Evidence-based recommendations for the management of acne fulminans and its variants.
Acne fulminans (AF) is a severe variant of inflammatory acne. It typically manifests as an explosive worsening and ulceration of skin lesions, and can be associated with systemic symptoms. However, there is a paucity of evidence-based information and no clear guidelines concerning the classification and treatment of AF. To better define the spectrum of AF and its variants, devise optimal therapeutic approaches, and identify areas of future research. A panel of physicians with expertise in severe acne vulgaris was convened after a comprehensive literature review of severe acne variants. Priority topics were reviewed and presented by each panelist at a 5-hour conference. Following review of the audiotape and scribed notes from the conference, surveys were utilized to address points of controversy and to clarify consensus recommendations. Appropriate clinical case presentations and consensus survey questions were utilized to create final recommendations based on both the literature and the expert consensus. Limited evidenced-based data and prospective studies in the literature concerning the treatment of AF is available. These guidelines better characterize AF and provide health care practitioners approaches to the classification, treatment, and prevention of AF and its variants.


Hand, Foot, and Mouth Disease in Thailand: A Comprehensive Modelling of Epidemic Dynamics.
Hand, foot, and mouth disease (HFMD) is a highly contagious disease with several outbreaks in Asian-Pacific countries, including Thailand. With such epidemic characteristics and potential economic impact, HFMD is a significant public health issue in Thailand. Generally, contagious/infectious diseases' transmission dynamics vary across geolocations due to different socioeconomic situations, demography, and lifestyles. Hence, a nationwide comprehensive model of the disease's epidemic dynamics can provide information to understand better and predict a potential outbreak of this disease and efficiently and effectively manage its impact. However, there is no nationwide and comprehensive (i.e., the inclusion of reinfections in the model) model of HFDM dynamics for Thailand. This paper has endeavoured to promote nationwide comprehensive modelling of HFMD's epidemic dynamics and comprehend the reinfection cases. We have formulated the SEIRS epidemiological model with dynamic vitals, including reinfections, to explore this disease's prevalence. We also introduced periodic seasonality to reproduce the seasonal effect. The pattern of spread of this disease is uneven across the provinces in Thailand, so we used K-means clustering algorithm to cluster those provinces into three groups (i.e., highly, moderately, and least affected levels). We also analysed health records collected from district hospitals, which suggest significant reinfection cases. For example, we found that 11% (approximately) of infectious patients return for repeat treatment within the study period. We also performed sensitivity analysis which indicates that the basic reproduction number (R 0) is sensitive to the rate of transmission (β) and the rate at which infected people recover (γ). By fitting the model with HFMD confirmed data for the provinces in each cluster, the basic reproduction number (R 0) was estimated to be 2.643, 1.91, and 3.246 which are greater than 1. Based on this high R 0, this study recommends that this disease will persist in the coming years under identical cultural and environmental conditions.


Use of simulator for EUS training in the diagnosis of pancreatobiliary diseases.
EUS has been widely used in the diagnosis of pancreatobiliary diseases. However, improvements in the conventional training pattern of EUS are needed urgently. In this study, we compared the results achieved after use of clinical practice training patterns combined with or without simulator training and evaluated the effectiveness of simulator use in EUS training. The trainees were randomly divided into two groups: the experimental group was trained with both clinical practice and simulator training system and the control group was only trained through clinical practice. After 1 month of training, trainees of both groups were tested with an established technical evaluation procedure that aimed to assess trainees' ability to examine the normal anatomical structure. Then, trainees in the experimental group completed a questionnaire. The mean test score of the experimental group (64.53 ± 4.91) was significantly greater than that of the control group (60.09 ± 5.49; P= 0.028). Moreover, the individual test score of trainees in the experimental group was positively correlated with the frequency of simulator use (P = 0.242). Simulator training can promote trainees' ability to evaluate the normal anatomical structure, and thus, can improve the efficiency of the EUS training program.


The pursuit of better diagnostic performance: a human factors perspective.
Despite the relatively slow start in treating diagnostic error as an amenable research topic at the beginning of the patient safety movement, interest has steadily increased over the past few years in the form of solicitations for research, regularly scheduled conferences, an expanding literature and even a new professional society. Yet improving diagnostic performance increasingly is recognised as a multifaceted challenge. With the aid of a human factors perspective, this paper addresses a few of these challenges, including questions that focus on who owns the problem, treating cognitive and system shortcomings as separate issues, why knowledge in the head is not enough, and what we are learning from health information technology (IT) and the use of checklists. To encourage empirical testing of interventions that aim to improve diagnostic performance, a systems engineering approach making use of rapid-cycle prototyping and simulation is proposed. To gain a fuller understanding of the complexity of the sociotechnical space where diagnostic work is performed, a final note calls for the formation of substantive partnerships with those in disciplines beyond the clinical domain.


Potential biomarkers for lung cancer screening.
Notwithstanding the encouraging results of the National Lung Screening Trial (NLST) the scientific community still debates on the cost-benefit profile of low dose computed tomography (LDCT) lung cancer screening. Several major concerns regard how to identify subjects at high risk of developing lung cancer, the optimal diagnostic algorithm, the management of lung nodules and the high false positive rates. The use of complementary biomarkers would be a useful strategy for dealing with most of these issues. This short review will focus on candidates' biomarkers circulating in serum or plasma that already reached an advanced validation phase also in LDCT lung cancer screening series. The biomarkers presented below are examples of the value of searching candidates by looking not only to the tumor itself but also to the interplay between the tumor and the host in order to identify early changes related to the biological reactivity of the host to a developing cancer.


Inhibitors of the 5-lipoxygenase pathway activate pannexin1 channels in macrophages via the thromboxane receptor.
A multitude of environmental signaling molecules influence monocyte and macrophage innate and adaptive immune responses, including ATP and prostanoids. Interestingly, purinergic (P2) and eicosanoid receptor signaling interact such that the activation of P2 receptors leads to prostanoid production, which can then interfere with P2Y-mediated macrophage migration. Recent studies suggest that blockade of 5-lipoxygenase (5-LOX) in macrophages can activate a permeation pathway involved in the influx of dye and the release of ATP. Here, we provide evidence that pannexin1 (Panx1) is a component of this pathway and present the intracellular signaling molecules linking the thromboxane (TP) receptor to Panx1-mediated dye influx and ATP release. Using pharmacological tools and transgenic mice deficient in Panx1, we show that two 5-LOX pathway inhibitors induce ATP release and influx of dye in a Panx1-dependent manner. Electrophysiological recordings performed in wild-type and Panx1-deficient macrophages confirmed that these 5-LOX pathway inhibitors activate currents characteristic of Panx1 channels. We found that the mechanism by which Panx1 channels are activated under this condition involves activation of the TP receptor that is mediated by the cAMP/PKA pathway. This is to our knowledge the first evidence for the involvement of Panx1 in the TP receptor signaling pathway. Future studies aimed to clarify the contribution of this TP-Panx1 signaling network to macrophage immune responses are likely to be important for targeting inflammatory and autoimmune diseases.


Effect of Royal Jelly on premenstrual syndrome among Iranian medical sciences students: a randomized, triple-blind, placebo-controlled study.
Premenstrual syndrome (PMS) may have negative effects on women's health and sometimes need therapeutic non-pharmacological management. To determine the effect of oral consumption of 1000 mg Royal Jelly capsule on premenstrual syndrome. This is a randomized, triple-blind, placebo-controlled clinical trial, which was conducted in Tehran University of Medical Sciences female dormitories between December 2011 and October 2012. The study population comprised 110 medical sciences student with PMS, whom were randomly assigned to an intervention or a control group. Each participant in the intervention group took one Royal jelly capsule orally per day, starting on the first day of menstruation and continued the same treatment daily throughout two consecutive menstrual cycles, while participants in the intervention group took placebo capsules as same method. The outcome measure in this study was PMS score as obtained through the Premenstrual Profile 2005. The mean of personal characteristics and baseline level of the premenstrual score before intervention did not differ between groups. After two consecutive months consumption of Royal Jelly, PMS score had decreased from 23.17 ± 17.43 to 11.42 ± 14.58 (mean change: 11.75; 95% confidence interval [CI]: 8.31-15.19) and in Placebo, PMS score changed from 21.48 ± 16.39 to 20.27 ± 15.76 (mean change: 1.20; 95% CI: -1.69 to 4.10). Also difference between mean changes was significant (mean difference: 10.54; 95% CI: 6.10-14.98). The results of the study have demonstrated that 2 months consumption of Royal Jelly was effective in reducing PMS.


Cell cycle-dependent expression of cIAP2 at G2/M phase contributes to survival during mitotic cell cycle arrest.
cIAP2 (cellular inhibitor of apoptosis protein 2) is induced by NF-kappaB (nuclear factor kappaB) when cells need to respond quickly to different apoptotic stimuli. A recent study using cDNA microarray technology has suggested that cIAP2 transcription is regulated in a cell cycle-dependent manner, although the mechanism for such regulation is unknown. In this study, we confirmed the cell cycle-dependent regulation of cIAP2 expression at both the mRNA and protein levels. Additionally, we found that a bipartite CDE (cell cycle-dependent element)/CHR (cell cycle gene homology region) element in the cIAP2 promoter mediates cIAP2 gene activation in G2/M phase. Cell cycle-dependent G2/M-phase-specific cIAP2 expression is enhanced by NF-kappaB activation, and selective down-regulation of cIAP2 causes cells blocked in mitosis with nocodazole to become susceptible to apoptosis, indicating that the G2/M-phase-specific expression of cIAP2 contributes to the survival of mitotically arrested cells. Our studies describing the NF-kappaB-independent G2/M-phase-specific expression of cIAP2 will help in further understanding the molecular basis of cIAP2 over-expression in a variety of human cancers.


