A Survey of the Community Water Supply of some rural Riverine Communities in the Niger Delta region, Nigeria: Health implications and literature search for suitable interventions.
BACKGROUND: Water is a fundamental human need. This is the basis for target 10, goal 7 of the Millennium Development Goals which sets to reduce the proportion of people without access to safe water by half by 2015. This study assessed the access to safe water supply in 22 riverine communities in the Niger delta region of Nigeria. MATERIALS AND METHOD: The study was carried out using a descriptive cross-sectional study design, with the data collected using a structured interviewer-administered questionnaire, field observations and focused group discussions. The questionnaire was administered to female heads of household, and used to collect information on the main source of drinking water, the time it took for the round trip to the main water sources, and methods used for the treatment of water of suspicious quality. An inventory of all the community water facilities in the communities was also taken, and information collected on the functionality of the facilities, and how they were constructed, operated and maintained. A sample of the water from each of the facilities was also collected in a sterile container for microbiological analysis. RESULTS: A total of 456 questionnaires were administered and retrieved. The most common source of drinking water was surface water (37.9%), and most (61.2%) of the water drawers spent less than 15 minutes to complete the round trip to the water sources. There were an average of 17 community water supply facilities, but only 23.8% of the facilities were functional during the study. Most of the functional facilities were being managed by community members. More than two third (67.9%) of the samples tested were found to contain significant numbers of Escherichia coli. CONCLUSION: The communities had easy access to water supply, but most of the facilities were either contaminated or nonfunctional. The management of the facilities by members of the communities, and the promotion of point-of-use purification systems are hereby advocated.


The risk of ureteric injury associated with hysterectomy: a 10-year retrospective cohort study.
To evaluate the rates of ureteric injury among women undergoing hysterectomy. Retrospective cohort. English National Health Service hospitals. Women undergoing hysterectomy in 2001-2010. Unadjusted rates of ureteric injury, within 1 year of hysterectomy, calculated by indication and type of procedure. Multivariable logistic regression used to assess the risk of ureteric injury with year of surgery. Ureteric injury within a year of the hysterectomy. In 2001-2010, 377 073 women underwent hysterectomy, of whom 1792 (0.5%) experienced a ureteric injury. In both benign and malignant groups the rate of injury was higher in 2006-2010 than 2001-2005. After 2006, ureteric injuries were most common for abdominal radical hysterectomy for uterine cancer (10.7%; 95% CI 7.3-15.1%). The proportion of women having a ureteric injury was similar for ovarian and cervical cancer (1.9-4.0% depending on type of procedure). For benign conditions, the rate of injury tended to be lower, typically <1%. Women with endometriosis had the highest risk among this group (1.7% following total abdominal hysterectomy; 95% CI 1.4-2.0%). The risk of ureteric injury within 1 year of hysterectomy varied by type of hysterectomy for benign and malignant conditions. The rates of injury have increased between 2001 and 2010. Ten-year study shows ureteric injury rates have increased.


TNR and conservation on a university campus: a political ecological perspective.
How to manage the impact of free-ranging cats on native wildlife is a polarizing issue. Conservation biologists largely support domestic cat euthanasia to mitigate impacts of free-ranging cat predation on small animal populations. Above all else, animal welfare activists support the humane treatment of free-ranging cats, objecting to euthanasia. Clearly, this issue of how to control free-ranging cat predation on small animals is value laden, and both positions must be considered and comprehended to promote effective conservation. Here, two gaps in the free-ranging cat-small-animal conservation literature are addressed. First, the importance of understanding the processes of domestication and evolution and how each relates to felid behavioral ecology is discussed. The leading hypothesis to explain domestication of wildcats (Felis silvestris) relates to their behavioral ecology as a solitary predator, which made them suited for pest control in early agricultural villages of the Old World. The relationship humans once had with cats, however, has changed because today domesticated cats are usually household pets. As a result, concerns of conservation biologists may relate to cats as predators, but cat welfare proponents come from the position of assuming responsibility for free-ranging household pets (and their feral offspring). Thus, the perceptions of pet owners and other members of the general public provide an important context that frames the relationship between free-ranging cats and small animal conservation. The second part of this paper assesses the effects of an information-based conservation approach on shifting student's perception of a local Trap-Neuter-Return (TNR) program in introductory core science classes at the University of North Texas (UNT). UNT students are (knowingly or unknowingly) regularly in close proximity to a TNR program on campus that supports cat houses and feeding stations. A survey design implementing a tailored-information approach was used to communicate what TNR programs are, their goals, and the "conservationist" view of TNR programs. We gauged favorability of student responses to the goals of TNR programs prior to and after exposure to tailored information on conservation concerns related to free-ranging cats. Although these results are from a preliminary study, we suggest that an information-based approach may only be marginally effective at shifting perceptions about the conservation implications of free-ranging cats. Our position is that small animal conservation in Western societies occurs in the context of pet ownership, thus broader approaches that promote ecological understanding via environmental education are more likely to be successful than information-based approaches.


Grading and staging of bladder carcinoma in transurethral resection specimens. Correlation with 105 matched cystectomy specimens.
We compared the grading and staging of transurethral resection of the bladder (TURB) and cystectomy specimens for 105 patients who underwent radical cystectomy for urothelial carcinoma between 1980 and 1984. Of 105 patients, 96% underwent cystectomy within 100 days of TURB (median interval, 10 days). Grading was performed according to the 1998 World Health Organization/International Society of Urologic Pathology grading system and staging according to the 1997 TNM classification. Histologic grade was low-grade, 13; high-grade, 92 in TURB specimens; low-grade, 17; high-grade, 88 in cystectomy specimens. Pathologic stage was Ta, 15; T1, 55; and T2, 35 in TURB specimens; Ta, 5; T1, 19; T2, 19; T3, 46; and T4, 16 in cystectomy specimens. Histologic grade at TURB was associated with pathologic stage at cystectomy (P < .001). When all advanced-stage (muscle-invasive) carcinomas (pT2 or more) were considered together, 55 patients were understaged by TURB, 4 had higher stage in TURB than in cystectomy, and 46 were the same stage as by cystectomy. Forty-three of 55 patients with stage T1 carcinoma at TURB had advanced-stage carcinoma at cystectomy, including 34 who had extravesicular extension (pT3 or more). We found pathologic understanding by TURB occurs in a significant number of patients with bladder cancer; the newly proposed grading system predicted final pathologic stage.


