancy outcome. No polymorphism was detected in any of the four exons examined. It is unlikely that the beneficial effects of maternal folate supplementation in preventing NTDs acts through a mechanism involving pharmacological correction of a variant form of folate receptor alpha.


Widespread expression of Huntington's disease gene (IT15) protein product.
Huntington's Disease (HD) is caused by expansion of a CAG repeat within a putative open reading frame of a recently identified gene, IT15. We have examined the expression of the gene's protein product using antibodies developed against the N-terminus and an internal epitope. Both antisera recognize a 350 kDa protein, the predicted size, indicating that the CAG repeat is translated into polyglutamine. The HD protein product is widely expressed, most highly in neurons in the brain. There is no enrichment in the striatum, the site of greatest pathology in HD. Within neurons, the protein is diminished in nuclei and mitochondria and is present in the soluble cytoplasmic compartment, as well as loosely associated with membranes or cytoskeleton, in cell bodies, dendrites, and axons. It is concentrated in nerve terminals, including terminals within the caudate and putamen. Thus, the normal HD gene product may be involved in common intracellular functions, and possibly in regulation of nerve terminal function. The product of the expanded allele is expressed, consistent with a gain of function mechanism for HD at the protein level.


Spatio-temporal optimization of sampling for bluetongue vectors (Culicoides) near grazing livestock.
Estimating the abundance of Culicoides using light traps is influenced by a large variation in abundance in time and place. This study investigates the optimal trapping strategy to estimate the abundance or presence/absence of Culicoides on a field with grazing animals. We used 45 light traps to sample specimens from the Culicoides obsoletus species complex on a 14 hectare field during 16 nights in 2009. The large number of traps and catch nights enabled us to simulate a series of samples consisting of different numbers of traps (1-15) on each night. We also varied the number of catch nights when simulating the sampling, and sampled with increasing minimum distances between traps. We used resampling to generate a distribution of different mean and median abundance in each sample. Finally, we used the hypergeometric distribution to estimate the probability of falsely detecting absence of vectors on the field. The variation in the estimated abundance decreased steeply when using up to six traps, and was less pronounced when using more traps, although no clear cutoff was found. Despite spatial clustering in vector abundance, we found no effect of increasing the distance between traps. We found that 18 traps were generally required to reach 90% probability of a true positive catch when sampling just one night. But when sampling over two nights the same probability level was obtained with just three traps per night. The results are useful for the design of vector monitoring programmes on fields with grazing animals.


Utilizing spatial demographic and life history variation to optimize sustainable yield of a temperate sex-changing fish.
Fish populations vary geographically in demography and life history due to environmental and ecological processes and in response to exploitation. However, population dynamic models and stock assessments, used to manage fisheries, rarely explicitly incorporate spatial variation to inform management decisions. Here, we describe extensive geographic variation in several demographic and life history characteristics (e.g., size structure, growth, survivorship, maturation, and sex change) of California sheephead (Semicossyphus pulcher), a temperate rocky reef fish targeted by recreational and commercial fisheries. Fish were sampled from nine locations throughout southern California in 2007-2008. We developed a dynamic size and age-structured model, parameterized separately for each location, to assess the potential cost or benefit in terms of fisheries yield and conservation objectives of changing minimum size limits and/or fishing mortality rates (compared to the status quo). Results indicate that managing populations individually, with location-specific regulations, could increase yield by over 26% while maintaining conservative levels of spawning biomass. While this local management approach would be challenging to implement in practice, we found statistically similar increases in yield could be achieved by dividing southern California into two separate management regions, reflecting geographic similarities in demography. To maximize yield, size limits should be increased by 90 mm in the northern region and held at current levels in the south. We also found that managing the fishery as one single stock (the status quo), but with a size limit 50 mm greater than the current regulations, could increase overall fishery yield by 15%. Increases in size limits are predicted to enhance fishery yield and may also have important ecological consequences for the predatory role of sheephead in kelp forests. This framework for incorporating demographic variation into fisheries models can be exported generally to other species and may aid in identifying the appropriate spatial scales for fisheries management.


Transferable mixing of atomistic and coarse-grained water models.
Dual-resolution approaches for molecular simulations combine the best of two worlds, providing atomic details in regions of interest and coarser but much faster descriptions of less-relevant parts of molecular systems. Given the abundance of water in biomolecular systems, reducing the computational cost of simulating bulk water without perturbing the solute's properties is a very attractive strategy. Here we show that the coarse-grained model for water called WatFour (WT4) can be combined with any of the three most used water models for atomistic simulations (SPC, TIP3P, and SPC/E) without modifying the characteristics of the atomistic solvent and solutes. The equivalence of fully atomistic and hybrid solvation approaches is assessed by comparative simulations of pure water, electrolyte solutions, and the β1 domain of streptococcal protein G, for which comparisons between experimental and calculated chemical shifts at (13)Cα are equivalent.


Recruitment of receptors at supported lipid bilayers promoted by the multivalent binding of ligand-modified unilamellar vesicles.
The development of model systems that mimic biological interactions and allow the control of both receptor and ligand densities, is essential for a better understanding of biomolecular processes, such as the recruitment of receptors at interfaces, at the molecular level. Here we report a model system based on supported lipid bilayers (SLBs) for the investigation of the clustering of receptors at their interface. Biotinylated SLBs, used as cell membrane mimics, were functionalized with streptavidin (SAv), used here as receptor. Subsequently, biotinylated small (SUVs) and giant (GUVs) unilamellar vesicles were bound to the SAv-functionalized SLBs by multivalent interactions and found to induce the recruitment of both SAv on the SLB surface and the biotin moieties in the vesicles. The recruitment of receptors was investigated with quartz crystal microbalance with dissipation monitoring (QCM-D), which allowed the identification of the biotin and SAv densities necessary to obtain receptor recruitment. At approx. 0.6% of biotin in the vesicles, a transition between dense and low vesicle packing was observed, which coincided with the transitions between recruitment in the vesicles vs. recruitment in the SLB and between full and partial use of the biotin moieties in the vesicle. Direct optical visualization of the clustering at the interface of individual GUVs with the SLB platform was achieved with fluorescence microscopy, showing recruitment of SAv at the contact area as well as the deformation of the vesicles upon binding. Different vesicle binding regimes were observed for lower and higher biotin densities in the vesicles and at the SLBs. A more quantitative analysis of the molecular parameters implied in the interaction, indicated that approx. 10% of the vesicle area constitutes the contact area. Moreover, the SUV binding and recruitment appeared to be fast on the analysis time scale, whereas the binding of GUVs is slower due to the larger SLB area over which SAv recruitment needs to occur. The mechanisms revealed in this study may provide insight in biological processes in which recruitment occurs.


Sternal-sparing approach for reoperative bilateral lung transplantation.
A sternal-sparing approach for bilateral lung transplantation was recently applied to reoperative lung transplant cases and is compared with the traditional clamshell approach. A retrospective analysis of 15 consecutive reoperative bilateral lung transplants performed from January 2008 to April 2011 was conducted. Outcomes were compared between the first 11 patients who underwent the traditional clamshell and the most recent 4 patients who underwent the sternal-sparing approach. The indication for retransplantation was obliterative bronchiolitis in all patients. Both groups were similar with regard to age, allograft ischaemic time and operative time. Cardiopulmonary bypass was more frequent in the sternal-sparing group although required for a shorter period of time. The need for postoperative extracorporeal membrane oxygenation for primary graft dysfunction was similar in both groups. The length of ICU care and total hospitalization length of stay were similar for the sternal-sparing group compared with the traditional clamshell approach. Operative mortality and overall survival also did not differ. Reoperative bilateral lung transplantation with a sternal-sparing approach is feasible and may yield outcomes similar to those in the traditional clamshell approach. Further analysis with larger numbers of patients is warranted to delineate the benefits of this approach for patients requiring reoperative lung transplantation.