Exploring the Metabolic Stability of Engineered Hairy Roots after 16 Years Maintenance.
Plants remain a major source of new drugs, leads and fine chemicals. Cell cultures deriving from plants offer a fascinating tool to study plant metabolic pathways and offer large scale production systems for valuable compounds - commercial examples include compounds such as paclitaxel. The major constraint with undifferentiated cell cultures is that they are generally considered to be genetically unstable and cultured cells tend to produce low yields of secondary metabolites especially over time. Hairy roots, a tumor tissue caused by infection of Agrobacterium rhizogenes is a relevant alternative for plant secondary metabolite production for being fast growing, able to grow without phytohormones, and displaying higher stability than undifferentiated cells. Although genetic and metabolic stability has often been connected to transgenic hairy roots, there are only few reports on how a very long-term subculturing effects on the production capacity of hairy roots. In this study, hairy roots producing high tropane alkaloid levels were subjected to 16-year follow-up in relation to genetic and metabolic stability. Cryopreservation method for hairy roots of Hyoscyamus muticus was developed to replace laborious subculturing, and although the post-thaw recovery rates remained low, the expression of transgene remained unaltered in cryopreserved roots. It was shown that although displaying some fluctuation in the metabolite yields, even an exceedingly long-term subculturing was successfully applied without significant loss of metabolic activity.


First Report of Erwinia amylovora on Firethorn (Pyracantha coccinea) and Mountainash (Sorbus sp.) in Turkey.
Fire blight, caused by the bacterium Erwinia amylovora, is a serious disease of apples (Malus spp.) and pears (Pyrus spp.) but can also infect many ornamental species in the Rosaceae family. In the summers of 2009 and 2010, leaf and shoot blight and reddish colored cankers were observed on firethorn (Pyracantha coccinea) and brown discolored leaves and necrotic stem lesions on mountain ash (Sorbus sp.) both from the landscape areas of Konya province. Investigation of these symptoms showed that in an 85-ha area, disease incidence was estimated at 1.5% and 1% on firethorn and mountain ash, respectively. Bacteria were consistently isolated from both leaf and lesions onto nutrient sucrose agar medium. Nine representative bacterial colonies from firethorn isolations and six from mountain ash isolations purified and characterized as gram-negative, rod-shaped, mucoid, fermentative, yellow-orange on Miller & Scroth medium, positive for levan formation and acetoin production, no growth at 36°C, positive for gelatin and esculin hydrolysis, and negative for indole, urease, oxidase, arginine dehydrolase, reduction of nitrate, and acid production from lactose and inositol (2). Two reference strains of E. amylovora (EaP28 and NCPPB 2791) obtained from culture collection at Selcuk University, Department of Plant Protection, Konya, Turkey, were used as positive controls. All strains induced a hypersensitive response in tobacco (Nicotiana tobaccum cv. White Burley) and produced ooze when stab inoculated on immature pear fruits. In addition, all strains and the references were identified as E. amylovora on the basis of a 1-kb DNA fragment amplification with a species-specific primer set, A/B (1) in PCR. Pathogenicity tests were performed by injecting a bacterial suspension (108 CFU ml-1) into the shoot tips of 3-year-old firethorn and mountain ash seedlings, resulting in leaf and shoot blight symptoms observed 10 to 15 days after inoculation. No symptoms were observed on control plants treated with sterile water. E. amylovora was positively reisolated from leaf and shoot lesions from the inoculated seedlings and identified as described above. To our knowledge, this is the first report of E. amylovora on P. coccinea and Sorbus sp. in Turkey. References: (1) S. Bereswill et al. Appl. Environ. Microbiol. 58:3522, 1992 (2) A. L. Jones and K. Geider. Page 40 in: Laboratory Guide for Identification of Plant Pathogenic Bacteria, 2001.


Dosimetric precision of an ion beam tracking system.
Scanned ion beam therapy of intra-fractionally moving tumors requires motion mitigation. GSI proposed beam tracking and performed several experimental studies to analyse the dosimetric precision of the system for scanned carbon beams. A beam tracking system has been developed and integrated in the scanned carbon ion beam therapy unit at GSI. The system adapts pencil beam positions and beam energy according to target motion. Motion compensation performance of the beam tracking system was assessed by measurements with radiographic films, a range telescope, a 3D array of 24 ionization chambers, and cell samples for biological dosimetry. Measurements were performed for stationary detectors and moving detectors using the beam tracking system. All detector systems showed comparable data for a moving setup when using beam tracking and the corresponding stationary setup. Within the target volume the mean relative differences of ionization chamber measurements were 0.3% (1.5% standard deviation, 3.7% maximum). Film responses demonstrated preserved lateral dose gradients. Measurements with the range telescope showed agreement of Bragg peak depth under motion induced range variations. Cell survival experiments showed a mean relative difference of -5% (-3%) between measurements and calculations within the target volume for beam tracking (stationary) measurements. The beam tracking system has been successfully integrated. Full functionality has been validated dosimetrically in experiments with several detector types including biological cell systems.


Influence of Resistance Training Frequency on Muscular Adaptations in Well-Trained Men.
The purpose of this study was to investigate the effects of training muscle groups 1 day per week using a split-body routine (SPLIT) vs. 3 days per week using a total-body routine (TOTAL) on muscular adaptations in well-trained men. Subjects were 20 male volunteers (height = 1.76 ± 0.05 m; body mass = 78.0 ± 10.7 kg; age = 23.5 ± 2.9 years) recruited from a university population. Participants were pair matched according to baseline strength and then randomly assigned to 1 of the 2 experimental groups: a SPLIT, where multiple exercises were performed for a specific muscle group in a session with 2-3 muscle groups trained per session (n = 10) or a TOTAL, where 1 exercise was performed per muscle group in a session with all muscle groups trained in each session (n = 10). Subjects were tested pre- and poststudy for 1 repetition maximum strength in the bench press and squat, and muscle thickness (MT) of forearm flexors, forearm extensors, and vastus lateralis. Results showed significantly greater increases in forearm flexor MT for TOTAL compared with SPLIT. No significant differences were noted in maximal strength measures. The findings suggest a potentially superior hypertrophic benefit to higher weekly resistance training frequencies.


Congenital hypomyelinating neuropathy with lethal conduction failure in mice carrying the Egr2 I268N mutation.
Mouse models of human disease are helpful for understanding the pathogenesis of the disorder and ultimately for testing potential therapeutic agents. Here, we describe the engineering and characterization of a mouse carrying the I268N mutation in Egr2, observed in patients with recessively inherited Charcot-Marie-Tooth (CMT) disease type 4E, which is predicted to alter the ability of Egr2 to interact with the Nab transcriptional coregulatory proteins. Mice homozygous for Egr2(I268N) develop a congenital hypomyelinating neuropathy similar to their human counterparts. Egr2(I268N) is expressed at normal levels in developing nerve but is unable to interact with Nab proteins or to properly activate transcription of target genes critical for proper peripheral myelin development. Interestingly, Egr2(I268N/I268N) mutant mice maintain normal weight and have only mild tremor until 2 weeks after birth, at which point they rapidly develop worsening weakness and uniformly die within several days. Nerve electrophysiology revealed conduction block, and neuromuscular junctions showed marked terminal sprouting similar to that seen in animals with pharmacologically induced blockade of action potentials or neuromuscular transmission. These studies describe a unique animal model of CMT, whereby weakness is due to conduction block or neuromuscular junction failure rather than secondary axon loss and demonstrate that the Egr2-Nab complex is critical for proper peripheral nerve myelination.


Natural variation of barley vernalization requirements: implication of quantitative variation of winter growth habit as an adaptive trait in East Asia.
In many temperate plant species, prolonged cold treatment, known as vernalization, is one of the most critical steps in the transition from the vegetative to the reproductive stage. In contrast to recent advances in understanding the molecular basis of vernalization in Arabidopsis non-vernalization mutants or the spring growth habits of cereal crops such as wheat and barley, natural variations in winter growth habits and their geographic distribution are poorly understood. We analyzed varietal variation and the geographic distribution of the degree of vernalization requirements in germplasms of domesticated barley and wild barley collections. We found a biased geographic distribution of vernalization requirements in domesticated barley: Western regions were strongly associated with a higher degree of spring growth habits, and the extreme winter growth habits were localized to Far Eastern regions including China, Korea and Japan. Both wild accessions and domesticated landraces, the regions of distribution of which overlapped each other, mainly belonged to the moderate class of winter growth habit. As a result of quantitative evaluations performed in this study, we provide evidence that the variation in the degree of winter growth habit in recombinant inbred lines was controlled by quantitative trait loci including three vernalization genes (VRN1, VRN2 and VRN3) that account for 37.9% of the variation in vernalization requirements, with unknown gene(s) explaining the remaining two-thirds of the variation. This evidence implied that the Far Eastern accessions might be a genetically differentiated group derived for an evolutionary reason, resulting in their greater tendency towards a winter growth habit.


Effective lock-in strategy for proteomic analysis of corona complexes bound to amino-free ligands of gold nanoparticles.
For specific applications, gold nanoparticles (GNPs) are commonly functionalized with various biological ligands, including amino-free ligands such as amino acids, peptides, proteins, and nucleic acids. Upon entering a biological fluid, the protein corona that forms around GNPs can conceal the targeting ligands and sterically hinder the functional properties. The protein corona is routinely prepared by standard centrifugation or sucrose cushion centrifugation. However, such methodologies are not applicable to the exclusive analysis of a ligand-binding protein corona. In this study, we first proposed a lock-in strategy based on a combination of rapid crosslinking and stringent washing. Cysteine was used as a model of amino-free ligands and attached to GNPs. After corona formation in the human plasma, GNP cysteine and corona proteins were quickly fixed by 5 s of crosslinking with 7.5% formaldehyde. After stringent washing using SDS buffer with sonication, the cysteine-bound proteins were effectively separated from unbound proteins. Qualitative and quantitative analyses using a mass spectrometry-based proteomics approach indicated that the protein composition of the cysteine-binding corona from the new method was significantly different from the composition of the whole corona from the two conventional methods. Furthermore, network and formaldehyde-linked site analyses of cysteine-binding proteins provided useful information toward a better knowledge of the behavior of protein-ligand and protein-protein interactions. Collectively, our new strategy has the capability to particularly characterize the protein composition of a cysteine-binding corona. The presented methodology in principal provides a generic way to analyze a nanoparticle corona bound to amino-free ligands and has the potential to decipher corona-masked ligand functions.