A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria.
An assessment of the correlation between anti-malarial treatment outcome and molecular markers would improve the early detection and monitoring of drug resistance by Plasmodium falciparum. The purpose of this systematic review was to determine the risk of treatment failure associated with specific polymorphisms in the parasite genome or gene copy number. Clinical studies of non-severe malaria reporting on target genetic markers (SNPs for pfmdr1, pfcrt, dhfr, dhps, gene copy number for pfmdr1) providing complete information on inclusion criteria, outcome, follow up and genotyping, were included. Three investigators independently extracted data from articles. Results were stratified by gene, codon, drug and duration of follow-up. For each study and aggregate data the random effect odds ratio (OR) with 95%CIs was estimated and presented as Forest plots. An OR with a lower 95th confidence interval > 1 was considered consistent with a failure being associated to a given gene mutation. 92 studies were eligible among the selection from computerized search, with information on pfcrt (25/159 studies), pfmdr1 (29/236 studies), dhfr (18/373 studies), dhps (20/195 studies). The risk of therapeutic failure after chloroquine was increased by the presence of pfcrt K76T (Day 28, OR = 7.2 [95%CI: 4.5-11.5]), pfmdr1 N86Y was associated with both chloroquine (Day 28, OR = 1.8 [95%CI: 1.3-2.4]) and amodiaquine failures (OR = 5.4 [95%CI: 2.6-11.3, p < 0.001]). For sulphadoxine-pyrimethamine the dhfr single (S108N) (Day 28, OR = 3.5 [95%CI: 1.9-6.3]) and triple mutants (S108N, N51I, C59R) (Day 28, OR = 3.1 [95%CI: 2.0-4.9]) and dhfr-dhps quintuple mutants (Day 28, OR = 5.2 [95%CI: 3.2-8.8]) also increased the risk of treatment failure. Increased pfmdr1 copy number was correlated with treatment failure following mefloquine (OR = 8.6 [95%CI: 3.3-22.9]). When applying the selection procedure for comparative analysis, few studies fulfilled all inclusion criteria compared to the large number of papers identified, but heterogeneity was limited. Genetic molecular markers were related to an increased risk of therapeutic failure. Guidelines are discussed and a checklist for further studies is proposed.


Epistatic and gene wide effects in YWHA and aromatic amino hydroxylase genes across ADHD and other common neuropsychiatric disorders: Association with YWHAE.
Monoamines critically modulate neurophysiological functions affected in several neuropsychiatric disorders. We therefore examined genes encoding key enzymes of catecholamine and serotonin biosynthesis (tyrosine and tryptophan hydroxylases-TH and TPH1/2) as well as their regulatory 14-3-3 proteins (encoded by YWHA-genes). Previous studies have focused mainly on the individual genes, but no analysis spanning this regulatory network has been reported. We explored interactions between these genes in Norwegian patients with adult attention deficit hyperactivity disorder (aADHD), followed by gene-complex association tests in four major neuropsychiatric conditions; childhood ADHD (cADHD), bipolar disorder, schizophrenia, and major depressive disorder. For interaction analyses, we evaluated 55 SNPs across these genes in a sample of 583 aADHD patients and 637 controls. For the gene-complex tests, we utilized the data from large-scale studies of The Psychiatric Genomics Consortium (PGC). The four major neuropsychiatric disorders were examined for association with each of the genes individually as well as in three complexes as follows: (1) TPH1 and YWHA-genes; (2) TH, TPH2 and YWHA-genes; and (3) all genes together. The results show suggestive epistasis between YWHAE and two other 14-3-3-genes - YWHAZ, YWHAQ - in aADHD (nominal P-value of 0.0005 and 0.0008, respectively). In PGC data, association between YWHAE and schizophrenia was noted (P = 1.00E-05), whereas the combination of TPH1 and YWHA-genes revealed signs of association in cADHD, schizophrenia, and bipolar disorder. In conclusion, polymorphisms in the YWHA-genes and their targets may exert a cumulative effect in ADHD and related neuropsychiatric conditions, warranting the need for further investigation of these gene-complexes. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.


Modeling phosphorus in the Lake Allatoona watershed using SWAT: I. Developing phosphorus parameter values.
Lake Allatoona is a large reservoir north of Atlanta, GA, that drains an area of about 2870 km2 scheduled for a phosphorus (P) total maximum daily load (TMDL). The Soil and Water Assessment Tool (SWAT) model has been widely used for watershed-scale modeling of P, but there is little guidance on how to estimate P-related parameters, especially those related to in-stream P processes. In this paper, methods are demonstrated to individually estimate SWAT soil-related P parameters and to collectively estimate P parameters related to stream processes. Stream related parameters were obtained using the nutrient uptake length concept. In a manner similar to experiments conducted by stream ecologists, a small point source is simulated in a headwater sub-basin of the SWAT models, then the in-stream parameter values are adjusted collectively to get an uptake length of P similar to the values measured in the streams in the region. After adjusting the in-stream parameters, the P uptake length estimated in the simulations ranged from 53 to 149 km compared to uptake lengths measured by ecologists in the region of 11 to 85 km. Once the a priori P-related parameter set was developed, the SWAT models of main tributaries to Lake Allatoona were calibrated for daily transport. Models using SWAT P parameters derived from the methods in this paper outperformed models using default parameter values when predicting total P (TP) concentrations in streams during storm events and TP annual loads to Lake Allatoona.


Radiographic appearances of mycoplasma pneumonia.
The chest radiographs of 60 adult patients with serologically proven mycoplasma pneumonia were reviewed. Confluent or patchy consolidation was most commonly seen, and involved one lobe only in 40% of patients. Widespread nodular opacities were seen much less frequently (7%). Pleural fluid was rare. Complete resolution was almost invariable, 40% of radiographs having cleared by four weeks and 96% by eight weeks.