Error-free transmission of microring-modulated BPSK.
We demonstrate the generation of error-free binary-phase-shift-keyed (BPSK) data at 5 Gb/s using a silicon microring modulator. The microring-modulated BPSK signal is propagated at fiber lengths up to 80 km, maintaining error-free performance, while demonstrating resilience to chromatic dispersion. Bit-error-rate measurements and eye diagrams show near equivalent performance of a microring-based BPSK modulator as compared to commercial LiNbO₃ phase modulators.


The Ideal Hospital Discharge Summary: A Survey of U.S. Physicians.
Hospital discharge summaries enable communication between inpatient and outpatient physicians. Despite existing guidelines for discharge summaries, they are frequently suboptimal. The aim of this study was to assess physicians' perspectives about discharge summaries and the differences between summaries' authors (hospitalists) and readers (primary care physicians [PCPs]). A national survey of 1600 U.S. physicians was undertaken. Primary measures included physicians' preferences in discharge summary standardization, content, format, and audience. A total of 815 physicians responded (response rate = 51%). Eighty-nine percent agreed that discharge summaries "should have a standardized format." Most agreed that summaries should "document everything that was done, found, and recommended in the hospital" (64%) yet "only include details that are highly pertinent to the hospitalization" (66%). Although 74% perceived patients as an important audience of discharge summaries, only 43% agreed that summaries "should be written in language that patients…can easily understand," and 68% agreed that it "should be written solely for provider-to-provider communication." Compared with hospitalists, PCPs preferred comprehensive summaries (68% versus 59%, P = 0.002). More PCPs agreed that separate summaries should be created for patients and for provider-to-provider communication than hospitalists (60% versus 47%, P < 0.001). Compared with PCPs, more hospitalists believe that "hospitalists are too busy to prepare a high-quality discharge summary" (44% versus 23%, P < 0.001) and "PCPs have insufficient time to read an entire discharge summary" (60% versus 38%, P < 0.001). Physicians believe that discharge summaries should have a standardized format but do not agree on how comprehensive or in what format they should be. Efforts are necessary to build consensus toward the ideal discharge summary.


Is Mycoplasma genitalium in women the "New Chlamydia?" A community-based prospective cohort study.
The role of Mycoplasma genitalium in pelvic inflammatory disease is unclear. We conducted a cohort study to determine the prevalence and predictors of M. genitalium infection in female students, to explore its role in pelvic inflammatory disease and to estimate its annual incidence and persistence rate. Two thousand three hundred seventy-eight multiethnic, sexually active female students (mean age, 21 years) provided duplicate self-taken vaginal samples for a chlamydia screening trial. From this population, 2246 (94%) were followed up after 12 months and assessed for incidence of clinical pelvic inflammatory disease. In addition, 900 women (38%) returned follow-up samples via the postal service 11-32 months after recruitment. Stored samples were tested for M. genitalium. The prevalence of M. genitalium at baseline was 3.3% (78 of 2378 women; 95% confidence interval [CI], 2.6%-4.1%). Infection was more common in women reporting ≥ 2 sexual partners in the previous year, those with bacterial vaginosis, women aged < 18 years, women of black ethnicity, and smokers. Multiple partners and bacterial vaginosis were independent risk factors for M. genitalium (adjusted risk ratio, 2.23 [95% CI, 1.39-3.58] and 2.54 [95% CI, 1.61-4.01], respectively). The incidence of pelvic inflammatory disease over 12 months was 3.9% (3 of 77 women) among women with M. genitalium infection, compared with 1.7% (36 of 2169 women) among those without infection (risk ratio, 2.35; 95% CI, 0.74-7.46; P = .14). Annual incidence of M. genitalium infection in 873 women without M. genitalium infection at baseline who returned samples via the postal service was 0.9% (95% CI, 0.5%-1.6%). Seven (26%; 95% CI, 9%-43%) of 27 women with M. genitalium infection at baseline remained positive after 12-21 months; genotyping results suggest that these were persistent infections. M. genitalium infection is unlikely to be a major risk factor for clinical pelvic inflammatory disease in this population.


Promoting partnership working for undergraduate students.
Interprofessional working is an important NHS policy aim (Department of Health 2000; Barrett et al 2005), which has meant that interprofessional education (IPE) is an increasingly important topic for higher education institutions (Caldwell and Atwal, 2003; Barr and Ross, 2006). The argument for IPE is based on the assumption that it will enhance interprofessional working and assist in ameliorating many of the challenges of contemporary health-care. However, there is a dearth of evidence of the effectiveness of IPE in the UK, particularly at undergraduate level. This does not necessarily mean that IPE is ineffective, but suggests the need to explore ways of introducing and evaluating IPE locally for undergraduate students. This article reports on an evaluation of a pilot IPE initiative for undergraduate students from different disciplines, in an attempt to consider how sustainable IPE could be introduced in one institution.


Open-label study of the efficacy and safety of intravenous ferric carboxymaltose in pregnant women with restless legs syndrome.
The objective of this study was to test the efficacy and safety of intravenous ferric carboxymaltose (FCM) in pregnant women with restless legs syndrome (RLS) and iron deficiency or anemia. The open-label pilot study (exploratory) was performed at the University Hospital of Zürich and the Neurocenter of Southern Switzerland (Lugano). Nineteen women in the third trimester of pregnancy with moderate-to-severe RLS and serum ferritin levels <35 µg/l or hemoglobin (Hb) < 11.0 g/dl were included in the study. RLS was graded according to the International Restless Legs Syndrome (IRLS) Study Group rating scale. All participants had a score of ≥20 or had RLS ≥3 times/week. Based on the Hb levels, 500 or 700 mg of FCM was administered over 20 min. The primary end point was a ≥ 50% reduction in the mean IRLS score one week after FCM infusion. The secondary end points included periodic limb movements (PLMs; assessed using nocturnal foot actigraphy), sleep quality (assessed using the Pittsburgh Sleep Quality Index), and safety. The IRLS score decreased from 23 ± 7 (baseline) to 13 ± 7 (P <0.01), whereas the PLM index decreased from 35 ± 26 (baseline) to 25 ± 20 (P <0.001). Significant improvement in sleep quality was also reported (P <0.029), and treatment was well tolerated. Three serious adverse events were reported, but they were considered unrelated to treatment. These data provide promising evidence on the safety and efficacy of FCM for moderate-to-severe RLS in pregnant women with iron deficiency or anemia. Therefore, a future placebo-controlled study is warranted.


Performance of preschoolers on the Pediatric Clinical Test of Sensory Interaction for Balance.
The purposes of this study were to describe the performance of 40 children aged 4 and 5 years on the Pediatric Clinical Test of Sensory Interaction for Balance (P-CTSIB) and to determine whether age- and gender-related differences were present. The P-CTSIB measures standing balance when sensory input is systematically altered. Kruskal-Wallis one-way analyses of variance by ranks (p less than or equal to .05) were used for comparisons by age and gender. When the 4-year-olds were compared with the 5-year-olds, significant duration differences were found in 4 of the 6 conditions in the heel-toe position of the P-CTSIB. The age-related differences on the remaining 2 heel-toe conditions, as well as on Condition 6 of the feet-together position, approached significance. Gender differences with 4-year-olds and 5-year-olds combined were statistically non-significant in all instances; however, girls performed better on 9 of the 12 conditions of the P-CTSIB. The results indicate that the feet-together position can discriminate between children without balance deficits and children with balance deficits. The heel-toe position is difficult for children aged 4 and 5 years without balance deficits and consequently has limited diagnostic value for this age group.


Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.
To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey. International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course. A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide. The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.