Effect of exogenous amylolytic enzymes on the accumulation of chlorogenic acid isomers in wounded potato tubers.
Potato tubers under wounding stress synthesize chlorogenic acid isomers, which are phenolic compounds that prevent chronic diseases. The biosynthesis of phenolic compounds in plants requires aromatic amino acids that are produced from sugars. Therefore, in this study, we hypothesized that the wound-induced accumulation of chlorogenic acid isomers in potatoes could be enhanced if the availability of sugars is increased by exogenous amylolytic enzymes applied to the surface of the site of wounding. To test this hypothesis, wounded potatoes stored at 20 °C were treated with amylolytic enzymes (pullulanase and amyloglucosidase, 282 units/mL, 10 mL/kg) after being stored for 0 (E0h), 48 (E48h), or 96 h (E96h). The highest level of accumulation of total chlorogenic acid isomers (∼210% higher than that of time 0 h samples) was observed after storage for 120 h for the E96h treatment. The results suggest that increasing the availability of carbon sources needed for the biosynthesis of phenolic compounds would trigger their accumulation in wounded plants.


Changing patterns of antimicrobial susceptibility of Shigella serotypes isolated from children with acute diarrhea in Manipal, South India, a 5 year study.
This study was carried out to determine the current pattern of Shigella serogroups and their antimicrobial resistance in children with acute gastroenteritis in Manipal, South India. A total of 1,200 stool samples were collected from April 2001 to May 2006 in children suffering from acute gastroenteritis attending the out-patient department of pediatrics at Kasturba Hospital, Manipal, South India. These samples were cultured for enteric pathogens. The isolates were confirmed to be Shigella by biochemical reactions and slide agglutination tests using specific antisera. Antimicrobial susceptibility was performed using an agar diffusion technique method following the National Committee for Clinical Laboratory Standard guidelines. Of 1,200 stool samples, 68 (5.6%) were positive for Shigella spp, 31 (45%) were Shigella flexneri followed by S. sonnei in 20 (31%), S. boydii in 10 (15%), and S. dysenteriae in 6 (8%). Of the 68 isolates, 58 (85.7%) showed resistance to various drugs and 47 (70%) were resistant to two or more drugs. Resistance to trimethoprim-sulfmethoxazole, tetracycline, nalidixic acid and ampicillin was observed in this study. All the strains were resistant to nalidixic acid (100%) but sensitive to cefotaxime and ceftriaxone.


Association of chromosome 8q variants with prostate cancer risk in Caucasian and Hispanic men.
Genotyping of a 615 kb region within 8q24 with 49 haplotype-tagged single-nucleotide polymorphisms (SNPs) in 2109 samples (797 cases and 1312 controls) of two ethnic/racial groups found SNPs that are significantly associated with the risk for prostate cancer (PCa). The highest significance in Caucasian men was found for rs6983267; the AA genotype reduced the risk for PCa [odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.35-0.65, P = 2.74 x 10(-6)]. This SNP also had a significant independent effect from other SNPs in the region in this group. In Hispanic men, rs7837328 and rs921146 showed independent effects (OR = 2.55, 95% CI = 1.51-4.31, P = 4.33 x 10(-4), OR = 2.09, 95% CI = 1.40-3.12, P = 3.13 x 10(-4), respectively). Significant synergist effects for increasing numbers of high-risk alleles were found in both ethnicities. Haplotype analysis revealed major haplotypes, containing the non-risk alleles, conferred protection against PCa. We found high linkage disequilibrium between significant SNPs within the region and SNPs within the CUB and Sushi Multiple Domains 1 gene (CSMD1), on the short arm of chromosome 8 in both ethnicities. These data suggest that multiple interacting SNPs within 8q24, as well as different regions on chromosome 8 far beyond this 8q24 candidate region, may confer increased risk of PCa. This is the first report to investigate the involvement of 8q24 variants in the susceptibility for PCa in Hispanic men.


Allelic loss at 19q12 and Xq11-12 predict an adverse clinical outcome in patients with mucinous ovarian tumours of low malignant potential.
Ovarian tumours of low malignant potential (LMP) are intermediate between adenomas and ovarian carcinomas. These tumours are often associated with a significantly better prognosis than ovarian carcinomas. However, a subset of these tumours can progress and become lethal. In order to seek sensitive diagnostic tools for monitoring patients after surgical operation, we performed a genome-wide scan for loss of heterozygosity (LOH) in 41 mucinous LMPs using 91 polymorphic microsatellite markers at an average interval of 50 cM across all of the human chromosomes and 25 LOH markers reportedly associated with ovarian carcinoma. In addition, we assessed whether clinicopathological parameters, microvessel density, Ki-67 labeling index, apoptotic index or p53 overexpression would be useful for predicting the postoperative outcome of LMP patients. Of the 116 markers examined, 19q12 and Xq11-12 showed significant correlation between postoperative progression-free survival time and LOH status (P<0.05). Patients with a high Ki-67 labeling index had a significantly poorer progression-free survival time than those with lower levels (P=0.042). Other clinicopathological factors and immunohistochemical analysis had no correlation with progression-free survival time in this series of patients. When the combination of LOH at 19q12 and/or Xq11-12 was assessed using Cox's regression analysis, patients with tumours that showed LOH at these positions were at greatest risk of progression (P=0.0073). These findings suggest that the identification of LOH at 19q12 and/or Xq11-12 in former mucinous LMP sites should alert the clinician to the presence of a potentially aggressive lesion in the coelomic epithelium, even if a distinction between second primary tumours or recurrence could not be determined.


The presumptive CDR3 regions of both T cell receptor alpha and beta chains determine T cell specificity for myoglobin peptides.
The T cell receptor alpha/beta (TCR-alpha/beta) is encoded by variable (V), diversity (D), joining (J), and constant (C) segments assembled by recombination during thymocyte maturation to produce a heterodimer that imparts antigenic specificity to the T cell. Unlike immunoglobulins (Igs), which bind free antigen, the ligands of TCR-alpha/beta are cell surface complexes of intracellularly degraded antigens (i.e., peptides) bound to and presented by polymorphic products of the major histocompatibility complex (MHC). Therefore, antigen recognition by T cells is defined as MHC restricted. A model has been formulated based upon the similarity between TCR-alpha/beta V region and Ig Fab amino acid sequences, and the crystal structure of the MHC class I and Ig molecules. This model predicts that the complementarity determining regions (CDR) 1 and 2, composed of TCR V alpha and V beta segments, primarily contact residues of the MHC alpha helices, whereas V/J alpha and V/D/J beta junctional regions (the CDR3 equivalent) contact the peptide in the MHC binding groove. Because polymorphism in MHC proteins is limited relative to the enormous diversity of antigenic peptides, the TCR may have evolved to position the highly diverse junctional residues (CDR3), where they have maximal contact with antigen bound in the MHC peptide groove. Here, we demonstrate a definitive association between CDR3 sequences in both TCR alpha and beta chains, and differences in recognition of antigen fine specificity using a panel of I-Ed-restricted, myoglobin-reactive T cell clones. Acquisition of these data relied in part upon a modification of the polymerase chain reaction that uses a degenerate, consensus primer to amplify TCR alpha chains without foreknowledge of the V alpha segments they utilize.


Assessment of health-related quality of life in patients with lymphedema of the lower limb.
The purpose of this study was to examine the use of a number of tools in the evaluation of health-related quality of life in patients with lower limb lymphedema, and to determine the consequences of cancer history and concurrent leg ulceration. Patients in one health trust having lower limb lymphedema were identified and interviewed at entry and after 24 weeks. The short form-36 (SF-36), modified Barthel scale, McGill short form pain questionnaire, and Euroqol were administered at both time points. Of the 164 (median age=76.9 years, 70.7% women) patients who comprised the study population, 15.2% had a history of cancer and 30.4% had coexisting current leg ulceration. Internal consistencies were high for all scales (Cronbach's alpha >0.80). There were high ceiling effects for a number of SF-36 scores, and high floor effects in these and the McGill short form pain questionnaire, scales. Despite these limitations, there was strong evidence that treatment led to significant improvements in six of eight scores of the SF-36, three of three scores of the McGill short form pain questionnaire and the modified Barthel scale (all p<0.05). The improvement in physical functioning was significantly greater for patients who entered the study with a leg ulcer (mean different=9.1, 95% confidence interval 2.1-16.1, p=0.011). Patients treated with compression bandaging had significantly greater improvements for physical functioning (10.2) than those treated with compression hosiery (-1.5) or no treatment (-2.0), p=0.001. Of the tools assessed, the SF-36, appears to be the most appropriate for use in this patient group.


Potential Energy Surface Reconstruction and Lifetime Determination of Molecular Double-Core-Hole States in the Hard X-Ray Regime.
A combination of resonant inelastic x-ray scattering and resonant Auger spectroscopy provides complementary information on the dynamic response of resonantly excited molecules. This is exemplified for CH_{3}I, for which we reconstruct the potential energy surface of the dissociative I 3d^{-2} double-core-hole state and determine its lifetime. The proposed method holds a strong potential for monitoring the hard x-ray induced electron and nuclear dynamic response of core-excited molecules containing heavy elements, where ab initio calculations of potential energy surfaces and lifetimes remain challenging.