Isoliquiritigenin Ameliorates Indomethacin-Induced Small Intestinal Damage by Inhibiting NOD-Like Receptor Family, Pyrin Domain-Containing 3 Inflammasome Activation.
Activation of the NOD-Like Receptor Family, Pyrin Domain-Containing 3 (NLRP3) inflammasome, which consists of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1, triggers pro-caspase-1 cleavage promoting the processing of pro-interleukin (IL)-1β into mature IL-1β, which is critical for the development of non-steroidal anti-inflammatory drug (NSAID)-induced enteropathy. We investigated the effects of isoliquiritigenin, a flavonoid derived from the roots of Glycyrrhiza species, on NSAID-induced small intestinal damage and the inflammasome activation. To induce enteropathy, mice were administered indomethacin by gavage with or without isoliquiritigenin pretreatment. Some mice received an intraperitoneal injection of recombinant murine IL-1β in addition to isoliquiritigenin and indomethacin. Indomethacin induced small intestinal damage and increased protein levels of cleaved caspase-1 and mature IL-1β in the small intestine. Treatment with 7.5 and 75 mg/kg isoliquiritigenin inhibited indomethacin-induced small intestinal damage by 40 and 56%, respectively. Isoliquiritigenin also inhibited the indomethacin-induced increase in cleaved caspase-1 and mature IL-1β protein levels, whereas it did not affect the mRNA expression of NLRP3, ASC, caspase-1, and IL-1β. Protection against intestinal damage in isoliquiritigenin-treated mice was completely abolished with exogenous IL-1β. NLRP3-/- and caspase-1-/- mice exhibited resistance to intestinal damage, and isoliquiritigenin treatment failed to inhibit the damage in NLRP3-/- and caspase-1-/- mice. Isoliquiritigenin prevents NSAID-induced small intestinal damage by inhibiting NLRP3 inflammasome activation.


A proton wire to couple aminoacyl-tRNA accommodation and peptide-bond formation on the ribosome.
During peptide-bond formation on the ribosome, the α-amine of an aminoacyl-tRNA attacks the ester carbonyl carbon of a peptidyl-tRNA to yield a peptide lengthened by one amino acid. Although the ribosome's contribution to catalysis is predominantly entropic, the lack of high-resolution structural data for the complete active site in complex with full-length ligands has made it difficult to assess how the ribosome might influence the pathway of the reaction. Here, we present crystal structures of preattack and postcatalysis complexes of the Thermus thermophilus 70S ribosome at ~2.6-Å resolution. These structures reveal a network of hydrogen bonds along which proton transfer could take place to ensure the concerted, rate-limiting formation of a tetrahedral intermediate. We propose that, unlike earlier models, the ribosome and the A-site tRNA facilitate the deprotonation of the nucleophile through the activation of a water molecule.


Development of RNA aptamers targeting Ebola virus VP35.
Viral protein 35 (VP35), encoded by filoviruses, is a multifunctional dsRNA binding protein that plays important roles in viral replication, innate immune evasion, and pathogenesis. The multifunctional nature of these proteins also presents opportunities to develop countermeasures that target distinct functional regions. However, functional validation and the establishment of therapeutic approaches toward such multifunctional proteins, particularly for nonenzymatic targets, are often challenging. Our previous work on filoviral VP35 proteins defined conserved basic residues located within its C-terminal dsRNA binding interferon (IFN) inhibitory domain (IID) as important for VP35 mediated IFN antagonism and viral polymerase cofactor functions. In the current study, we used a combination of structural and functional data to determine regions of Ebola virus (EBOV) VP35 (eVP35) to target for aptamer selection using SELEX. Select aptamers, representing, two distinct classes, were further characterized based on their interaction properties to eVP35 IID. These results revealed that these aptamers bind to distinct regions of eVP35 IID with high affinity (10-50 nM) and specificity. These aptamers can compete with dsRNA for binding to eVP35 and disrupt the eVP35-nucleoprotein (NP) interaction. Consistent with the ability to antagonize the eVP35-NP interaction, select aptamers can inhibit the function of the EBOV polymerase complex reconstituted by the expression of select viral proteins. Taken together, our results support the identification of two aptamers that bind filoviral VP35 proteins with high affinity and specificity and have the capacity to potentially function as filoviral VP35 protein inhibitors.


Prevalence of Haemoproteus spp. in Tumbler Pigeons (Columba livia domestica) in Kirikkale Province, Turkey.
Haemoproteus spp. are common blood parasites of pigeons. They have been reported in pigeons in many regions worldwide, including Turkey. Pigeon breeding is a popular hobby in Kirikkale province, and there is no information about the prevalence of Haemoproteus spp. The present study aimed to determine the prevalence of Haemoproteus spp. in tumbler pigeons in Kirikkale province (Kırıkkale and Yahsihan district). Blood samples were taken from the wing vein of pigeons (n: 173) through microcapillary (with/heparin) tubes between February and March 2016. Blood smears were stained with 5% Giemsa solution. Ectoparasites of the pigeons were collected in separate sealed boxes. Epidemiological data of the sampled pigeons (age and sex) were obtained from the breeders. In total, 23 (%13.2) of 173 pigeons were infected with Haemoproteus spp. Parasite was detected in 73.9% of pigeons over 1 year old and 26.1% of pigeon under 1 year age. Haemoproteus spp. was observed in 56.2% of females (13/23) and 43.4% of males (10/23), Sex-related differences were not observed (p = 0.821). Ectoparasites of the pigeons were identified as Columbicola spp. To the best of our knowledge, this is the first study in Kirikkale province that reported the prevalence of Haemoproteus spp. in pigeons.


cAMP response element-binding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs.
Antidepressant drugs activate the cAMP signal transduction pathway through a variety of monoamine neurotransmitter receptors. Recently, molecular studies have identified a role for cAMP response element-binding protein (CREB) in the mechanism of action of chronically administered antidepressant drugs. However, the function of CREB in the behavioral and endocrine responses to these drugs has not been thoroughly investigated. We have used CREB-deficient mice to study the effects of two antidepressants, desipramine (DMI) and fluoxetine (FLX), in behavioral, endocrine, and molecular analyses. Behaviorally, CREB-deficient mice and wild-type mice respond similarly to DMI and FLX administration in the forced swim test and tail suspension test. Furthermore, the ability of DMI to suppress an acute corticosterone response after swim stress is maintained in CREB-deficient mice. However, upregulation of a molecular target of CREB, BDNF, is abolished in the CREB-deficient mice after chronic administration of DMI. These data are the first to demonstrate that CREB activation is upstream of BDNF mechanistically in response to antidepressant drug treatment. Therefore, although behavioral and endocrine responses to antidepressants may occur by CREB-independent mechanisms, CREB is critical to target gene regulation after chronic drug administration, which may contribute to long-term adaptations of the system to antidepressant drug treatment.