Personality pathology recorded by severity: national survey.
Current classifications of personality disorders do not classify severity despite clinical practice favouring such descriptions. To assess whether an existing measure of severity of personality disorder predicted clinical pathology and societal dysfunction in a community sample. UK national epidemiological study in which personality status was measured using the screening version of the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II) and reclassified to five levels using a modified severity index. Associations between levels of severity of personality pathology and social, demographic and clinical variables were measured. Of 8391 individuals interviewed and their personality status assessed, only a minority (n = 1933, 23%) had no personality pathology. The results supported the hypothesis. More severe personality pathology was associated incrementally with younger age, childhood institutional care, expulsion from school, contacts with the criminal justice system, economic inactivity, more Axis I pathology and greater service contact (primary care and secondary care, all P<0.001). Significant handicap was noted among people with even low levels of personality pathology. No differences contradicted the main hypothesis. A simple reconstruction of the existing classification of personality disorder is a good predictor of social dysfunction and supports the development of severity measures as a critical requirement in both DSM-V and ICD-11 classifications.


Bacteriophage Associated Silicon Particles: Design and Characterization of a Novel Theranostic Vector with Improved Payload Carrying Potential.
There has been extensive research on the use of nanovectors for cancer therapy. Targeted delivery of nanotherapeutics necessitates two important characteristics; the ability to accumulate at the disease locus after overcoming sequential biological barriers and the ability to carry a substantial therapeutic payload. Successful combination of the above two features is challenging, especially in solid porous materials where chemical conjugation of targeting entities on the particle surface will generally prevent successful loading of the therapeutic substance. In this study, we propose a novel strategy for decorating the surface of mesoporous silicon particles with targeting entities (bacteriophage) and gold nanoparticles (AuNP) while maintaining their payload carrying potential. The resulting Bacteriophage Associated Silicon Particles (BASP) demonstrates efficient encapsulation of macromolecules and therapeutic nanoparticles into the porous structures. In vitro targeting data show enhanced targeting efficiency with about four orders of magnitude lower concentration of bacteriophage. In vivo targeting data suggest that BASP maintain their integrity following intravenous administration in mice and display up to three fold higher accumulation in the tumor.


Optimizing performance and interpretation of prostate biopsy: a critical analysis of the literature.
The number and location of biopsy cores and the interpretation of prostate biopsy in different clinical settings remain the subjects of continuing debate. Our aim was to review the current evidence regarding the performance and interpretation of initial, repeat, and saturation prostatic biopsy. A comprehensive Medline search was performed using the Medical Subject Heading search terms prostate biopsy, prostate cancer, detection, transrectal ultrasound (TRUS), nomogram, and diagnosis. Results were restricted to the English language, with preference given to those published within the last 3 yr. At initial biopsy, a minimum of 10 but not >18 systematic cores are recommended, with 14-18 cores in glands ≥ 50 cm³. Biopsies should be directed laterally, and transition zone (TZ) cores are not recommended in the initial biopsy setting. Further biopsy sets, either as an extended repeat or as a saturation biopsy (≥ 20 cores) including the TZ, are warranted in young and fit men with a persistent suspicion of prostate cancer. An immediate repeat biopsy is not indicated for prior high-grade prostatic intraepithelial neoplasia diagnosis given an adequate extended initial biopsy. Conversely, biopsies with atypical glands that are suspicious but not diagnostic of cancer should be repeated within 3-6 mo. Overall recommendations for further biopsy sets (a third set or more) cannot be made. Transrectal ultrasound-guided systematic biopsies represent the standard-of-care method of prostate sampling. However, transperineal biopsies are an up-to-standard alternative. The optimal prostatic biopsy regimen should be based on the individualized clinical setting of the patient and should follow the minimum standard requirements reported in this paper.


Rethinking health systems in the context of urbanisation: challenges from four rapidly urbanising low-income and middle-income countries.
The world is now predominantly urban; rapid and uncontrolled urbanisation continues across low-income and middle-income countries (LMICs). Health systems are struggling to respond to the challenges that urbanisation brings. While better-off urbanites can reap the benefits from the 'urban advantage', the poorest, particularly slum dwellers and the homeless, frequently experience worse health outcomes than their rural counterparts. In this position paper, we analyse the challenges urbanisation presents to health systems by drawing on examples from four LMICs: Nigeria, Ghana, Nepal and Bangladesh. Key challenges include: responding to the rising tide of non-communicable diseases and to the wider determinants of health, strengthening urban health governance to enable multisectoral responses, provision of accessible, quality primary healthcare and prevention from a plurality of providers. We consider how these challenges necessitate a rethink of our conceptualisation of health systems. We propose an urban health systems model that focuses on: multisectoral approaches that look beyond the health sector to act on the determinants of health; accountability to, and engagement with, urban residents through participatory decision making; and responses that recognise the plurality of health service providers. Within this model, we explicitly recognise the role of data and evidence to act as glue holding together this complex system and allowing incremental progress in equitable improvement in the health of urban populations.


The unity and diversity of executive functions: A systematic review and re-analysis of latent variable studies.
Confirmatory factor analysis (CFA) has been frequently applied to executive function measurement since first used to identify a three-factor model of inhibition, updating, and shifting; however, subsequent CFAs have supported inconsistent models across the life span, ranging from unidimensional to nested-factor models (i.e., bifactor without inhibition). This systematic review summarized CFAs on performance-based tests of executive functions and reanalyzed summary data to identify best-fitting models. Eligible CFAs involved 46 samples (N = 9,756). The most frequently accepted models varied by age (i.e., preschool = one/two-factor; school-age = three-factor; adolescent/adult = three/nested-factor; older adult = two/three-factor), and most often included updating/working memory, inhibition, and shifting factors. A bootstrap reanalysis simulated 5,000 samples from 21 correlation matrices (11 child/adolescent; 10 adult) from studies including the three most common factors, fitting seven competing models. Model results were summarized as the mean percent accepted (i.e., average rate at which models converged and met fit thresholds: CFI ≥ .90/RMSEA ≤ .08) and mean percent selected (i.e., average rate at which a model showed superior fit to other models: ΔCFI ≥ .005/.010/ΔRMSEA ≤ -.010/-.015). No model consistently converged and met fit criteria in all samples. Among adult samples, the nested-factor was accepted (41-42%) and selected (8-30%) most often. Among child/adolescent samples, the unidimensional model was accepted (32-36%) and selected (21-53%) most often, with some support for two-factor models without a differentiated shifting factor. Results show some evidence for greater unidimensionality of executive function among child/adolescent samples and both unity and diversity among adult samples. However, low rates of model acceptance/selection suggest possible bias toward the publication of well-fitting but potentially nonreplicable models with underpowered samples. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


National routine adult immunisation programmes among World Health Organization Member States: an assessment of health systems to deploy COVID-19 vaccines.
IntroductionAs SARS-CoV-2 disproportionately affects adults, the COVID-19 pandemic vaccine response will rely on adult immunisation infrastructures.AimTo assess adult immunisation programmes in World Health Organization (WHO) Member States.MethodsWe evaluated country reports from 2018 on adult immunisation programmes sent to WHO and UNICEF. We described existing programmes and used multivariable regression to identify independent factors associated with having them.ResultsOf 194 WHO Member States, 120 (62%) reported having at least one adult immunisation programme. The Americas and Europe had the highest proportions of adult immunisation programmes, most commonly for hepatitis B and influenza vaccines (> 47% and > 91% of countries, respectively), while Africa and South-East Asia had the lowest proportions, with < 11% of countries reporting adult immunisation programmes for hepatitis B or influenza vaccines, and none for pneumococcal vaccines. In bivariate analyses, high or upper-middle country income, introduction of new or underused vaccines, having achieved paediatric immunisation coverage goals and meeting National Immunisation Technical Advisory Groups basic functional indicators were significantly associated (p < 0.001) with having an adult immunisation programme. In multivariable analyses, the most strongly associated factor was country income, with high- or upper-middle-income countries significantly more likely to report having an adult immunisation programme (adjusted odds ratio: 19.3; 95% confidence interval: 6.5-57.7).DiscussionWorldwide, 38% of countries lack adult immunisation programmes. COVID-19 vaccine deployment will require national systems for vaccine storage and handling, delivery and waste management to target adult risk groups. There is a need to strengthen immunisation systems to reach adults with COVID-19 vaccines.