Cell-specific localization of insulin-like growth factor binding protein mRNAs in rat liver.
The liver is a major source of circulating insulin-like growth factor I (IGF-I), and it also synthesizes several classes of IGF binding proteins (IGFBPs). Synthesis of IGF-I and IGFBPs is regulated by hormones, growth factors, and cytokines. They are nutritionally regulated and expressed in developmentally specific patterns. To gain insight into cellular regulatory mechanisms that determine hepatic synthesis of IGF-I and IGFBPs and to identify potential target cells for IGF-I within the liver, we studied the cellular sites of synthesis of IGF-I, IGF receptor, growth hormone (GH) receptor, and IGFBPs in freshly isolated rat hepatocytes, endothelial cells, and Kupffer cells. We also localized cellular sites of IGFBP synthesis by in situ hybridization histochemistry. Western ligand and immunoblot analyses were used to determine IGFBP secretion by isolated cells. Two IGF-I mRNA subtypes with different 5' ends (class 1 and class 2) were detected in all isolated liver cell preparations. Type 1 IGF receptor mRNA was detected in endothelial cells, indicating that these cells are a local target for IGF actions in liver. GH receptor was expressed in all cell preparations, consistent with GH regulation of IGF-I and IGFBP synthesis in multiple liver cell types. The IGFBPs expressed striking cell-specific expression. IGFBP-1 was synthesized only in hepatocytes, and IGFBP-3 was expressed in Kupffer and endothelial cells. IGFBP-4 was expressed at high levels in hepatocytes and at low levels in Kupffer and endothelial cells. Cell-specific expression of distinct IGFBPs in the liver provides the potential for cell-specific regulation of hepatic and endocrine actions of IGF-I.


Sing the mind electric - principles of deep brain stimulation.
The remarkable efficacy of deep brain stimulation (DBS) for a range of treatment-resistant disorders is still not matched by a comparable understanding of the underlying neural mechanisms. Some progress has been made using translational research with a range of neuroscientific techniques, and here we review the most promising emerging principles. On balance, DBS appears to work by restoring normal oscillatory activity between a network of key brain regions. Further research using this causal neuromodulatory tool may provide vital insights into fundamental brain function, as well as guide targets for future treatments. In particular, DBS could have an important role in restoring the balance of the brain's default network and thus repairing the malignant brain states associated with affective disorders, which give rise to serious disabling problems such as anhedonia, the lack of pleasure. At the same time, it is important to proceed with caution and not repeat the errors from the era of psychosurgery.


The Driver of Extreme Human-Specific Olduvai Repeat Expansion Remains Highly Active in the Human Genome.
Sequences encoding Olduvai protein domains (formerly DUF1220) show the greatest human lineage-specific increase in copy number of any coding region in the genome and have been associated, in a dosage-dependent manner, with brain size, cognitive aptitude, autism, and schizophrenia. Tandem intragenic duplications of a three-domain block, termed the Olduvai triplet, in four NBPF genes in the chromosomal 1q21.1-0.2 region, are primarily responsible for the striking human-specific copy number increase. Interestingly, most of the Olduvai triplets are adjacent to, and transcriptionally coregulated with, three human-specific NOTCH2NL genes that have been shown to promote cortical neurogenesis. Until now, the underlying genomic events that drove the Olduvai hyperamplification in humans have remained unexplained. Here, we show that the presence or absence of an alternative first exon of the Olduvai triplet perfectly discriminates between amplified (58/58) and unamplified (0/12) triplets. We provide sequence and breakpoint analyses that suggest the alternative exon was produced by an nonallelic homologous recombination-based mechanism involving the duplicative transposition of an existing Olduvai exon found in the CON3 domain, which typically occurs at the C-terminal end of NBPF genes. We also provide suggestive in vitro evidence that the alternative exon may promote instability through a putative G-quadraplex (pG4)-based mechanism. Lastly, we use single-molecule optical mapping to characterize the intragenic structural variation observed in NBPF genes in 154 unrelated individuals and 52 related individuals from 16 families and show that the presence of pG4-containing Olduvai triplets is strongly correlated with high levels of Olduvai copy number variation. These results suggest that the same driver of genomic instability that allowed the evolutionarily recent, rapid, and extreme human-specific Olduvai expansion remains highly active in the human genome.


Repetitive DNA and chromosome evolution in plants.
Most higher plant genomes contain a high proportion of repeated sequences. Thus repetitive DNA is a major contributor to plant chromosome structure. The variation in total DNA content between species is due mostly to variation in repeated DNA content. Some repeats of the same family are arranged in tandem arrays, at the sites of heterochromatin. Examples from the Secale genus are described. Arrays of the same sequence are often present at many chromosomal sites. Heterochromatin often contains arrays of several unrelated sequences. The evolution of such arrays in populations is discussed. Other repeats are dispersed at many locations in the chromosomes. Many are likely to be or have evolved from transposable elements. The structures of some plant transposable elements, in particular the sequences of the terminal inverted repeats, are described. Some elements in soybean, antirrhinum and maize have the same inverted terminal repeat sequences. Other elements of maize and wheat share terminal homology with elements from yeast, Drosophila, man and mouse. The evolution of transposable elements in plant populations is discussed. The amplification, deletion and transposition of different repeated DNA sequences and the spread of the mutations in populations produces a turnover of repetitive DNA during evolution. This turnover process and the molecular mechanisms involved are discussed and shown to be responsible for divergence of chromosome structure between species. Turnover of repeated genes also occurs. The molecular processes affecting repeats imply that the older a repetitive DNA family the more likely it is to exist in different forms and in many locations within a species. Examples to support this hypothesis are provided from the Secale genus.


Interventions for investigating and identifying the causes of stillbirth.
Identification of the causes of stillbirth is critical to the primary prevention of stillbirth and to the provision of optimal care in subsequent pregnancies. A wide variety of investigations are available, but there is currently no consensus on the optimal approach. Given their cost and potential to add further emotional burden to parents, there is a need to systematically assess the effect of these interventions on outcomes for parents, including psychosocial outcomes, economic costs, and on rates of diagnosis of the causes of stillbirth. To assess the effect of different tests, protocols or guidelines for investigating and identifying the causes of stillbirth on outcomes for parents, including psychosocial outcomes, economic costs, and rates of diagnosis of the causes of stillbirth. We searched Cochrane Pregnancy and Childbirth's Trials Register (31 August 2017), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (15 May 2017). We planned to include randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs. We planned to include studies published as abstract only, provided there was sufficient information to allow us to assess study eligibility. We planned to exclude cross-over trials.Participants included parents (including mothers, fathers, and partners) who had experienced a stillbirth of 20 weeks' gestation or greater.This review focused on interventions for investigating and identifying the causes of stillbirth. Such interventions are likely to be diverse, but could include:* review of maternal and family history, and current pregnancy and birth history;* clinical history of present illness;* maternal investigations (such as ultrasound, amniocentesis, antibody screening, etc.);* examination of the stillborn baby (including full autopsy, partial autopsy or noninvasive components, such as magnetic resonance imaging (MRI), computerised tomography (CT) scanning, and radiography);* umbilical cord examination;* placental examination including histopathology (microscopic examination of placental tissue); and* verbal autopsy (interviews with care providers and support people to ascertain causes, without examination of the baby).We planned to include trials assessing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth, compared with the absence of a test, protocol or guideline, or usual care (further details are presented in the Background, see Description of the intervention).We also planned to include trials comparing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth with another, for example, the use of a limited investigation protocol compared with a comprehensive investigation protocol. Two review authors assessed trial eligibility independently. We excluded five studies that were not RCTs. There were no eligible trials for inclusion in this review. There is currently a lack of RCT evidence regarding the effectiveness of interventions for investigating and identifying the causes of stillbirth. Seeking to determine the causes of stillbirth is an essential component of quality maternity care, but it remains unclear what impact these interventions have on the psychosocial outcomes of parents and families, the rates of diagnosis of the causes of stillbirth, and the care and management of subsequent pregnancies following stillbirth. Due to the absence of trials, this review is unable to inform clinical practice regarding the investigation of stillbirths, and the specific investigations that would determine the causes.Future RCTs addressing this research question would be beneficial, but the settings in which the trials take place, and their design, need to be given careful consideration. Trials need to be conducted with the utmost care and consideration for the needs, concerns, and values of parents and families. Assessment of longer-term psychosocial variables, economic costs to health services, and effects on subsequent pregnancy care and outcomes should also be considered in any future trials.


Role of government in public health: Current scenario in India and future scope.
The new agenda for Public Health in India includes the epidemiological transition, demographical transition, environmental changes and social determinants of health. Based on the principles outlined at Alma-Ata in 1978, there is an urgent call for revitalizing primary health care in order to meet these challenges. The role of the government in influencing population health is not limited within the health sector but also by various sectors outside the health systems. This article is a literature review of the existing government machinery for public health needs in India, its success, limitations and future scope. Health system strengthening, human resource development and capacity building and regulation in public health are important areas within the health sector. Contribution to health of a population also derives from social determinants of health like living conditions, nutrition, safe drinking water, sanitation, education, early child development and social security measures. Population stabilization, gender mainstreaming and empowerment, reducing the impact of climate change and disasters on health, improving community participation and governance issues are other important areas for action. Making public health a shared value across the various sectors is a politically challenging strategy, but such collective action is crucial.


DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats.
Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells.


Living technology: exploiting life's principles in technology.
The concept of living technology-that is, technology that is based on the powerful core features of life-is explained and illustrated with examples from artificial life software, reconfigurable and evolvable hardware, autonomously self-reproducing robots, chemical protocells, and hybrid electronic-chemical systems. We define primary (secondary) living technology according as key material components and core systems are not (are) derived from living organisms. Primary living technology is currently emerging, distinctive, and potentially powerful, motivating this review. We trace living technology's connections with artificial life (soft, hard, and wet), synthetic biology (top-down and bottom-up), and the convergence of nano-, bio-, information, and cognitive (NBIC) technologies. We end with a brief look at the social and ethical questions generated by the prospect of living technology.