Cooperative Assembly of Magneto-Nanovesicles with Tunable Wall Thickness and Permeability for MRI-Guided Drug Delivery.
This article describes the fabrication of nanosized magneto-vesicles (MVs) comprising tunable layers of densely packed superparamagnetic iron oxide nanoparticles (SPIONs) in membranes via cooperative assembly of polymer-tethered SPIONs and free poly(styrene)- b-poly(acrylic acid) (PS- b-PAA). The membrane thickness of MVs could be well controlled from 9.8 to 93.2 nm by varying the weight ratio of PS- b-PAA to SPIONs. The increase in membrane thickness was accompanied by the transition from monolayer MVs, to double-layered MVs and to multilayered MVs (MuMVs). This can be attributed to the variation in the hydrophobic/hydrophilic balance of polymer-grafted SPIONs upon the insertion and binding of PS- b-PAA onto the surface of nanoparticles. Therapeutic agents can be efficiently encapsulated in the hollow cavity of MVs and the release of payload can be tuned by varying the membrane thickness of nanovesicles. Due to the high packing density of SPIONs, the MuMVs showed the highest magnetization and transverse relaxivity rate ( r2) in magnetic resonance imaging (MRI) among these MVs and individual SPIONs. Upon intravenous injection, doxorubicin-loaded MuMVs conjugated with RGD peptides could be effectively enriched at tumor sites due to synergetic effect of magnetic and active targeting. As a result, they exhibited drastically enhanced signal in MRI, improved tumor delivery efficiency of drugs as well as enhanced antitumor efficacy, compared with groups with only magnetic or active targeting strategy. The unique nanoplatform may find applications in effective disease control by delivering imaging and therapy to organs/tissues that are not readily accessible by conventional delivery vehicles.


A longitudinal study of chiropractic use among older adults in the United States.
Longitudinal patterns of chiropractic use in the United States, particularly among Medicare beneficiaries, are not well documented. Using a nationally representative sample of older Medicare beneficiaries we describe the use of chiropractic over fifteen years, and classify chiropractic users by annual visit volume. We assess the characteristics that are associated with chiropractic use versus nonuse, as well as between different levels of use. We analyzed data from two linked sources: the baseline (1993-1994) interview responses of 5,510 self-respondents in the Survey on Assets and Health Dynamics Among the Oldest Old (AHEAD), and their Medicare claims from 1993 to 2007. Binomial logistic regression was used to identify factors associated with chiropractic use versus nonuse, and conditional upon use, to identify factors associated with high volume relative to lower volume use. There were 806 users of chiropractic in the AHEAD sample yielding a full period prevalence for 1993-2007 of 14.6%. Average annual prevalence between 1993 and 2007 was 4.8% with a range from 4.1% to 5.4%. Approximately 42% of the users consumed chiropractic services only in a single calendar year while 38% used chiropractic in three or more calendar years. Chiropractic users were more likely to be women, white, overweight, have pain, have multiple comorbid conditions, better self-rated health, access to transportation, higher physician utilization levels, live in the Midwest, and live in an area with fewer physicians per capita. Among chiropractic users, 16% had at least one year in which they exceeded Medicare's "soft cap" of 12 visits per calendar year. These over-the-cap users were more likely to have arthritis and mobility limitations, but were less likely to have a high school education. Additionally, these over-the-cap individuals accounted for 58% of total chiropractic claim volume. High volume users saw chiropractors the most among all types of providers, even more than family practice and internal medicine combined. There is substantial heterogeneity in the patterns of use of chiropractic services among older adults. In spite of the variability of use patterns, however, there are not many characteristics that distinguish high volume users from lower volume users. While high volume users accounted for a significant portion of claims, the enforcement of a hard cap on annual visits by Medicare would not significantly decrease overall claim volume. Further research to understand the factors causing high volume chiropractic utilization among older Americans is warranted to discern between patterns of "need" and patterns of "health maintenance".


Introduction of a natural resource balance indicator to assess soil organic carbon management: Agricultural Biomass Productivity Benefit.
The rising demand for feed and food has put an increasing pressure on agriculture, with agricultural intensification as a direct response. Notwithstanding the higher crop productivity, intensive agriculture management entails many adverse environmental impacts. Worldwide, soil organic carbon (SOC) decline is hereby considered as a main danger which affects soil fertility and productivity. The life cycle perspective helps to get a holistic overview when evaluating the environmental sustainability of agricultural systems, though the impact of farm management on soil quality aspects is often not integrated. In this paper, we introduce an indicator called Agricultural Biomass Productivity Benefit of SOC management (ABB_SOC), which, relying on natural resource consumption, enables to estimate the net effect of the efforts made to attain a better soil quality. Hereby the focus is put on SOC. First, we introduce a framework to describe the SOC trend due to farm management decisions. The extent to which remediation measures are required are used as a measure for the induced SOC losses. Next, ABB_SOC values are calculated as the balance between the natural resource consumption of the inputs (including remediation efforts) and the desired output of arable crop production systems. The models RothC and EU-Rotate_N are used to simulate the SOC evolution due to farm management and the response of the biomass productivity, respectively. The developed indicator is applied on several rotation systems in Flanders, comparing different remediation strategies. The indicator could be used as a base for a method to account for soil quality in life cycle analysis.


Recent Advances on Detection and Characterization of Fruit Tree Viruses Using High-Throughput Sequencing Technologies.
Perennial crops, such as fruit trees, are infected by many viruses, which are transmitted through vegetative propagation and grafting of infected plant material. Some of these pathogens cause severe crop losses and often reduce the productive life of the orchards. Detection and characterization of these agents in fruit trees is challenging, however, during the last years, the wide application of high-throughput sequencing (HTS) technologies has significantly facilitated this task. In this review, we present recent advances in the discovery, detection, and characterization of fruit tree viruses and virus-like agents accomplished by HTS approaches. A high number of new viruses have been described in the last 5 years, some of them exhibiting novel genomic features that have led to the proposal of the creation of new genera, and the revision of the current virus taxonomy status. Interestingly, several of the newly identified viruses belong to virus genera previously unknown to infect fruit tree species (e.g., Fabavirus, Luteovirus) a fact that challenges our perspective of plant viruses in general. Finally, applied methodologies, including the use of different molecules as templates, as well as advantages and disadvantages and future directions of HTS in fruit tree virology are discussed.