The population genetics and dynamics of the thalassemias.
The inherited disorders of hemoglobin, including the thalassemias, are by far the commonest monogenic diseases. Although several factors are responsible for their very high frequency, the major mechanism seems to be natural selection mediated by heterozygote protection against severe forms of malaria. Recent work has highlighted the complexity of the interplay among the different hemoglobin variants themselves and among different levels of malaria resistance, and is helping to explain the extraordinary heterogeneity in the distribution of the hemoglobin disorders even within short geographical distances. Some progress has also been made toward understanding the cellular and immune mechanisms that may underlie heterozygote protection against malaria in these conditions. In addition to providing valuable information about human evolutionary biology, work in this field has an increasingly important influence on the development of programs for the better management of the hemoglobin disorders, particularly in the poorer countries of the tropical world.


Transgenerational epigenetic effects on brain functions.
Psychiatric diseases are multifaceted disorders with complex etiology, recognized to have strong heritable components. Despite intense research efforts, genetic loci that substantially account for disease heritability have not yet been identified. Over the last several years, epigenetic processes have emerged as important factors for many brain diseases, and the discovery of epigenetic processes in germ cells has raised the possibility that they may contribute to disease heritability and disease risk. This review examines epigenetic mechanisms in complex diseases and summarizes the most illustrative examples of transgenerational epigenetic inheritance in mammals and their relevance for brain function. Environmental factors that can affect molecular processes and behavior in exposed individuals and their offspring, and their potential epigenetic underpinnings, are described. Possible routes and mechanisms of transgenerational transmission are proposed, and the major questions and challenges raised by this emerging field of research are considered.


NKp46+ Innate Lymphoid Cells Dampen Vaginal CD8 T Cell Responses following Local Immunization with a Cholera Toxin-Based Vaccine.
Innate and adaptive immune cells work in concert to generate efficient protection at mucosal surface. Vaginal mucosa is an epithelial tissue that contains innate and adaptive immune effector cells. Our previous studies demonstrated that vaginal administration of Cholera toxin -based vaccines generate antigen-specific CD8 T cells through the stimulation of local dendritic cells (DC). Innate lymphoid cells (ILC) are a group of lymphocytes localized in epithelial tissues that have important immune functions against pathogens and in tissue homeostasis. Their contribution to vaccine-induced mucosal T cell responses is an important issue for the design of protective vaccines. We report here that the vaginal mucosa contains a heterogeneous population of NKp46+ ILC that includes conventional NK cells and ILC1-like cells. We show that vaginal NKp46+ ILC dampen vaccine-induced CD8 T cell responses generated after local immunization. Indeed, in vivo depletion of NKp46+ ILC with anti-NK1.1 antibody or NKG2D blockade increases the magnitude of vaginal OVA-specific CD8 T cells. Furthermore, such treatments also increase the number of DC in the vagina. NKG2D ligands being expressed by vaginal DC but not by CD8 T cells, these results support that NKp46+ ILC limit mucosal CD8 T cell responses indirectly through the NKG2D-dependent elimination of vaginal DC. Our data reveal an unappreciated role of NKp46+ ILC in the regulation of mucosal CD8 T cell responses.


Cardiovascular risk among patients on clopidogrel anti-platelet therapy after placement of drug-eluting stents is modified by genetic variants in both the CYP2C19 and ABCB1 genes.
Long-term (at least one year) dual anti-platelet therapy incorporating aspirin and clopidogrel is currently recommended following percutaneous coronary intervention with placement of a drug-eluting stent (DES). Genetic variants in both the ABCB1 and CYP2C19 genes have been associated with cardiovascular events among patients on clopidogrel. We examined the concurrent contribution of the CYP2C19 *2 and *17 alleles and the ABCB1 3435 alleles to one-year clinical risk among patients (n=1,034 on clopidogrel therapy following the placement of a DES. For CYP2C19*2, event rates were 8.4%, 10.9% and 44.4% for patients with 0, 1 and 2 *2 alleles, respectively (p=0.016). ABCB1 3435 was not associated with events in univariate analysis. However, 72% of patients with a *2 variant also possessed the ABCB1 3435 C allele; among these patients (*2/C genotype) the event rate for myocardial infarction (MI) was 14.2% vs. 6.9% for those lacking both *2 and C alleles (p=0.027) and for MI/death, 16.9% vs. 9.6% (p=0.046). Overall for all genotypes, the presence of the gain-of-function (protective) *17 allele significantly reduced the one-year rate of MI from 11.1% to 7.0% (p=0.045) and trended to reduce the combined rate of MI/death from 13.8% to 10.5% (p=0.182). In conclusion, the ABCB1 3435 locus and the *2 allele combine to impart a significant trend toward increased risk. This trend was largely reversed by the simultaneous carriage of one or two *17 alleles. These findings suggest that assessment of a combined genotype may improve risk assessment.


Prolactin receptor antagonism reduces the clonogenic capacity of breast cancer cells and potentiates doxorubicin and paclitaxel cytotoxicity.
Exogenous prolactin is mitogenic and antiapoptotic in breast cancer cells, and overexpression of autocrine prolactin cDNA in breast cancer cell lines has been shown to stimulate their growth and to protect against chemotherapy-induced apoptosis. We examined the effects of the 'pure' prolactin receptor antagonist Delta1-9-G129R-hPrl (Delta1-9) on the breast cancer cell number and clonogenicity, alone and in combination with chemotherapy. The effects of doxorubicin, paclitaxel and Delta1-9 on the growth of breast cancer cell lines (MCF-7, T47D, MDA-MB-453, MDA-MB-468 and SK-BR-3) in monolayer culture were assessed by the sulphorhodamine B assay. Effects on clonogenicity were assessed by soft agar assay for the cell lines and by the mammosphere assay for disaggregated primary ductal carcinoma in situ samples. Dual-fluorescence immunocytochemistry was used to identify subpopulations of cells expressing the prolactin receptor and autocrine prolactin. Delta1-9 as a single agent had no effect on the cell number in monolayer culture, but potentiated the cytotoxic effects of doxorubicin and paclitaxel. Doxorubicin accordingly induced expression of prolactin mRNA and protein in all five breast cancer cell lines tested. Delta1-9 alone inhibited the clonogenicity in soft agar of cell lines by ~90% and the mammosphere forming efficiency of six disaggregated primary ductal carcinoma in situ samples by a median of 56% (range 32% to 88%). Subpopulations of cells could be identified in the cell lines based on the prolactin receptor and prolactin expression. Autocrine prolactin appears to act as an inducible survival factor in a clonogenic subpopulation of breast cancer cells. The rational combination of cytotoxics and Delta1-9 may therefore improve outcomes in breast cancer therapy by targeting this cell population.


Krill faecal pellets drive hidden pulses of particulate organic carbon in the marginal ice zone.
The biological carbon pump drives a flux of particulate organic carbon (POC) through the ocean and affects atmospheric levels of carbon dioxide. Short term, episodic flux events are hard to capture with current observational techniques and may thus be underrepresented in POC flux estimates. We model the potential hidden flux of POC originating from Antarctic krill, whose swarming behaviour could result in a major conduit of carbon to depth through their rapid exploitation of phytoplankton blooms and bulk egestion of rapidly sinking faecal pellets (FPs). Our model results suggest a seasonal krill FP export flux of 0.039 GT C across the Southern Ocean marginal ice zone, corresponding to 17-61% (mean 35%) of current satellite-derived export estimates for this zone. The magnitude of our conservatively estimated flux highlights the important role of large, swarming macrozooplankton in POC export and, the need to incorporate such processes more mechanistically to improve model projections.