DNA complex lesions induced by protons and alpha-particles: track structure characteristics determining linear energy transfer and particle type dependence.
The yield of DNA double-strand breaks (dsb) and DNA complex lesions induced by protons and alpha-particles of various energies was simulated using a Monte Carlo track structure code (MOCA15) and a simple model of the DNA molecule. DNA breaks of different complexity were analysed. The linear energy transfer (LET) and particle-type dependence of lesions of higher complexity seems to confirm the importance of clustered damage in DNA as a relevant step leading to biological endpoints such as cell inactivation. The detailed structure of proton and alpha-particle tracks was analysed to identify the main characteristics possibly responsible for such a dependence. The role of the primary ion and of its secondary electrons in inducing dsb and complex lesions is described, showing that the relative contribution of secondary electron tracks alone in inducing clustered lesions is almost negligible at high LET, but tends to dominate below = 10 keV/micron. This is consistent with the observed similar effectiveness of low-LET fast particle radiation and sparsely ionizing radiation such as x-rays. The dependence on LET and particle type is mainly due to energy deposition events of the primary ion together with short range electrons surrounding the ion track; the yield of complex lesions due to secondary electron tracks alone is substantially LET independent. The radial distributions of the energy contributing to the induction of complex lesions were analyzed and compared with the radial distributions of energy deposition of the full tracks. The results suggest that the stochastic behaviour (i.e. cluster properties) of the energy deposition pattern within a radius of a few nanometers around the ion track plays a relevant role in determining the biological radiation effectiveness.


A pilot cluster randomised controlled trial of a support and training intervention to improve the mental health of secondary school teachers and students - the WISE (Wellbeing in Secondary Education) study.
Secondary school teachers are at heightened risk of psychological distress, which can lead to poor work performance, poor quality teacher-student relationships and mental illness. A pilot cluster randomised controlled trial (RCT) - the WISE study - evaluated the feasibility of a full-scale RCT of an intervention to support school staff's own mental health, and train them in supporting student mental health. Six schools were randomised to an intervention or control group. In the intervention schools i) 8-9 staff received Mental Health First Aid (MHFA) training and became staff peer supporters, and ii) youth MHFA training was offered to the wider staff body. Control schools continued with usual practice. We used thematic qualitative data analysis and regression modelling to ascertain the feasibility, acceptability and potential usefulness of the intervention. Thirteen training observations, 14 staff focus groups and 6 staff interviews were completed, and 438 staff (43.5 %) and 1,862 (56.3 %) students (years 8 and 9) completed questionnaires at baseline and one year later. MHFA training was considered relevant for schools, and trainees gained in knowledge, confidence in helping others, and awareness regarding their own mental health. Suggestions for reducing the length of the training and focusing on helping strategies were made. A peer support service was established in all intervention schools and was perceived to be helpful in supporting individuals in difficulty - for example through listening, and signposting to other services - and raising the profile of mental health at a whole school level. Barriers to use included lack of knowledge about the service, concerns about confidentiality and a preference for accessing support from pre-existing networks. The WISE intervention is feasible and acceptable to schools. Results support the development of a full-scale cluster RCT, if steps are taken to improve response rates and implement the suggested improvements to the intervention. International Standard Randomised Controlled Trial Number: ISRCTN13255300 retrospectively registered 28/09/16.


Human brain gangliosides in development, aging and disease.
In this study, brain gangliosides in prenatal and postnatal human life and Alzheimer's disease were analyzed. Immunohistochemically, the presence of the "c"-series of gangliosides (GQ1c) was only registered in the embryonic brain at 5 weeks of gestation. Biochemical results indicated a two-fold increase in ganglioside concentration in the human cortex between 16 and 22 weeks of gestation. The increasing ganglioside concentration was based on an increasing GD1a ganglioside fraction in all regions analyzed except in the cerebellar cortex, which was characterized by increasing GT1b. During prenatal human development, regional differences in ganglioside composition could only be detected between the cerebrum ("a"-pathway) and the cerebellum ("b"-pathway). Between birth and 20-30 years of age, a cerebral neocortical difference of ganglioside composition occurred, characterized by the lowest GD1a in visual cortex. Analyzing the composition of gangliosides in cortical regions during aging, they were observed to follow region-specific alterations. In the frontal cortex, there was a greater decrease in GD1a and GM1 than in GT1b and GD1b, but in the occipital (visual) cortex there was no change in individual gangliosides. In hippocampus, GD1a moderately decreased, whereas other fractions were stable. In the cerebellar cortex, GD1b and GT1b fractions decreased with aging. In Alzheimer's disease, we found all ganglio-series gangliosides (GM1, GD1a, GD1b, GT1b) to be decreased in regions (temporal and frontal cortex and nucleus basalis of Meynert) involved in pathogenesis of disease. In addition, in Alzheimer's disease we found simple gangliosides (GN2, GM3) to be elevated in the frontal and parietal cortex, which might correlate accelerated lysosomal degradation of gangliosides and/or astrogliosis occurring during neuronal death.


Intermolecular sp3-C-H Amination for the Synthesis of Saturated Azacycles.
The preparation of substituted azetidines and larger ring, nitrogen-containing saturated heterocycles is enabled through efficient and selective intermolecular sp3-C-H amination of alkyl bromide derivatives. A range of substrates are demonstrated to undergo C-H amination and subsequent sulfamate alkylation in good to excellent yield. N-Phenoxysulfonyl-protected products can be unmasked under neutral or mild basic conditions to yield the corresponding cyclic secondary amines. The preparative convenience of this protocol is demonstrated through gram-scale and telescoped multistep procedures. Application of this technology is highlighted in a nine-step total synthesis of an unusual azetidine-containing natural product, penaresidin B.


Brain imaging and human nutrition: which measures to use in intervention studies?
The present review describes brain imaging technologies that can be used to assess the effects of nutritional interventions in human subjects. Specifically, we summarise the biological relevance of their outcome measures, practical use and feasibility, and recommended use in short- and long-term nutritional studies. The brain imaging technologies described consist of MRI, including diffusion tensor imaging, magnetic resonance spectroscopy and functional MRI, as well as electroencephalography/magnetoencephalography, near-IR spectroscopy, positron emission tomography and single-photon emission computerised tomography. In nutritional interventions and across the lifespan, brain imaging can detect macro- and microstructural, functional, electrophysiological and metabolic changes linked to broader functional outcomes, such as cognition. Imaging markers can be considered as specific for one or several brain processes and as surrogate instrumental endpoints that may provide sensitive measures of short- and long-term effects. For the majority of imaging measures, little information is available regarding their correlation with functional endpoints in healthy subjects; therefore, imaging markers generally cannot replace clinical endpoints that reflect the overall capacity of the brain to behaviourally respond to specific situations and stimuli. The principal added value of brain imaging measures for human nutritional intervention studies is their ability to provide unique in vivo information on the working mechanism of an intervention in hypothesis-driven research. Selection of brain imaging techniques and target markers within a given technique should mainly depend on the hypothesis regarding the mechanism of action of the intervention, level (structural, metabolic or functional) and anticipated timescale of the intervention's effects, target population, availability and costs of the techniques.


Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer.
Lung cancer is the leading cause of death from cancer in the US and the world. The high mortality rate (80-85% within 5 years) results, in part, from a lack of effective tools to diagnose the disease at an early stage. Given that cigarette smoke creates a field of injury throughout the airway, we sought to determine if gene expression in histologically normal large-airway epithelial cells obtained at bronchoscopy from smokers with suspicion of lung cancer could be used as a lung cancer biomarker. Using a training set (n = 77) and gene-expression profiles from Affymetrix HG-U133A microarrays, we identified an 80-gene biomarker that distinguishes smokers with and without lung cancer. We tested the biomarker on an independent test set (n = 52), with an accuracy of 83% (80% sensitive, 84% specific), and on an additional validation set independently obtained from five medical centers (n = 35). Our biomarker had approximately 90% sensitivity for stage 1 cancer across all subjects. Combining cytopathology of lower airway cells obtained at bronchoscopy with the biomarker yielded 95% sensitivity and a 95% negative predictive value. These findings indicate that gene expression in cytologically normal large-airway epithelial cells can serve as a lung cancer biomarker, potentially owing to a cancer-specific airway-wide response to cigarette smoke.


Pattern recognition with an adaptive joint transform correlator.
An adaptive joint transform correlator for real-time pattern recognition is presented. A reference image for the correlator is generated with a new iterative algorithm. The training algorithm is based on synthetic discriminant functions. The obtained reference image contains the information needed to reliably discriminate a target against known false objects and a cluttered background. Calibration lookup tables of all optoelectronics elements used are included in the design of the adaptive joint transform correlator. Two methods for the implementation of the proposed joint transform correlator in an optodigital setup are considered. Experimental results are provided and compared with those of computer simulations.


IGFBP-5 overexpression as a poor prognostic factor in patients with urothelial carcinomas of upper urinary tracts and urinary bladder.
Urothelial carcinoma (UC) is prevalent worldwide. Dysregulation of cell growth is a critical event of tumorigenesis and has not been assessed systemically in UC. We thus assessed the published transcriptome of urinary bladder urothelial carcinoma (UBUC) and identified insulin-like growth factor-binding protein-5 (IGFBP-5) as the most significantly upregulated gene associated with the regulation of cell growth. Moreover, validated by using public domain data set, IGFBP-5 expression also significantly predicted worse outcome. IGFBP-5 is one of the binding proteins that regulate insulin-like growth factors (IGFs) and its significance has not been comprehensively evaluated in UCs. Using immunohistochemistry, we evaluated the IGFBP-5 expression status and its associations with clinicopathological features and survival in 340 cases of upper urinary tract urothelial carcinoma (UTUC) and 295 cases of UBUC. Western blot analysis was used to evaluate IGFBP-5 protein expression in human urothelial cell (HUC) lines. IGFBP-5 overexpression was significantly associated with advanced pT stage (p<0.001), high histological grade (UTUC, p<0.001; UBUC, p=0.035), lymph node metastasis (UTUC, p=0.006; UBUC, p=0.004), vascular invasion (UTUC, p<0.001; UBUC, p=0.003), perineural invasion (UTUC, p=0.034; UBUC, p=0.021) and frequent mitosis (UTUC, p<0.001; UBUC, p=0.023). IGFBP-5 overexpression also independently predicted poor disease-specific survival and metastasis-free survival in both groups of patients. Western blot analysis showed IGFBP-5 protein as overexpressed in human urothelial cancer cell lines and not in normal urothelial cancer cells. IGFBP-5 plays an important role in tumour progression in UC. Its overexpression is associated with advanced tumour stage and conferred poorer clinical outcome.