Research questions and priorities for tuberculosis: a survey of published systematic reviews and meta-analyses.
Systematic reviews are increasingly informing policies in tuberculosis (TB) care and control. They may also be a source of questions for future research. As part of the process of developing the International Roadmap for TB Research, we did a systematic review of published systematic reviews on TB, to identify research priorities that are most frequently suggested in reviews. We searched EMBASE, MEDLINE, Web of Science, and the Cochrane Library for systematic reviews and meta-analyses on any aspect of TB published between 2005 and 2010. One reviewer extracted data and a second reviewer independently extracted data from a random subset of included studies. In total, 137 systematic reviews, with 141 research questions, were included in this review. We used the UK Health Research Classification System (HRCS) to help us classify the research questions and priorities. The three most common research topics were in the area of detection, screening and diagnosis of TB (32.6%), development and evaluation of treatments and therapeutic interventions (23.4%), and TB aetiology and risk factors (19.9%). The research priorities determined were mainly focused on the discovery and evaluation of bacteriological TB tests and drug-resistant TB tests and immunological tests. Other important topics of future research were genetic susceptibility linked to TB and disease determinants attributed to HIV/TB. Evaluation of drug treatments for TB, drug-resistant TB and HIV/TB were also frequently proposed research topics. Systematic reviews are a good source of key research priorities. Findings from our survey have informed the development of the International Roadmap for TB Research by the TB Research Movement.


Simple markers for initiating antiretroviral therapy among HIV-infected Ethiopians.
We explored the relevance of simple markers (clinical or laboratory markers not requiring sophisticated laboratories) in the decision of initiation of therapy in resource-poor settings. Among HIV-infected Ethiopian cohort participants, simple markers predicting short-term death were examined using time-dependent Cox proportional hazards models. Timing of hypothetical treatment was compared between guidelines using the simple markers (based on presence of at least one marker), guidelines recommended by the United States Department of Health and Human Services (based on CD4 cell count and viral load), and guidelines for resource-limited settings recommended by the World Health Organization (WHO). From February 1997 to August 2001, 35 deaths were recorded among 155 HIV-positive participants. Simple independent predictors of death were low body mass index, HIV-related conditions, anaemia, and lymphocyte count < 1500 x 10(6)/l. In such time as was covered by our study, 135 (87%) of 155 cohort participants would have had the same management under both the simple markers and the DHHS guidelines, i.e., would have been treated (n = 114, 74%) or not treated (n = 21, 14%). Of the 114 participants hypothetically treated under either set of guidelines, 91 (80%) would have started treatment at the same time. Application of the WHO guidelines for resource-limited settings (without CD4 cell counts) would have resulted in 11 participants dying without ever meeting a treatment indication during regular follow-up visits. Simple markers for the initiation of highly active antiretroviral therapy were identified among HIV-infected Ethiopian patients. The validity of these markers for monitoring patients' improvement following therapy remains to be evaluated.


NF-kappaB-independent actions of sulfasalazine dissociate the CD95L- and Apo2L/TRAIL-dependent death signaling pathways in human malignant glioma cells.
Death receptor-mediated apoptosis of human malignant glioma cells triggered by CD95 ligand (CD95L) or Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) share several features, including processing of multiple caspases and mitochondrial cytochrome c release. We here report that CD95L-induced cell death is inhibited by sulfasalazine (SS) in all of four human glioma cell lines, both in the absence and presence of cycloheximide (CHX). Coexposure to CD95L and SS prevents the CD95L-evoked processing of caspases 2, 3, 8 and 9, the release of cytochrome c from mitochondria, and the loss of BCL-x(L) protein. This places the protective effect of SS proximal to most known events triggered by the CD95-dependent signaling pathway in glioma cells. CD95L promotes the accumulation of nuclear factor kappa B (NF-kappaB) in the nucleus and induces the DNA-binding activity of NF-kappaB assessed by electrophoretic mobility shift assay. The total levels of p50, p65 and IkappaBalpha remain unchanged, but the levels of phosphorylated IkappaBalpha and of nuclear p65 increase, in response to CD95L. IkappaBalpha phosphorylation as well as nuclear NF-kappaB translocation and DNA binding are blocked by SS. However, unlike SS, dominant-negative IkappaBalpha (IkappaBdn) does not block apoptosis, suggesting that SS inhibits CD95L-mediated apoptosis in an NF-kappaB-independent manner. In contrast to CD95L, the cytotoxic effects of Apo2L/TRAIL are enhanced by SS, and SS facilitates Apo2L/TRAIL-evoked caspase processing, cytochrome c release, and nuclear translocation of p65. These effects of SS are nullified in the presence of CHX, suggesting that the effects of SS and CHX are redundant or that enhanced apoptosis mediated by SS requires protein synthesis. IkappaBdn fails to modulate Apo2L/TRAIL-induced apoptosis. Similar effects of SS on CD95L- and Apo2L/TRAIL-induced apoptosis are observed in MCF-7 breast and HCT116 colon carcinoma cells. Interestingly, HCT cells lacking p21 (80S14(p21-/-)) are only slightly protected by SS from CD95L-induced apoptosis, but sensitized to Apo2L/TRAIL-induced apoptosis, indicating a link between the actions of SS and p21. Thus, SS modulates the death cascades triggered by CD95L and Apo2L/TRAIL in opposite directions in an NF-kappaB-independent manner, and SS may be a promising agent for the augmentation of Apo2L/TRAIL-based cancer therapies.


Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice.
The nonsteroidal anti-inflammatory drug (NSAID), tolfenamic acid (TA) is emerging as a new anti-cancer agent. TA induces the degradation of specific Specificity protein (Sp) transcription factors, Sp1, Sp3 and Sp4 which are associated with tumor growth and metastasis. In this study we have evaluated the effect of TA on lung cancer using both in vitro and in vivo models. TA in a dose dependent manner inhibited proliferation and cell viability of two different lung cancer cells, A549 and CRL5803. TA treatment for 48 h significantly decreased the expression of Sp1, Sp3 and Sp4. The hepatocyte growth factor receptor, c-Met is overexpressed in a variety of cancers including lung cancer and Sp proteins mediate the regulation of c-Met. TA diminished the expression of c-Met protein and modulates its downstream signaling pathway. Furthermore, TA treatment significantly increased the number of apoptotic cells and pro-apoptotic markers c-PARP and Bax confirming the activation of apoptotic pathways. In vivo studies using the orthotopic mice model for lung cancer showed that TA (25 mg/kg/2 days and 50 mg/kg/2 days) resulted in a dose dependent decrease in tumor formation. The immunohistochemical staining of lung tissue showed high expression of Sp1, Sp3, Sp4, c-Met and phospho Met in control group and a dose dependent decrease in TA treated groups. The crucial findings of this study support that targeting c-Met with a potent inhibitor of Sp proteins is a robust strategy for the implications in lung cancer treatment and TA can serve as a therapeutic agent for this devastating disease.