Hidden treasure of the Gobi: understanding how water limits range use of khulan in the Mongolian Gobi.
Most large herbivores in arid landscapes need to drink which constrains their movements and makes them vulnerable to disturbance. Asiatic wild ass or khulan (Equus hemionus) were widespread and abundant throughout the arid landscapes of Central Asia and Mongolia, but have undergone dramatic population declines and range constrictions; denying khulan access to water is believed to have played a major role. Mongolia's South Gobi Region now houses the world largest remaining khulan population, but is undergoing rapid land use changes. Khulan water use is poorly understood, largely due to the difficulty of mapping waterpoints used by khulan throughout their exceptionally large ranges, prone to high variations in precipitation. We used the special movement path characteristics of GPS tagged khulan to show us where water is located. We identified 367 waterpoints, 53 of which were of population importance, characterized the seasonal and circadian use, and identified snow cover as the most important variable predicting khulan visits during the non-growing season, and vegetation greenness during the growing season. Our results provide a data layer to help guide a regional khulan conservation strategy, allow predictions for other part of the global khulan range, and illustrates the overall importance of waterpoints for dryland herbivores.


Albertian errors in head-mounted displays: I. Choice of eye-point location for a near- or far-field task visualization.
A theoretical investigation of rendered depth and angular errors, or Albertian errors, linked to natural eye movements in binocular head-mounted displays (HMDs) is presented for three possible eye-point locations: the center of the entrance pupil, the nodal point, and the center of rotation of the eye. A numerical quantification was conducted for both the pupil and the center of rotation of the eye under the assumption that the user will operate solely in either the near field under an associated instrumentation setting or the far field under a different setting. Under these conditions, the eyes are taken to gaze in the plane of the stereoscopic images. Across conditions, results show that the center of the entrance pupil minimizes rendered angular errors, while the center of rotation minimizes rendered position errors. Significantly, this investigation quantifies that under proper setting of the HMD and correct choice of the eye points, rendered depth and angular errors can be brought to be either negligible or within specification of even the most stringent applications in performance of tasks in either the near field or the far field.


Smoking and mortality--beyond established causes.
Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States. However, if smoking causes additional diseases, these official estimates may significantly underestimate the number of deaths attributable to smoking. We pooled data from five contemporary U.S. cohort studies including 421,378 men and 532,651 women 55 years of age or older. Participants were followed from 2000 through 2011, and relative risks and 95% confidence intervals were estimated with the use of Cox proportional-hazards models adjusted for age, race, educational level, daily alcohol consumption, and cohort. During the follow-up period, there were 181,377 deaths, including 16,475 among current smokers. Overall, approximately 17% of the excess mortality among current smokers was due to associations with causes that are not currently established as attributable to smoking. These included associations between current smoking and deaths from renal failure (relative risk, 2.0; 95% confidence interval [CI], 1.7 to 2.3), intestinal ischemia (relative risk, 6.0; 95% CI, 4.5 to 8.1), hypertensive heart disease (relative risk, 2.4; 95% CI, 1.9 to 3.0), infections (relative risk, 2.3; 95% CI, 2.0 to 2.7), various respiratory diseases (relative risk, 2.0; 95% CI, 1.6 to 2.4), breast cancer (relative risk, 1.3; 95% CI, 1.2 to 1.5), and prostate cancer (relative risk, 1.4; 95% CI, 1.2 to 1.7). Among former smokers, the relative risk for each of these outcomes declined as the number of years since quitting increased. A substantial portion of the excess mortality among current smokers between 2000 and 2011 was due to associations with diseases that have not been formally established as caused by smoking. These associations should be investigated further and, when appropriate, taken into account when the mortality burden of smoking is investigated. (Funded by the American Cancer Society.).


Metabolic fingerprint after acute and under sustained consumption of a functional beverage based on grape skin extract in healthy human subjects.
Grape-derived polyphenols are considered to be one of the most promising ingredients for functional foods due to their health-promoting activities. We applied a HPLC-MS-based untargeted metabolomic approach in order to evaluate the impact of a functional food based on grape skin polyphenols on the urinary metabolome of healthy subjects. Thirty-one volunteers participated in two dietary crossover randomized intervention studies: with a single-dose intake (187 mL) and with a 15-day sustained consumption (twice per day, 187 mL per day in total) of a functional beverage (FB). Postprandial (4-hour) and 24-hour urine samples collected after acute consumption and on the last day of sustained FB consumption, respectively, were analysed using an untargeted HPLC-qTOF-MS approach. Multivariate modelling with subsequent application of an S-plot revealed differential mass features related to acute and prolonged consumption of FB. More than half of the mass features were shared between the two types of samples, among which several phase II metabolites of grape-derived polyphenols were identified at confidence level II. Prolonged consumption of FB was specifically reflected in urine metabolome by the presence of first-stage microbial metabolites of flavanols: hydroxyvaleric acid and hydroxyvalerolactone derivatives. Overall, several epicatechin and phenolic acid metabolites both of tissular and microbiota origin were the most representative markers of FB consumption. To our knowledge, this is one of the first studies where an untargeted LC-MS metabolomic approach has been applied in nutrition research on a grape-derived FB.


Gene expression differences in mice divergently selected for methamphetamine sensitivity.
In an effort to identify genes that may be important for drug-abuse liability, we mapped behavioral quantitative trait loci (bQTL) for sensitivity to the locomotor stimulant effect of methamphetamine (MA) using two mouse lines that were selectively bred for high MA-induced activity (HMACT) or low MA-induced activity (LMACT). We then examined gene expression differences between these lines in the nucleus accumbens, using 20 U74Av2 Affymetrix microarrays and quantitative polymerase chain reaction (qPCR). Expression differences were detected for several genes, including Casein Kinase 1 Epsilon (Csnkle), glutamate receptor, ionotropic, AMPA1 (GluR1), GABA B1 receptor (Gabbr1), and dopamine- and cAMP-regulated phosphoprotein of 32 kDa (Darpp-32). We used the www.WebQTL.org database to identify QTL that regulate the expression of the genes identified by the microarrays (expression QTL; eQTL). This approach identified an eQTL for Csnkle on Chromosome 15 (LOD = 3.8) that comapped with a bQTL for the MA stimulation phenotype (LOD = 4.5), suggesting that a single allele may cause both traits. The chromosomal region containing this QTL has previously been associated with sensitivity to the stimulant effects of cocaine. These results suggest that selection was associated with (and likely caused) altered gene expression that is partially attributable to different frequencies of gene expression polymorphisms. Combining classical genetics with analysis of whole-genome gene expression and bioinformatic resources provides a powerful method for provisionally identifying genes that influence complex traits. The identified genes provide excellent candidates for future hypothesis-driven studies, translational genetic studies, and pharmacological interventions.