Delineation of biological and molecular mechanisms underlying the diverse anticancer activities of mycophenolic acid.
Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA) which has been widely used for the prevention of acute graft rejection, is a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and potentially a target for cancer therapy. MPA is known to inhibit cancer cell proliferation and induces apoptosis; however, the underlying molecular mechanisms remain elusive. We first demonstrated MPA's antiproliferative and proapoptotic activities using in vitro studies of 13 cancer cell lines and a xenograft model. Key proteins involved in cell cycle, proliferation and apoptosis were analyzed by Western blotting. In vitro treatment of thirteen cancer cell lines indicated that five cell lines (AGS, NCI-N87, HCT-8, A2780 and BxPC-3) are highly sensitive to MPA (IC50 < 0.5 μg/ml), four cell lines (Hs746T, PANC-1, HepG2 and MCF-7) are very resistant to MPA (IC50 > 20 μg/ml) and the four other cell lines (KATO III, SNU-1, K562 and HeLa) have intermediate sensitivity. The anticancer activity of MPA was confirmed in vivo using xenograft model with gastric AGS cell line. Further in vitro analyses using AGS cells indicated that MPA can potently induce cell cycle arrest and apoptosis as well as inhibition of cell proliferation. Targeted proteomic analyses indicate that many critical changes responsible for MPA's activities occur at the protein expression and phosphorylation levels. MPA-induced cell cycle arrest is achieved through reduction of many cell cycle regulators such as CDK4, BUB1, BOP1, Aurora A and FOXM1. We also demonstrate that MPA can inhibit the PI3K/AKT/mTOR pathway and can induce caspase-dependent apoptosis. These results suggest that MPA has beneficial activities for anticancer therapy through diverse molecular pathways and biological processes.


Strange Bedfellows: Native American Tribes, Big Pharma, and the Legitimacy of Their Alliance.
Lost in the cacophony surrounding the debate about high drug prices is the fundamental principle that pharmaceutical innovation will not occur without the prospect of outsized returns enabled through market exclusivity. Biopharmaceutical patents are currently under siege, subject to challenge both in inter partes review ("IPR") proceedings and in Hatch-Waxman actions. These twin assaults threaten to eliminate the incentives necessary for biotechnological innovation--particularly for discoveries made upstream in the innovation pipeline--thus imperiling the development of new drug therapies. But a fascinating solution has emerged: invoking tribal immunity to shield pharmaceutical patents from IPR before the Patent Trial and Appeal Board ("PTAB"). This serves two critically important objectives: promoting tribal self-sufficiency, and encouraging investment in life-saving and life-improving new drugs. Contractual partnerships between Native American tribes and pharmaceutical companies not only provide the tribes with a steady stream of royalty revenue, but also insulate biopharmaceutical patents from challenge in IPR proceedings through the invocation of long-established principles of tribal sovereign immunity. This Note is the first piece of scholarship to comprehensively analyze, and advocate for, the right to invoke tribal sovereign immunity in IPR proceedings.


Optimization of electromagnetic hot spots in surface-enhanced Raman scattering substrates for an ultrasensitive drug assay of emergency department patients' plasma.
Herein we report the programmable preparation of ultrasensitive surface-enhanced Raman scattering (SERS)-based nanoplasmonic superlattice substrates to assay fentanyl and cocaine (detection and quantification) from 10 μL aliquots of emergency department patient plasma without the need for purification steps. Highly homogeneous three-dimensional (3D) nanoplasmonic superlattices are generated through the droplet evaporation-based self-assembly process of chemically-synthesized, polyethylene glycol thiolate-coated gold triangular nanoprisms (Au TNPs). Close-packed, solid-state 3D superlattice substrates produce electromagnetic hot spots due to near-field plasmonic coupling of Au TNPs, which display unique localized surface plasmonic resonance properties. These uniquely prepared superlattice substrates enable strong SERS enhancement to achieve a parts-per-quadrillion limit of detection using the label-free SERS-based technique. Our reported limit of detection is at least 100-fold better than any known SERS substrates for the drug assay. Importantly, our density functional theory calculations show that a specific electronic interaction between the drug molecule and novel nanoplasmonic superlattice substrates plays a critical role that may trigger achieving this unprecedentedly high sensitivity. Additionally, we show high selectivity of the superlattice substrate in the SERS-based detection of analytes from different patient samples, which do and do not contain target analytes (i.e., fentanyl and/or cocaine). The demonstrated sensitivity and selectivity of 3D superlattice substrates for SERS-based drug analysis in real toxicological samples are expected to advance the field of measurement science, and forensic and clinical toxicology by obviating the need for complicated sample processing steps, long assay times, and the low sensitivity of existing "gold standard" analytical techniques including gas chromatography/mass spectrometry, liquid chromatography/mass spectrometry and enzyme-linked immunosorbent assays. Taken together, we believe that this entirely new and reproducible superlattice substrate for the SERS analysis will aid scientific, forensic, and healthcare communities to battle the drug overdose epidemic in the United States.


Optical induction of autophagy via Transcription factor EB (TFEB) reduces pathological tau in neurons.
Pathological accumulation of microtubule associated protein tau in neurons is a major neuropathological hallmark of Alzheimer's disease (AD) and related tauopathies. Several attempts have been made to promote clearance of pathological tau (p-Tau) from neurons. Transcription factor EB (TFEB) has shown to clear p-Tau from neurons via autophagy. However, sustained TFEB activation and autophagy can create burden on cellular bioenergetics and can be deleterious. Here, we modified previously described two-plasmid systems of Light Activated Protein (LAP) from bacterial transcription factor-EL222 and Light Responsive Element (LRE) to encode TFEB. Upon blue-light (465 nm) illumination, the conformation changes in LAP induced LRE-driven expression of TFEB, its nuclear entry, TFEB-mediated expression of autophagy-lysosomal genes and clearance of p-Tau from neuronal cells and AD patient-derived human iPSC-neurons. Turning the blue-light off reversed the expression of TFEB-target genes and attenuated p-Tau clearance. Together, these results suggest that optically regulated TFEB expression unlocks the potential of opto-therapeutics to treat AD and other dementias.


Molecular evolution of the Escherichia coli chromosome. III. Clonal frames.
PCR fragments, 1500-bp, from 15 previously sequenced regions in the Escherichia coli chromosome have been compared by restriction analysis in a large set of wild (ECOR) strains. Prior published observations of segmental clonality are confirmed: each of several sequence types is shared by a number of strains. The rate of recombinational replacement and the average size of the replacements are estimated in a set of closely related strains in which a clonal frame is dotted with occasional stretches of DNA belonging to other clones. A clonal hierarchy is described. Some new comparative sequencing data are presented.


Structurally plastic peptide capsules for synthetic antimicrobial viruses.
A conceptual design for artificial antimicrobial viruses is described. The design emulates viral assembly and function to create self-assembling peptide capsules that promote efficient gene delivery and silencing in mammalian cells. Unlike viruses, however, the capsules are antimicrobial, which allows them to exhibit a dual biological function: gene transport and antimicrobial activity. Unlike other antimicrobials, the capsules act as pre-concentrated antimicrobial agents that elicit rapid and localised membrane-disrupting responses by converting into individual pores at their precise landing positions on membranes. The concept holds promise for engineering virus-like scaffolds with biologically tuneable properties.


Online chemotherapy symptom care and patient management system: an evaluative study.
Health delivery practices are shifting toward home care, because of better possibilities for managing chronic care, controlling health delivery costs, and increasing the quality of life and quality of health services, and the distinct possibility of predicting and thus avoiding serious complications. The study aimed to explore the benefits of an online Symptom Care and Management System in the home for patients receiving chemotherapy. A single-group experimental design was used. Thirty patients aged between 37 and 77 years undergoing their first or commencing a new course of chemotherapy treatment were recruited from November 2010 and December 2012 at a cancer center in Singapore. All patients used the Symptom Care and Management System to send daily symptom reports to the cancer center and received symptom management advice from the oncology nurse via teleconferencing during the first four chemotherapy treatment cycles. Patients' perceptions of the use of the Symptom Care and Management System were evaluated. All participants perceived the Symptom Care and Management System as a user-friendly interface and believed that they felt more involved in their care, and the system made it easier to understand some of the problems they experienced and helped them manage the symptoms more easily during the treatment. In addition, 29 participants (96.7%) felt that the nurse could contact them better via the Symptom Care and Management System, the Symptom Care and Management System helped them explain their symptoms to the nurse, and that it was simple to understand. The results presented in this study suggested that the Symptom Care and Management System has the potential to enhance remote monitoring and provides a feasible and acceptable way for a specific group of cancer patients to manage their symptoms at home.


3D Modeling of craniofacial ontogeny and sexual dimorphism in children.
The range of normal variation of growth and development of the craniofacial region is of direct clinical interest but incompletely understood. Here we develop a statistical model of craniofacial growth and development to compare craniofacial ontogeny between age groups and sexes and pilot an approach to modeling that is relatively straightforward to apply in the context of clinical research and assessment. The sample comprises head surface meshes captured using a 3dMD five-camera system from 65 males and 47 females (range 3-20 years) from the Headspace project, Liverpool, UK. The surface meshes were parameterized using 16 anatomical landmarks and 59 semilandmarks on curves and surfaces. Modes and degrees of growth and development were assessed and compared among ages and sexes using Procrustes based geometric morphometric methods. Regression analyses indicate that 3-10 year olds undergo greater changes than 11-20 year olds and that craniofacial growth and development differs between these age groups. The analyses indicate that males extend growth allometrically into larger size ranges, contributing substantially to adult dimorphism. Comparisons of ontogenetic trajectories between sexes find no significant differences, yet when hypermorphosis is accounted for in the older age group there is a significant residual sexual dimorphism. The study adds to knowledge of how adult craniofacial form and sexual dimorphism develop. It was carried out using readily available software which facilitates replication of this work in diverse populations to underpin clinical assessment of deformity and the outcomes of corrective interventions.


Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on indices of dopaminergic, endocannabinoid and GABAergic pathways.
Cannabis use confers a two-fold increase in risk for psychosis, with adolescent use conferring an even greater risk. A high-low activity polymorphism in catechol-O-methyltransferase (COMT), a gene encoding the COMT enzyme involved in dopamine clearance in the brain, may interact with adolescent cannabis exposure to increase risk for schizophrenia. The impact of such an interaction on central neurotransmitter pathways implicated in schizophrenia is unknown. Male mice with knockout of the COMT gene were treated chronically with delta-9-tetrahydrocannabinol (THC) during adolescence (postnatal day 32-52). We measured the size and density of GABAergic cells and the protein expression of cannabinoid receptor 1 (CB1R) in the prefrontal cortex (PFC) and hippocampus (HPC) in knockout mice relative to heterozygous mutants and wild-type controls. Size and density of dopaminergic neurons was also assessed in the ventral tegmental area (VTA) across the genotypes. COMT genotype × THC treatment interactions were observed for: (1) dopaminergic cell size in the VTA, (2) CB1R protein expression in the HPC, and (3) parvalbumin (PV) cell size in the PFC. No effects of adolescent THC treatment were observed for PV and dopaminergic cell density across the COMT genotypes. COMT genotype modulates the effects of chronic THC administration during adolescence on indices of neurotransmitter function in the brain. These findings illuminate how COMT deletion and adolescent cannabis use can interact to modulate the function of neurotransmitters systems implicated in schizophrenia.


Direct comparison of characteristics, treatment, and outcomes of patients enrolled versus patients not enrolled in a clinical trial at centers participating in the TIMI 9 Trial and TIMI 9 Registry.
Questions about the generalizability of randomized trial results to clinical practice have arisen because the overall mortality rate is generally lower in trials, potentially because patients who are at lower risk are enrolled. However, little is known about the characteristics of patients included in clinical trials versus those who are not included. The Thrombolysis In Myocardial Infarction (TIMI) 9 Registry prospectively evaluated patients with ST-elevation myocardial infarction at 20 hospitals during the TIMI 9 trial, which compared hirudin versus heparin with fibrinolysis. We compared the characteristics, treatment, and outcomes of patients enrolled in TIMI 9B (n = 3002) with other fibrinolytic-eligible patients not enrolled in TIMI 9B (n = 296) and with those not eligible for fibrinolysis by American College of Cardiology/American Heart Association criteria, at the same centers (n = 282), with the latter groups divided by use of reperfusion therapy. Across the groups, ranging from those in the TIMI 9 trial to those ineligible for fibrinolysis, we observed a gradient of higher-risk baseline characteristics, lower use of reperfusion therapy, and higher mortality rates (P <.001). In addition, comparing fibrinolytic-eligible patients in TIMI 9B versus those not enrolled in the trial, the use of aspirin, beta-blockers, and angiotensin-converting enzyme inhibitors was significantly higher in the TIMI 9B trial. Ineligible patients not treated with reperfusion therapy had much lower rates of use of these medications and the highest inhospital mortality rate (24%, adjusted odds ratio 2.8, P <.0001) In this prospective registry, patients not enrolled in a clinical trial had higher risk characteristics and worse outcomes; however, they also were treated less frequently with guideline-recommended medications, which may have contributed to their higher mortality rates.


Diffuse Large B-Cell Lymphoma of the Frontal Sinus Presenting as a Pott Puffy Tumor: Case Report.
Objective Sinonasal non-Hodgkin lymphoma (NHL) is a very rare condition. NHL located specifically in the frontal sinus is even rarer with only 14 cases in the literature reported to date. A unique case of diffuse large B-cell lymphoma of the frontal sinus that presented first and was treated as suspected Pott puffy tumor is presented along with a review of the literature. Case Report A 69-year-old white man with a history of sinusitis and two recent endoscopic sinus surgeries presented with enlargement of his right forehead. Computed tomography and magnetic resonance images revealed a dense opacification of the frontal sinus bilaterally, thickening and enhancement of the dura mater behind the right frontal sinus, and local osteomyelitis-like lytic bone changes. A bifrontal craniotomy was performed. Radical exoneration of the frontal sinus, copious antibiotic-impregnated irrigation after culture swabs, and resection of presumed granulation tissue was performed. Culture swabs remained negative, but histopathology revealed diffuse large B-cell lymphoma. Subsequent chemotherapy was administered. Conclusion Sinonasal NHL is very rare but can occur in the frontal sinus and may present as a suspected Pott puffy tumor. A high clinical suspicion is necessary for early diagnosis and treatment.


Exposure to extremely low-frequency (50 Hz) electromagnetic fields enhances adult hippocampal neurogenesis in C57BL/6 mice.
Throughout life, new neurons are continuously generated in the hippocampus, which is therefore a major site of structural plasticity in the adult brain. We recently demonstrated that extremely low-frequency electromagnetic fields (ELFEFs) promote the neuronal differentiation of neural stem cells in vitro by up-regulating Ca(v)1-channel activity. The aim of the present study was to determine whether 50-Hz/1 mT ELFEF stimulation also affects adult hippocampal neurogenesis in vivo, and if so, to identify the molecular mechanisms underlying this action and its functional impact on synaptic plasticity. ELFEF exposure (1 to 7 h/day for 7 days) significantly enhanced neurogenesis in the dentate gyrus (DG) of adult mice, as documented by increased numbers of cells double-labeled for 5-bromo-deoxyuridine (BrdU) and doublecortin. Quantitative RT-PCR analysis of hippocampal extracts revealed significant ELFEF exposure-induced increases in the transcription of pro-neuronal genes (Mash1, NeuroD2, Hes1) and genes encoding Ca(v)1.2 channel α(1C) subunits. Increased expression of NeuroD1, NeuroD2 and Ca(v)1 channels was also documented by Western blot analysis. Immunofluorescence experiments showed that, 30 days after ELFEF stimulation, roughly half of the newly generated immature neurons had survived and become mature dentate granule cells (as shown by their immunoreactivity for both BrdU and NeuN) and were integrated into the granule cell layer of the DG. Electrophysiological experiments demonstrated that the new mature neurons influenced hippocampal synaptic plasticity, as reflected by increased long-term potentiation. Our findings show that ELFEF exposure can be an effective tool for increasing in vivo neurogenesis, and they could lead to the development of novel therapeutic approaches in regenerative medicine.


Contribution of bacterial and viral infections to attributable mortality in patients with severe burns: an autopsy series.
Bacterial infections are a common cause of mortality in burn patients and viral infections, notably herpes simplex virus (HSV) and cytomegalovirus (CMV) have also been associated with mortality. This study is a retrospective review of all autopsy reports from patients with severe thermal burns treated at the US Army Institute of Research (USAISR) burn unit over 12 years. The review focused on those patients with death attributed to a bacterial or viral cause by autopsy report. Of 3751 admissions, 228 patients died with 97 undergoing autopsy. Death was attributed to bacteria for 27 patients and to virus for 5 patients. Bacterial pathogens associated with mortality included Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. This association with mortality was independent of % total body surface area burn, % full-thickness burn, inhalation injury, and day of death post-burn. Bloodstream infection was the most common cause of bacteria related death (50%), followed by pneumonia (44%) and wound infection (6%). Time to death following burn was < or =7 days in 30%, < or =14 days in 59% and < or =21 days in 67%. All of the viral infections associated with mortality involved the lower respiratory tract, HSV for 4 and CMV for 1. Four of these 5 patients had evidence of inhalation injury by bronchoscopy, all had facial and neck burns, and 2 had concomitant Staphylococcus pneumonia. Time to death following burn ranged from 14 to 42 days for the 5 patients. Despite advances in care, gram negative bacterial infections and infection with S. aureus remain the most common cause of bacteria related mortality early in the hospital course. Viral infections are also associated with mortality and numbers have remained stable when compared to data from prior years.


Increasing postpartum contraception in rural India: evaluation of a community-based behavior change communication intervention.
The Indian family planning program, though successful in increasing contraceptive use among couples who have achieved their desired family size, has not been equally successful in educating couples about the use of contraceptive methods for birth spacing. An evaluation was conducted of a behavior change communication intervention integrated into the existing government program to increase knowledge and use of the lactational amenorrhea method and postpartum contraception through counseling by community workers. The intervention, which ran between September 2006 and January 2007, was conducted among 959 pregnant women aged 15-24 who lived in Uttar Pradesh, India. The evaluation used logistic regression analyses to measure differences in knowledge and contraceptive use between baseline and the four- and nine-month postpartum follow-up surveys within and between the intervention and comparison groups. The follow-up data show increases in knowledge of the lactational amenorrhea method and spacing methods and in use of spacing methods. At four months postpartum, women in the intervention group were more likely to know the healthy spacing messages than those in the comparison group (odds ratio, 2.1). At nine months postpartum, women in the intervention group, those with higher knowledge of healthy spacing practices and those with correct knowledge of two or more spacing methods were more likely than others to be using a contraceptive method (1.5-3.5). Use of modern contraceptives for spacing at nine months postpartum was 57% in the intervention group versus 30% in the comparison group. Targeted behavior change communication using community workers is an effective and feasible strategy for promoting postpartum contraception.