Surviving Sepsis Campaign Guidelines 2021: highlights for the practicing clinician.
The 2021 Surviving Sepsis Campaign Guidelines provided evidence-based recommendations for adult patients with sepsis and septic shock. This iteration of the guidelines placed increased emphasis on a diverse, global perspective, as well as on the long-term sequelae of sepsis experienced by patients and their families. The guidelines encompassed the following sections: 1) screening and early treatment; 2) infection; 3) hemodynamic management; 4) ventilation; 5) additional therapies; and 6) goals of care and long-term outcomes. In this review, we provide a summary of key recommendations of interest to the practicing clinician, which are either novel or require a change in practice, as well as those for which the evidence has substantially evolved in the 5 years since the 2016 iteration of the Guidelines. Rather than reviewing the underlying evidence, we emphasize the practical aspects of interpretation, dissemination, and implementation of these recommendations in the clinical setting.


Systematic review of lumbar provocation discography in asymptomatic subjects with a meta-analysis of false-positive rates.
Lumbar provocation discography is a controversial diagnostic test. Currently, there is a concern that the test has an unacceptably high false-positive rate. Systematic review and meta-analysis. To perform a systematic review of lumbar discography studies in asymptomatic subjects and discs with a meta-analysis of the specificity and false-positive rate of lumbar discography. A systematic review of the literature was conducted via a PUBMED search. Studies were included/excluded according to modern discography practices. Study quality was scored using the Agency for Healthcare Research and Quality (AHRQ) instrument for diagnostic accuracy. Specific data was extracted from studies and tabulated per published criteria and standards to determine the false-positive rates. A meta-analysis of specificity was performed. Strength of evidence was rated according to the AHRQ U.S. Preventive Services Task Force (USPSTF) criteria. Eleven studies were identified. Combining all extractable data, a false-positive rate of 9.3% per patient and 6.0% per disc is obtained. Data pooled from asymptomatic subjects without low back pain or confounding factors, shows a false-positive rate of 3.0% per patient and 2.1% per disc. In data pooled from chronic pain patients, asymptomatic of low back pain, the false-positive rate is 5.6% per patient and 3.85% per disc. Chronic pain does not appear to be a confounding factor in a chronic low back pain patient's ability to distinguish between positive (pathologic) and negative (non-pathologic) discs. Among additional asymptomatic patient subgroups analyzed, the false-positive rate per patient and per disc is as follows: iliac crest pain 12.5% and 7.1%; chronic neck pain 0%; somatization disorder 50% and 22.2%, and, post-discectomy 15% and 9.1%, respectively. In patients with chronic backache, no false-positive rate can be calculated. Low-pressure positive criteria (< or = 15 psi a.o.) can obtain a low false-positive rate. Based on meta-analysis of the data, using the ISIS standard, discography has a specificity of 0.94 (95% CI 0.88 - 0.98) and a false-positive rate of 0.06. Strength of evidence is level II-2 based on the Agency for Healthcare Research Quality (USPSTF) for the diagnostic accuracy of discography. Contrary to recently published studies, discography has a low false-positive rate for the diagnosis of discogenic pain.


Cyclin D2 activates Cdk2 in preference to Cdk4 in human breast epithelial cells.
To investigate the possibility of differing roles for cyclins D1 and D2 in breast epithelial cells, we examined the expression, cell cycle regulation and activity of these two G1 cyclins in both 184 normal breast epithelial cells and T-47D breast cancer cells. Synchronisation studies in 184 cells demonstrated that cyclin D1 and cyclin D2 were differentially regulated during G1, with cyclin D2 abundance increasing by 3.7-fold but only small changes in cyclin D1 abundance observed. The functional consequences of increased cyclin D2 expression were examined in T-47D cells, which express no detectable cyclin D2. Induced expression of cyclin D2 resulted in increases in cyclin E expression, pRB phosphorylation and the percentage of cells in S-phase, while constitutive expression resulted in a consistent trend toward reduced dependence on serum for continued proliferation. Thus, cyclin D2 is a positive regulator of G1 progression in breast cells analogous to the well-documented effects of cyclin D1. Indeed, equimolar concentrations of inducible cyclin D1 and D2 resulted in quantitatively similar cell cycle effects. Marked divergence was found, however, in the CDKs activated by the two cyclins in breast epithelial cells. Cyclin D2 complexes contained a higher Cdk2/Cdk4 ratio than cyclin D1 complexes. The cyclin D2-associated kinase activity was largely inhibited by Cdk2-specific inhibitors and could phosphorylate histone H1, a substrate for Cdk2 but not for Cdk4 and Cdk6. Therefore, cyclin D2 preferentially activated Cdk2 in breast epithelial cells. In contrast, Cdk4 and Cdk6 were predominantly responsible for cyclin D1-associated kinase activity as previously reported. Thus, although cyclins D1 and D2 elicited similar effects on breast epithelial cell cycle progression they appeared to achieve this end via activation of different CDKs. This is the first evidence of cyclin D2 activating Cdk2 in mammalian cells thus providing further evidence that D-type cyclins are not necessarily redundant.


A national cross-sectional study of adherence to timely mammography use in Malta.
Routine mammography improves survival. To achieve health benefits, women must attend breast screening regularly at recommended time intervals. Maltese women are routinely invited to undergo mammography at three-year intervals at an organized breast screening programme (MBSP) or can opt to attend a private clinic. Previous research shows that health beliefs, particularly perceived barriers, were the most significant predictors of uptake to the first MBSP invitation. Whether these beliefs and other factors are predictive of adherence with recommended time intervals for mammography at organized or private screening in Malta is unknown. For the first time, this paper explores the predictors for Maltese women screened within or exceeding the recommended three-year frequency in organized or private screening in Malta. Information was obtained from a cross-sectional survey of 404 women, aged 50 to 60 years at the time of their first MBSP invitation, where women's characteristics, knowledge, health beliefs and illness perceptions were compared. The main variable of interest was women's mammography attendance within a three-year interval (ADHERENT) or exceeding three years (NON-ADHERENT). Data were analysed using descriptive statistics, chi-square test, Mann Whitney test, Independent Samples t-test and Shapiro Wilk test. At the time of the survey, 80.2% (n = 324) had been screened within three years (ADHERENT), 5.9% (n = 24) had exceeded the three-year frequency (NON-ADHERENT) while 13.9% (n = 56) never had a mammogram. No significant associations were found between ADHERENT or NON-ADHERENT women in relation to sociodemographic or health status variables (p > 0.05). Knowledge of screening frequency was significantly associated with women's mammography adherence (χ2 = 5.5, p = 0.020). Health beliefs were the strongest significant predictors to describe the variance between ADHERENT and NON-ADHERENT screeners. When Mann Whitney test and Independent Samples t-test were applied on mammography adherence, perceived barriers and cues to action were found to be the most important predictors (p = 0.000, p = 0.039 respectively). To increase routine and timely mammography practices, women who are non-adherent to recommended time frequency guidelines should be targeted, together with their health beliefs, predominantly perceived barriers and cues to action.