Remission of Type 2 Diabetes Following a Short-term Intensive Intervention With Insulin Glargine, Sitagliptin, and Metformin: Results of an Open-label Randomized Parallel-Design Trial.
The aim of the study was to evaluate remission of type 2 diabetes following a short-term intervention with insulin glargine, sitagliptin/metformin, and lifestyle approaches. In this open multicenter trial, 102 patients with type 2 diabetes were randomized to 1) a 12-week intervention with sitagliptin/metformin, insulin glargine, and lifestyle therapy or 2) control group. Participants with HbA1c <7.3% (<56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for evidence of relapse over 52 weeks. Diabetes relapse criteria included HbA1c ≥6.5% (≥48 mmol/mol), ≥50% of capillary glucose readings >10 mmol/L over 1 week, and reinitiation of diabetes medications with or without abnormal fasting plasma glucose (FPG) or 2-h plasma glucose on an oral glucose tolerance test (OGTT). Time-to-relapse analysis was conducted to compare the treatment groups with (primary analysis) and without (supplementary analysis) FPG/OGTT relapse criteria. With the FPG/OGTT relapse criteria included, the hazard ratio (HR) of relapse was 0.72 (95% CI 0.47-1.10) in the intervention group compared with the control group (primary analysis), and the number of participants remaining in remission was not significantly different between treatment groups at 24, 36, 48, and 64 weeks. In the supplementary analyses without these criteria, HR of relapse was 0.60 (95% CI 0.39-0.95), and the number of participants remaining in remission was significantly higher (26 vs. 10%) in the intervention group at 36 weeks. Although our primary outcome was not statistically significant, the tested approach deserves further study with further optimization of its components.


Effect of changing feedback delay on spontaneous oscillations in smooth pursuit eye movements of monkeys.
1. Our goal was to discriminate between two classes of models for pursuit eye movements. The monkey's pursuit system and both classes of model exhibit oscillations around target velocity during tracking of ramp target motion. However, the mechanisms that determine the frequency of oscillations differ in the two classes of model. In "internal feedback" models, oscillations are controlled by internal feedback loops, and the frequency of oscillation does not depend strongly on the delay in visual feedback. In "image motion" models, oscillations are controlled by visual feedback, and the frequency of oscillation does depend on the delay in visual feedback. 2. We measured the frequency of oscillation during pursuit of ramp target motion as a function of the total delay for visual feedback. For the shortest feedback delays of approximately 70 ms, the frequency of oscillation was between 6 and 7 Hz. Increases in feedback delay caused decreases in the frequency of oscillation. The effect of increasing feedback delay was similar, whether the increases were produced naturally by dimming and decreasing the size of the tracking target or artificially with the computer. We conclude that the oscillations in eye velocity during pursuit of ramp target motion are controlled by visual inputs, as suggested by the image motion class of models. 3. Previous experiments had suggested that the visuomotor pathways for pursuit are unable to respond well to frequencies as high as the 6-7 Hz at which eye velocity oscillates in monkeys. We therefore tested the response to target vibration at an amplitude of +/- 8 degrees/s and frequencies as high as 15 Hz. For target vibration at 6 Hz, the gain of pursuit, defined as the amplitude of eye velocity divided by the amplitude of target velocity, was as high as 0.65. We conclude that the visuomotor pathways for pursuit are capable of processing image motion at high temporal frequencies. 4. The gain of pursuit was much larger when the target vibrated around a constant speed of 15 degrees/s than when it vibrated around a stationary position. This suggests that the pursuit pathways contain a switch that must be closed to allow the visuomotor pathways for pursuit to operate at their full gain. The switch apparently remains open for target vibration around a stationary position. 5. The responses to target vibration revealed a frequency at which eye velocity lagged target velocity by 180 degrees and at which one monkey showed a local peak in the gain of pursuit.(ABSTRACT TRUNCATED AT 400 WORDS)


Dysfunctional visual word form processing in progressive alexia.
Progressive alexia is an acquired reading deficit caused by degeneration of brain regions that are essential for written word processing. Functional imaging studies have shown that early processing of the visual word form depends on a hierarchical posterior-to-anterior processing stream in occipito-temporal cortex, whereby successive areas code increasingly larger and more complex perceptual attributes of the letter string. A region located in the left lateral occipito-temporal sulcus and adjacent fusiform gyrus shows maximal selectivity for words and has been dubbed the 'visual word form area'. We studied two patients with progressive alexia in order to determine whether their reading deficits were associated with structural and/or functional abnormalities in this visual word form system. Voxel-based morphometry showed left-lateralized occipito-temporal atrophy in both patients, very mild in one, but moderate to severe in the other. The two patients, along with 10 control subjects, were scanned with functional magnetic resonance imaging as they viewed rapidly presented words, false font strings, or a fixation crosshair. This paradigm was optimized to reliably map brain regions involved in orthographic processing in individual subjects. All 10 control subjects showed a posterior-to-anterior gradient of selectivity for words, and all 10 showed a functionally defined visual word form area in the left hemisphere that was activated for words relative to false font strings. In contrast, neither of the two patients with progressive alexia showed any evidence for a selectivity gradient or for word-specific activation of the visual word form area. The patient with mild atrophy showed normal responses to both words and false font strings in the posterior part of the visual word form system, but a failure to develop selectivity for words in the more anterior part of the system. In contrast, the patient with moderate to severe atrophy showed minimal activation of any part of the visual word form system for either words or false font strings. Our results suggest that progressive alexia is associated with a dysfunctional visual word form system, with or without substantial cortical atrophy. Furthermore, these findings demonstrate that functional MRI has the potential to reveal the neural bases of cognitive deficits in neurodegenerative patients at very early stages, in some cases before the development of extensive atrophy.


Significance of elevated parathyroid hormone after parathyroidectomy for primary hyperparathyroidism.
To provide a clinical update on persistent parathyroid hormone (PTH) elevation after surgical resection for primary hyperparathyroidism (PHPT) and to suggest a schedule for follow-up monitoring and strategies for future study. We reviewed the literature targeting studies with detailed analysis of biochemical parameters before and after parathyroidectomy for PHPT. We focused on potential etiologies and currently available outcome data. PTH elevation with eucalcemia after parathyroidectomy for PHPT occurs in 12% to 43% of patients. Underlying etiology is probably multifactorial, and possible causes include bone hunger, vitamin D deficiency, inadequate calcium intake or absorption, reduced peripheral sensitivity to PTH, underlying chronic kidney disease, and/or a renal leak of calcium. No consensus exists on how to follow-up and treat these patients. Although most patients with PTH elevation after parathyroidectomy will have normalization of PTH levels with time and/or calcium and vitamin D supplementation, this finding may be an early indicator of autonomous parathyroid secretion in a small number of patients. Patients with persistent PTH elevation should be monitored over time for recurrence of PHPT and other possible complications. A standardized follow-up protocol is needed to better study and elucidate the clinical significance of elevated PTH after parathyroidectomy.


Heat shock proteins: new keys to the development of cytoprotective therapies.
All cells, from bacterial to human, have a common, intricate response to stress that protects them from injury. Heat shock proteins (Hsps), also known as stress proteins and molecular chaperones, play a central role in protecting cellular homeostatic processes from environmental and physiologic insult by preserving the structure of normal proteins and repairing or removing damaged ones. An understanding of the interplay between Hsps and cell stress tolerance will provide new tools for treatment and drug design that maximise preservation or restoration of health. For example, the increased vulnerability of tissues to injury in some conditions, such as ageing, diabetes mellitus and menopause, or with the use of certain drugs,, such as some antihypertensive medications, is associated with an impaired Hsp response. Additionally, diseases that are associated with tissue oxidation, free radical formation, disorders of protein folding, or inflammation, may be improved therapeutically by elevated expression of Hsps. The accumulation of Hsps, whether induced physiologically, pharmacologically, genetically, or by direct administration of the proteins, is known to protect the organism from a great variety of pathological conditions, including myocardial infarction, stroke, sepsis, viral infection, trauma, neurodegenerative diseases, retinal damage, congestive heart failure, arthritis, sunburn, colitis, gastric ulcer, diabetic complications and transplanted organ failure. Conversely, lowering Hsps in cancer tissues can amplify the effectiveness of chemo- or radiotherapy. Treatments and agents that induce Hsps include hyperthermia, heavy metals (zinc and tin), salicylates, dexamethasone, cocaine, nicotine, alcohol, alpha-adrenergic agonists, PPAR-gamma agonists, bimoclomol, geldanamycin, geranylgeranylacetone and cyclopentenone prostanoids. Compounds that suppress Hsps include quercetin (a bioflavinoid), 15-deoxyspergualin (an immunosuppressive agent) and retinoic acid. Researchers who are cognisant of the Hsp-related effects of these and other agents will be able to use them to develop new therapeutic paradigms.