Spatially controlled DNA unzipping by microfluidic interface positioning on a molecule perpendicular to a multicomponent flow.
A DNA molecule is rotated under a transversal electric field to be perpendicular to a longitudinal, multicomponent microfluidic flow. Positioning the interface allows us to control DNA unzipping with spatio-temporal resolution. This demonstrates that a microfluidic gradient can be applied at the single molecule level for a dynamic intramolecular stimulation.


Risk factors for perinatal mortality in Arua regional referral hospital, West Nile, Uganda.
In low-income countries, the majority of neonatal deaths occur during the perinatal period. The fourth millennium development goal of reducing child mortality cannot therefore be met without substantial reduction in perinatal deaths. To investigate the risk factors for perinatal mortality in Arua regional referral hospital, West Nile region. We conducted a facility based unmatched case-control study at Arua Regional Referral hospital during January- March 2006. A total of 60 new cases of perinatal deaths and 120 controls were selected over a 3 months period. A case was defined as any baby born after 28 weeks of gestation either as a still birth or born alive but died within 7 days post delivery. A control was any baby born after 28 weeks of gestation and survived the first seven days of life. Control mothers were followed at home after one week to check if any perinatal death occurred. Logistic regression analysis was used to determine the risk factors for perinatal mortality. The mean age of case mothers was similar to that of controls 24.1 years, range 15-38 years versus 24.9 years range 16-40 years (p - value = 0.52). Babies who died during the perinatal period were more likely not to have been resuscitated (OR = 24.85, 95% CI 8.77-74.17). Mothers whose babies died were more likely to have travelled more than 5 kilometres to Arua hospital (OR = 3.89 CI 1.96-7.74), having had transport problem (OR= 3.35, CI 1.00-12.00), first sought help from other health facilities or TBA (OR = 8.03, CI 3.38-19.46), have been referred due to obstetric complications (OR = 11.45, CI 4.75-27.59), and had obstetric interventions i.e. C/S or vacuum extraction (OR= 3.79, CI 1.64-8.83). After controlling for confounding, significant risk factors for perinatal deaths included living more than 5 kilometres from the hospital (Adjusted OR = 0.91, CI 0.83-0.95), transport problem (Adjusted OR = 4.37, CI 1.14-39.75), baby not being resuscitated (Adjusted OR=4.87, CI 4.371-7.11) and baby being born with low Apgar score (Adjusted OR= 6.76, CI 2.75-187.38). Our study has identified several risk factors for perinatal deaths related to poor accessibility to and low quality of health care services in the setting. The study underscores the importance of improved accessibility to and quality of basic and comprehensive emergency obstetrical care. The findings suggest the need to improve the capacity of local health system at first, second and tertiary levels, accessibility to and quality health care services in the settings.


Searching for peptide ligands with an epitope library.
Tens of millions of short peptides can be easily surveyed for tight binding to an antibody, receptor or other binding protein using an "epitope library." The library is a vast mixture of filamentous phage clones, each displaying one peptide sequence on the virion surface. The survey is accomplished by using the binding protein to affinity-purify phage that display tight-binding peptides and propagating the purified phage in Escherichia coli. The amino acid sequences of the peptides displayed on the phage are then determined by sequencing the corresponding coding region in the viral DNA's. Potential applications of the epitope library include investigation of the specificity of antibodies and discovery of mimetic drug candidates.


Carotid endarterectomy with normal findings from a completion study: Is there need for early duplex scan?
The objective of this study was to determine the value of early (< 6 months) duplex scanning after carotid endarterectomy (CEA) with an intraoperative completion study with normal results. Attention was paid to restenosis rates and reoperation for recurrent stenosis within the first 6 months. A retrospective review was performed on 380 CEAs (338 patients) with intraoperative completion studies and duplex surveillance within the first 6 months. Results of completion studies, restenosis rates, and recurrent symptoms were evaluated for each operation. Studies were performed from 0 to 200 days postoperatively (median, 28). Intraoperative completion studies included 333 angiograms, 26 duplex scans, and 21 angiograms with duplex scans. Of the 380 intraoperative completion studies, 28 (7.5%) had abnormal findings, including 14 abnormal internal carotid arteries (ICAs). Twenty-four procedures were revised, and the findings of all repeat completion studies were normal. Of the initial completion studies, in four cases, abnormalities (3 ICAs) were insignificant and did not warrant further intervention. Follow-up ICA duplex scans had normal results after 364 (95.8%) CEAs. There were 14 mild recurrent ICA stenoses and two moderate recurrent ICA stenoses; neither had abnormal findings from the completion study. There were no severe recurrent ICA stenoses. External carotid artery (ECA) recurrent stenosis included 7 mild, 15 moderate, and 9 severe restenoses. Only 0.5% of CEAs developed moderate restenosis. No procedures had severe recurrent stenosis on duplex scan within the first 6 months, and none required intervention. Duplex surveillance in the first 6 months is relatively unproductive, providing that there were normal results from an intraoperative completion study for each patient. Routine surveillance can be started at 1 year.


Maternal prepregnancy obesity and achievement of infant motor developmental milestones in the upstate KIDS study.
Maternal prepregnancy obesity is associated with several poor infant health outcomes; however, studies that investigated motor development have been inconsistent. Thus, maternal prepregnancy weight status and infants' gross motor development were examined. Participants consisted of 4,901 mother-infant pairs from the Upstate KIDS study, a longitudinal cohort in New York. Mothers indicated dates when infants achieved each of six gross motor milestones when infants were 4, 8, 12, 18, and 24 months old. Failure time modeling under a Weibull distribution was utilized to compare time to achievement across three levels of maternal prepregnancy BMI. Hazard ratios (HR) below one indicate a lower "risk" of achieving the milestone and translate to later achievement. Compared to infants born to thin and normal-weight mothers (BMI < 25), infants born to mothers with obesity (BMI > 30) were slower to sit without support (HR = 0.91, P = 0.03) and crawl on hands and knees (HR = 0.86, P < 0.001), after adjusting for maternal and birth characteristics. Increased gestational age was associated with faster achievement of all milestones, but additional adjustment did not impact results. Maternal prepregnancy obesity was associated with a slightly longer time for infant to sit and crawl, potentially due to a compromised intrauterine environment or reduced physically active play.


Application of the Blaivas-Groutz bladder outlet obstruction nomogram in women with urinary incontinence.
To test the applicability of the Blaivas-Groutz nomogram for female bladder outlet obstruction in urinary incontinent women presenting in a general gynecologic practice and to determine how the nomogram results related to the presence of obstructive symptoms according to a standardized questionnaire. All women with complaints of urinary incontinence underwent multichannel urodynamic testing, free uroflowmetry and were asked to complete a standardized quality of life questionnaire consisting of the urogenital distress inventory (UDI). The patients were classified according to the Blaivas-Groutz nomogram. One hundred and nine patients were classified according to the nomogram. Thirty-three patients (30.3%) were classified as unobstructed, 63 patients (57.8%) as mildly, 12 patients (11%) as moderately, and 1 patient (0.9%) was classified as severely obstructed. Fifty patients correctly completed the UDI. There was no significant difference (P = 0.61) in the score on the domain UDI obstruction between, according to the nomogram, obstructed and unobstructed patients. Only 18% of the obstructed patients had isolated voiding symptoms suggestive of obstruction. Forty-nine percent of the obstructed patients had urgency-frequency symptoms as well as voiding symptoms suggestive of obstruction. There was no correlation (Pearson, r = -0.06, P = 0.61) between the severity of the symptoms (assessed by the UDI scale) and the degree of obstruction (the four nomogram zones). Application of the Blaivas-Groutz nomogram gave an unlikely high prevalence of obstruction in our patient group, which showed no correlation with symptoms when measured with the UDI.


Distinct spatial and temporal functions for PS integrins during Drosophila wing morphogenesis.
At the onset of pupariation in the Drosophila wing, the PS1 and PS2 integrins are expressed preferentially on the dorsal and ventral wing epithelia, respectively. Clonal analysis experiments have indicated that integrins are required to maintain the tight association of the wing surfaces. Surprisingly, we find that even in clones of cells lacking integrins the wing layers become apposed early in metamorphosis. However, following the normal period of wing separation, large integrin mutant clones do not become re-apposed in the pupa, and integrins are not organized in basal plaques in cells opposite a mutant clone. Paradoxically, our experiments indicate that at least one integrin function requires different integrins on the dorsal and ventral wing surfaces, however in some cases both alphaPS subunits can function to some degree on each wing surface. Finally, overexpression of an alphaPS subunit throughout the wing leads to a dominant wing blister phenotype, and the critical period for this phenotype is the beginning of pupariation. These data indicate that integrin requirements in wing morphogenesis can be separated into early (prepupal) and late (pupal) functions. The late function seems to reflect the traditional view of integrins as cell-matrix adhesion proteins. The early requirement, which probably requires dorsoventral segregation of PS1 and PS2, suggests functions for PS1 and PS2 in signaling events that regulate morphogenesis.


Evolutionary ecology of human life history.
The human life history is characterized by several unusual features, including large babies, late puberty and menopause, and the fact that there is a strong cultural influence on reproductive decisions throughout life. In this review I examine human life history from an evolutionary ecological perspective. I first review the evidence for life history trade-offs between fertility and mortality in humans. Patterns of growth, fertility and mortality across the life span are then discussed and illustrated with data from a traditional Gambian population. After outlining the stages of the human life course, I discuss two phenomena of particular interest in evolutionary anthropology, both of which are apparently unique to humans and neither yet fully understood. First, I discuss the evolution of menopause, the curtailing of female reproduction long before death. The evidence that this evolved because investment in existing children's future reproductive success is more important than continuing child bearing into old age is reviewed, along with data relating to the biological constraints that may be operating. Second, I discuss the demographic transition. Declining fertility at a time of increasingly abundant resources represents a serious challenge to an evolutionary view of human life history and behaviour, and is thus examined in detail. Parental investment in children in competition with each other may be key to understanding both of these unusual human phenomena. Copyright 2000 The Association for the Study of Animal Behaviour.