Gastrointestinal stromal tumors: imatinib and beyond.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Clinicians previously classified GISTs as "benign" or "malignant," but now place resected tumors in risk categories that are based on size and mitotic rate. Historically, GIST patients were managed with surgery alone, as chemotherapy and radiotherapy have minimal activity in this disease. In the pre-imatinib era, patients with recurrent or metastatic disease generally did very poorly. GIST therapy was revolutionized following the discovery of oncogenic mutations in the c-kit gene, as well as in the platelet-derived growth factor receptor. Subsequently, it has been confirmed that the KIT receptor tyrosine kinase is both a diagnostic marker and a useful therapeutic target in GIST. Imatinib, a potent inhibitor of KIT activity, is now standard front-line therapy for advanced GIST. With the introduction of imatinib, there have been dramatic improvements in response rates, time to progression, and survival. Imatinib is now being investigated and shows promise in the neoadjuvant and adjuvant settings. Unfortunately, many patients eventually recur or progress during imatinib therapy. For these patients, imatinib dose escalation and/or surgical evaluation are appropriate. Additionally, a novel tyrosine kinase inhibitor such as SU11248 (sunitinib) is a reasonable option for progressive, imatinib-resistant disease. With the identification of other downstream pathways, several other promising therapies are under current investigation either alone or in combination with imatinib and surgery.


Targeting VEGF/VEGFR in the treatment of psoriasis.
Psoriasis is a common chronic skin disorder characterized by cutaneous inflammation and keratinocyte hyperproliferation. In the past decade, a number of novel effective biological agents have been developed to treat moderate-to-severe psoriasis. However, these drugs have potential serious side effects, particularly the development of infectious diseases. Therefore there is still a need for new therapies with better efficacy and less adverse effects. Angiogenesis is implicated in various pathological conditions including psoriasis. Direct targeting of angiogenesis becomes a new therapeutic strategy for the treatment of psoriasis. Vascular endothelial growth factor (VEGF), the most critical angiogenic factor, is thought to play important roles during the pathogenesis of psoriasis and may be a promising target for treating psoriasis. Therefore, we proposed that targeting VEGF/VEGFRs could lead to new treatments for psoriasis.


Piroxicam inhibits Masitinib-induced cyclooxygenase 2 expression in oral squamous cell carcinoma cells in vitro.
Development and characterization of animal models for human cancers is important for the improvement of diagnosis and therapy. The oral squamous cell carcinoma (OSCC) of domestic animals resembles human OSCC in many aspects; thus, cell lines derived from OSCC of cats and dogs are a valuable model for human OSCC. We characterized 1 feline OSCC (FeOSCC-Sidney) and 1 canine OSCC (K9OSCC-Abby) cell line and compared their characteristics with human OSCC cell line hSCC-25. We calculated the doubling time of the new OSCC cell lines and evaluated the expression profiles of cancer-related markers and cell-cycle proteins such as c-kit, platelet-derived growth factor receptor, vascular endothelial growth factor receptor, epidermal growth factor receptor, cyclooxygenase (COX)-1, COX-2, and p27 by immunocytochemistry and Western blot analysis. We evaluated the effects of novel receptor tyrosine kinase inhibitor (Masitinib, AB1010) and the nonsteroidal anti-inflammatory drug piroxicam on the previously mentioned OSCC cells. Interestingly, AB1010 increased expression levels of COX-2 in all tested OSCCs. Cotreatment of piroxicam with Masitinib significantly inhibited cell proliferation of OSCC as compared to either drug alone through the c-kit and AKT signaling pathways. Piroxicam inhibited Masitinib-induced COX-2 expression in all tested OSCCs. Therefore, targeting these two signaling pathways simultaneously was more efficient for inhibition of OSCCs across these species.


Physician assistants in English general practice: a qualitative study of employers' viewpoints.
Effective use of staff is a major aim in all health-care systems both to maximize their impact and to minimize costs. In England, a few general practitioners (GPs) have been recruiting physician assistants (PAs) to work in their practices, independent of any pilot schemes. Our objective was to study the motivation of GPs and practice managers who employed PAs and to understand the factors that sustained their employment. A qualitative study using semi-structured interviews, analysed thematically, was carried out with 13 GPs and three practice managers from 15 general practices employing PAs in five areas of England. All practices were employing USA-trained PAs. Motivating factors for their employment included increasing the general practice capacity to manage patient demand within government targets for access, broaden the skill-mix in the practice team and financial considerations. The issues that needed to be taken into account in employing PAs included: the requirement for medical supervision; the PAs current lack of a regulatory framework and prescribing authority; and some patients' lack of familiarity with the concept of the PA. General practice employers view PAs as a positive addition to a mixed skill team for meeting patient demand within a practice's finances. There is a need to develop stronger governance and regulatory frameworks for this emerging profession.


22q11.2DS deletion syndrome: developmental milestones in infants and toddlers.
The majority of children with 22q11.2DS deletion syndrome (22q11.2DS) have learning disabilities, and a substantial number have mental retardation. Although cognitive data have been reported on several samples of children with 22q11.2DS, data on their early developmental milestones are limited. The present study used a retrospective design and asked parents to recall developmental milestones. The participants were 88 children with 22q11.2DS, 47 community controls, and 29 sibling controls. Although very early gross motor and expressive language milestones did not differ significantly from comparison groups, subsequent gross motor and expressive language milestones did, suggesting that children with 22q11.2DS may begin to lag behind their peers sometime after the first year of life in these two domains. These patterns were also apparent when a subset of intellectually comparable children (22q11.2DS, n = 40 vs community controls, n = 24) was analyzed. We further found that receptive language and social adaptive milestones did not differ from comparison samples in either the early or later period. Receptive language delays were predictive of later Wechsler Intelligence Scale for Children-Third Edition Perceptual Organization Index scores, particularly in girls with 22q11.2DS. This suggests that although receptive language may be an area of relative strength in the developmental profile of young children with 22q11.2DS, even mild receptive delays should not be overlooked in early interventions with children with this disorder.