ONO-1078 antagonizes diarrhea-causing changes in ion transport and smooth muscle contraction induced by peptidoleukotrienes in rat and human colon in vitro.
Leukotrienes play important roles in inflammatory bowel diseases. Previous studies have revealed the effects of peptidoleukotrienes on smooth muscle contraction and transmucosal ion transport, which may cause hyperactive bowel movement and the loss of electrolytes and water, i.e., diarrhea. The purpose of the present study was to evaluate the effects of the peptidoleukotrienes antagonist ONO-1078 and to assess its possible future clinical use. We examined the effects of ONO-1078 on peptidoleukotrienes-induced changes in electrolyte transport and muscle contraction in the rat colon, with the Ussing and Magnus techniques. Human biopsy specimens obtained at colonoscopy were also used for ion transport studies. Transmucosal ion transport in both rats and humans, and smooth muscle contractions in the rat colon, were induced by similar doses of peptidoleukotrienes at estimated interstitial concentrations (1 nM-100 nM). The time course of changes in short circuit current had two phases, a rapid and transient decrease and a subsequent transient increase, which seemed to be due mainly to Na+ and Cl-, respectively. Rat colon smooth muscle contracted transiently after the addition of peptidoleukotrienes. These effects of peptidoleukotrienes, which could be related to the diarrhea in inflammatory bowel diseases, were inhibited by ONO-1078. ONO-1078 is expected to be effective in clinical use against peptidoleukotrienes-related diarrhea in mild to moderate inflammatory bowel diseases.


Completing Linnaeus's inventory of the Swedish insect fauna: Only 5,000 species left?
Despite more than 250 years of taxonomic research, we still have only a vague idea about the true size and composition of the faunas and floras of the planet. Many biodiversity inventories provide limited insight because they focus on a small taxonomic subsample or a tiny geographic area. Here, we report on the size and composition of the Swedish insect fauna, thought to represent roughly half of the diversity of multicellular life in one of the largest European countries. Our results are based on more than a decade of data from the Swedish Taxonomy Initiative and its massive inventory of the country's insect fauna, the Swedish Malaise Trap Project The fauna is considered one of the best known in the world, but the initiative has nevertheless revealed a surprising amount of hidden diversity: more than 3,000 new species (301 new to science) have been documented so far. Here, we use three independent methods to analyze the true size and composition of the fauna at the family or subfamily level: (1) assessments by experts who have been working on the most poorly known groups in the fauna; (2) estimates based on the proportion of new species discovered in the Malaise trap inventory; and (3) extrapolations based on species abundance and incidence data from the inventory. For the last method, we develop a new estimator, the combined non-parametric estimator, which we show is less sensitive to poor coverage of the species pool than other popular estimators. The three methods converge on similar estimates of the size and composition of the fauna, suggesting that it comprises around 33,000 species. Of those, 8,600 (26%) were unknown at the start of the inventory and 5,000 (15%) still await discovery. We analyze the taxonomic and ecological composition of the estimated fauna, and show that most of the new species belong to Hymenoptera and Diptera groups that are decomposers or parasitoids. Thus, current knowledge of the Swedish insect fauna is strongly biased taxonomically and ecologically, and we show that similar but even stronger biases have distorted our understanding of the fauna in the past. We analyze latitudinal gradients in the size and composition of known European insect faunas and show that several of the patterns contradict the Swedish data, presumably due to similar knowledge biases. Addressing these biases is critical in understanding insect biomes and the ecosystem services they provide. Our results emphasize the need to broaden the taxonomic scope of current insect monitoring efforts, a task that is all the more urgent as recent studies indicate a possible worldwide decline in insect faunas.


Accuracy of capsule colonoscopy in detecting colorectal polyps in a screening population.
Capsule colonoscopy is a minimally invasive imaging method. We measured the accuracy of this technology in detecting polyps 6 mm or larger in an average-risk screening population. In a prospective study, asymptomatic subjects (n = 884) underwent capsule colonoscopy followed by conventional colonoscopy (the reference) several weeks later, with an endoscopist blinded to capsule results, at 10 centers in the United States and 6 centers in Israel from June 2011 through April 2012. An unblinded colonoscopy was performed on subjects found to have lesions 6 mm or larger by capsule but not conventional colonoscopy. Among the 884 subjects enrolled, 695 (79%) were included in the analysis of capsule performance for all polyps. There were 77 exclusions (9%) for inadequate cleansing and whole-colon capsule transit time fewer than 40 minutes, 45 exclusions (5%) before capsule ingestion, 15 exclusions (2%) after ingestion and before colonoscopy, and 15 exclusions (2%) for site termination. Capsule colonoscopy identified subjects with 1 or more polyps 6 mm or larger with 81% sensitivity (95% confidence interval [CI], 77%-84%) and 93% specificity (95% CI, 91%-95%), and polyps 10 mm or larger with 80% sensitivity (95% CI, 74%-86%) and 97% specificity (95% CI, 96%-98%). Capsule colonoscopy identified subjects with 1 or more conventional adenomas 6 mm or larger with 88% sensitivity (95% CI, 82%-93) and 82% specificity (95% CI, 80%-83%), and 10 mm or larger with 92% sensitivity (95% CI, 82%-97%) and 95% specificity (95% CI, 94%-95%). Sessile serrated polyps and hyperplastic polyps accounted for 26% and 37%, respectively, of false-negative findings from capsule analyses. In an average-risk screening population, technically adequate capsule colonoscopy identified individuals with 1 or more conventional adenomas 6 mm or larger with 88% sensitivity and 82% specificity. Capsule performance seems adequate for patients who cannot undergo colonoscopy or who had incomplete colonoscopies. Additional studies are needed to improve capsule detection of serrated lesions. Clinicaltrials.gov number: NCT01372878.


Measuring hospital efficiency with Data Envelopment Analysis: nonsubstitutable vs. substitutable inputs and outputs.
There is a conflict between Data Envelopment Analysis (DEA) theory's requirement that inputs (outputs) be substitutable, and the ubiquitous use of nonsubstitutable inputs and outputs in DEA applications to hospitals. This paper develops efficiency indicators valid for nonsubstitutable variables. Then, using a sample of 87 community hospitals, it compares the new measures' efficiency estimates with those of conventional DEA measures. DEA substantially overestimated the hospitals' efficiency on the average, and reported many inefficient hospitals to be efficient. Further, it greatly overestimated the efficiency of some hospitals but only slightly overestimated the efficiency of others, thus making any comparisons among hospitals questionable. These results suggest that conventional DEA models should not be used to estimate the efficiency of hospitals unless there is empirical evidence that the inputs (outputs) are substitutable. If inputs (outputs) are not substitutes, efficiency indicators valid for nonsubstitutability should be employed, or, before applying DEA, the nonsubstitutable variables should be combined using an appropriate weighting scheme or statistical methodology.


The age of the 20 meter Solo River terrace, Java, Indonesia and the survival of Homo erectus in Asia.
Homo erectus was the first human lineage to disperse widely throughout the Old World, the only hominin in Asia through much of the Pleistocene, and was likely ancestral to H. sapiens. The demise of this taxon remains obscure because of uncertainties regarding the geological age of its youngest populations. In 1996, some of us co-published electron spin resonance (ESR) and uranium series (U-series) results indicating an age as young as 35-50 ka for the late H. erectus sites of Ngandong and Sambungmacan and the faunal site of Jigar (Indonesia). If correct, these ages favor an African origin for recent humans who would overlap with H. erectus in time and space. Here, we report (40)Ar/(39)Ar incremental heating analyses and new ESR/U-series age estimates from the "20 m terrace" at Ngandong and Jigar. Both data sets are internally consistent and provide no evidence for reworking, yet they are inconsistent with one another. The (40)Ar/(39)Ar analyses give an average age of 546±12 ka (sd±5 se) for both sites, the first reliable radiometric indications of a middle Pleistocene component for the terrace. Given the technical accuracy and consistency of the analyses, the argon ages represent either the actual age or the maximum age for the terrace and are significantly older than previous estimates. Most of the ESR/U-series results are older as well, but the oldest that meets all modeling criteria is 143 ka+20/-17. Most samples indicated leaching of uranium and likely represent either the actual or the minimum age of the terrace. Given known sources of error, the U-series results could be consistent with a middle Pleistocene age. However, the ESR and (40)Ar/(39)Ar ages preclude one another. Regardless, the age of the sites and hominins is at least bracketed between these estimates and is older than currently accepted.


The neuroprotective mechanisms and effects of sulforaphane.
Sulforaphane (SFN) is a phytochemical found in cruciferous vegetables. It has been shown to have many protective effects against many diseases, including multiple types of cancer. SFN is a potent activator of the nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (ARE) genetic pathway. Upregulation of Nrf2-ARE increases the availability of multiple antioxidants. A substantial amount of preclinical research regarding the ability of SFN to protect the nervous system from many diseases and toxins has been done, but only a few small human trials have been completed. Preclinical data suggest that SFN protects the nervous system through multiple mechanisms and may help reduce the risk of many diseases and reduce the burden of symptoms in existing conditions. This review focuses on the literature regarding the protective effects of SFN on the nervous system. A discussion of neuroprotective mechanisms is followed by a discussion of the protective effects elicited by SFN administration in a multitude of neurological diseases and toxin exposures. SFN is a promising neuroprotective phytochemical which needs further human trials to evaluate its efficacy in preventing and decreasing the burden of many neurological diseases.


Estrogen-receptor interaction.
The interaction of estradiol with uterine cells involves the association of the hormone with an extranuclear receptor protein, followed by temperature dependent translocation of the resulting complex to the nucleus. During this process, the steroid binding unit of the protein undergoes an alteration, called "receptor transformation," that can be recognized by an increase in its sedimentation rate from 3.8S to 5.2S, and by its acquisition of the ability to bind to isolated uterine nuclei and to alleviate a tissue specific deficiency in the RNA synthesizing capacity of such nuclei. Receptor transformation can be effected in the absence of nuclei by warming uterine cytosol with estradiol. This preparation of transformed complex resembles that extracted from nuclei both in its sedimentation rate (5.3S) and in its ability to bind to uterine nuclei and augment RNA synthesis, properties that are not shown by the native complex. It is proposed that receptor transformation is an important step in estrogen action and that a principal role of the hormone is to induce conversion of the receptor protein to a biochemically functional form.


Can multiphase CT scan distinguish between papillary renal cell carcinoma type 1 and type 2?
To investigate the utility of multiphase computed tomography (CT) and percutaneous renal mass biopsy (PRMB) in differentiating between papillary renal cell carcinoma (pRCC)-Type 1 and -Type 2, as emerging data have suggested differential enhancement patterns in different renal tumor histologies. Retrospective analysis of 51 patients (23 pRCC-Type 1/28 pRCC-Type 2) who underwent multiphase CT followed by surgery from July 2011 to April 2016 was performed. Data were analyzed between subgroups based on histology. Multiphase CT was analyzed for tumor size, and attenuation [Hounsfield Units (HU)]. Change in HU (ΔHU) was calculated between noncontrast (NC), corticomedullary (CM), nephrographic (N), and delayed (D) phases. Subset analysis was carried out on patients who underwent PRMB prior to surgery. There was no difference in median tumor size (pRCC-Type 1 2.8 vs. pRCC-Type 2 2.6 cm, p=0.832). In addition to tumor size being similar between groups, distribution of tumor stages between groups was also similar (p=0.651). Greater proportion of high-grade tumors (III/IV) was noted in pRCC-Type 2 (42.9% vs. 8.7%) (p=0.011). There was no difference in HU values for NC (p=0.961), CM (p=0.118), N (p=0.277), and D (p=0.256) phases, and in ΔHU between CM-NC (p=0.278), N-NC (p=0.316), and D-NC (p=0.103). Thirteen patients underwent percutaneous biopsy, 11 of whom had diagnostic samples. Examination of 10/11 (90.9%) samples accurately predicted correct histology, and of 6/11 (54.5%) samples correctly identified high-vs. low-grade histology. Our findings suggest substantial overlap of CT findings, despite pRCC-Type 2 having greater proportion of high-grade tumors. Utility of CT is limited in the differentiation between pRCC subtypes. Patients with suggested pRCC on CT imaging being considered for a non-extirpative strategy should undergo PRMB for risk stratification.


A Population-Average, Landmark- and Surface-based (PALS) atlas of human cerebral cortex.
This report describes a new electronic atlas of human cerebral cortex that provides a substrate for a wide variety of brain-mapping analyses. The Population-Average, Landmark- and Surface-based (PALS) atlas approach involves surface-based and volume-based representations of cortical shape, each available as population averages and as individual subject data. The specific PALS-B12 atlas introduced here is derived from structural MRI volumes of 12 normal young adults. Accurate cortical surface reconstructions were generated for each hemisphere, and the surfaces were inflated, flattened, and mapped to standard spherical configurations using SureFit and Caret software. A target atlas sphere was generated by averaging selected landmark contours from each of the 24 contributing hemispheres. Each individual hemisphere was deformed to this target using landmark-constrained surface registration. The utility of the resultant PALS-B12 atlas was demonstrated using a variety of analyses. (i) Probabilistic maps of sulcal identity were generated using both surface-based registration (SBR) and conventional volume-based registration (VBR). The SBR approach achieved markedly better consistency of sulcal alignment than did VBR. (ii) A method is introduced for 'multi-fiducial mapping' of volume-averaged group data (e.g., fMRI data, probabilistic architectonic maps) onto each individual hemisphere in the atlas, followed by spatial averaging across the individual maps. This yielded a population-average surface representation that circumvents the biases inherent in choosing any single hemisphere as a target. (iii) Surface-based and volume-based morphometry applied to maps of sulcal depth and sulcal identity demonstrated prominent left-right asymmetries in and near the superior temporal sulcus and Sylvian fissure. Moreover, shape variability in the temporal lobe is significantly greater in the left than the right hemisphere. The PALS-B12 atlas has been registered to other surface-based atlases to facilitate interchange of data and comparison across atlases. All data sets in the PALS-B12 atlas are accessible via the SumsDB database for online and offline visualization and analysis.


Methodological quality assessment of review articles evaluating interventions to improve microbial food safety.
Review articles are a means of summarizing the potentially vast volume of research on a topic. However, the methodological quality of review articles varies, and reviews on the same topic may reach different conclusions. We evaluated 65 review articles published between 2000 and 2005 that addressed the effectiveness of microbial food safety interventions, using criteria for methodological soundness developed in the medical field. Overall, the methodological quality of the review articles was poor, with none of the reviews providing information on the method of locating primary research studies or the inclusion/exclusion criteria for selecting primary studies. None of the reviews included a critical appraisal of the methodological quality of the primary studies. Less than half of the reviews stated a focused research question, explored possible reasons for differences in the results of primary studies, discussed the generalizability of results, or proposed directions for future research. There is a need to improve the methodological quality of review articles on microbial food safety interventions if they are to be of use in policy and decision making.