The role of ribonuclease II in the maturation of precursor 16S ribosomal ribonucleic acid in Escherichia coli.
The suggested involvement of ribonuclease II in the maturation of rRNA has been examined directly by determining the activity of the enzyme and the amount of p16S rRNA in cell-free extracts from Escherichia coli A19 and its temperature-sensitive derivative N464 grown under experimental conditions designed to vary the amounts of enzyme and precursor independently. In strain A19 the enzyme showed maximum activity in circumstances where the amount of p16S rRNA was normal (e.g. exponential-phase cells) or raised eight times (e.g. during inhibition of growth by methionine starvation of the relaxed auxotroph or by chloramphenicol or puromycin treatment). In strain N464 at the non-permissive temperature the ribonuclease II activity may be decreased by 50% without effect upon the amount of p16S rRNA, whereas in methionine starvation of this strain the enzyme activity is at a maximum and the p16S rRNA is eight times that in exponential-phase cells. These observations are discussed in relation to the previously implied role of ribonuclease II in the maturation of rRNA within ribosome precursors.


[18F]FLT-PET to predict pharmacodynamic and clinical response to cetuximab therapy in Ménétrier's disease.
Molecular imaging biomarkers of proliferation hold great promise for quantifying response to personalized medicine. One such approach utilizes the positron emission tomography (PET) tracer 3'-deoxy-3'[18F]-fluorothymidine ([18F]FLT), an investigational agent whose uptake reflects thymidine salvage-dependent DNA synthesis. The goal of this study was to evaluate [18F]FLT-PET in the setting of Ménétrier's disease (MD), a rare, premalignant hyperproliferative disorder of the stomach treatable with cetuximab therapy. Over 15 months, a patient with confirmed MD underwent cetuximab therapy and was followed with sequential [18F]FLT-PET. For comparison to MD, an [18F]FLT-PET study was conducted in another patient to quantify uptake in a normal stomach. Prior to cetuximab therapy, stomach tissue in MD was easily visualized with [18F]FLT-PET, with pre-treatment uptake levels exceeding normal stomach uptake by approximately fourfold. Diminished [18F]FLT-PET in MD was observed following the initial and subsequent doses of cetuximab and correlated with clinical resolution of the disease. To our knowledge, this study reports the first clinical use of [18F]FLT-PET to assess proliferation in a premalignant disorder. We illustrate that the extent of MD involvement throughout the stomach could be easily visualized using [18F]FLT-PET, and that response to cetuximab could be followed quantitatively and non-invasively in sequential [18F]FLT-PET studies. Thus, [18F]FLT-PET appears to have potential to monitor response to treatment in this and potentially other hyperproliferative disorders.


Differential effect of alcoholism and HIV infection on visuomotor procedural learning and retention.
Selective declarative memory processes are differentially compromised in chronic alcoholism (ALC) and HIV infection (HIV) and likely reflect neuropathology associated with each condition: frontocerebellar dysfunction in ALC and frontostriatal dysfunction in HIV infection. Evidence for disease overlap derives from observed exacerbated impairments in these declarative memory processes in ALC-HIV comorbidity. Less is known about nondeclarative memory processes in these disease conditions. Examination of visuomotor learning in chronic ALC and HIV infection could provide insight into the differential and combined contribution of selective disease-related injury to visuomotor procedural memory processes. We examined component processes of visuomotor learning and retention on the rotary pursuit task in 29 ALC, 23 HIV, 28 ALC + HIV, and 20 control subjects. Participants were given 4 rotary pursuit learning sessions over 2 testing days, typically separated by 1 week, to assess visuomotor learning and retention patterns. Ancillary measures of simple motor, psychomotor, explicit memory, and balance abilities were administered to test which component processes independently predicted visuomotor learning. All clinical groups showed visuomotor learning across rotary pursuit testing sessions, despite impairment in visuomotor speed in the HIV groups and impairment in explicit memory and psychomotor speed in the alcohol groups. The 2 alcoholic groups showed retention and consolidation over time (i.e., improved performance without further training), whereas the HIV-infected group showed learning and retention but no consolidation effect. The comorbid group shared impairments associated with the ALC-only group (explicit memory and psychomotor speed) and the HIV-only group (visuomotor speed), although there was no clear compounded effect of alcohol and HIV infection on visuomotor learning performance. This study supports the hypothesis that ALC and HIV infection exert differential effects on components of visuomotor procedural learning. Further, the results provide behavioral evidence for dissociable influences of frontocerebellar and frontostriatal disruption to visuomotor procedural learning and retention.


Vision Disturbances Following Traumatic Brain Injury.
Vision disturbances following traumatic brain injury (TBI) include anomalies of accommodation, version, vergence (nonstrabismic, as well as strabismic), photosensitivity, visual field integrity, and ocular health. Traumatic brain injury patients with complex diplopia patterns, noncomitant strabismic anomalies, and advanced ocular health anomalies are either monitored by or referred to neuro-ophthalmologists and ophthalmologists for evaluation and possible surgical or medical intervention, as needed. Anomalies of accommodation, vergence, version, photosensitivity, and field of vision are amenable to noninvasive, rehabilitative interventions, such as vision therapy, which is rendered by optometrists and is described in this article. Further, vision therapy may be performed in isolation or in conjunction with the application of the following: Fusional prism spectacles (for diplopia) Tinted spectacles (for photosensitivity) Yoked prism spectacles (for visual-spatial hemispheric inattention, with or without a manifest visual field defect), as appropriate Dependent on the severity of vision impairment post-TBI, other types of rehabilitation, such as vestibular, physical, cognitive, and occupational rehabilitation, are deferred pending the stabilization of vision function to an appropriate level. Rehabilitative optometric intervention is appropriate and beneficial for many TBI patients. Therefore, it should be offered as a possible evaluation and treatment option to investigate the patient's symptoms and determine the prognosis for treatment, as would be done with any other therapeutic modality.


Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation.
Pathogens often persist during infection because of antigenic variation in which they evade immunity by switching between distinct surface antigen variants. A central question is how ordered appearance of variants, an important determinant of chronicity, is achieved. Theories suggest that it results directly from a complex pattern of transition connectivity between variants or indirectly from effects such as immune cross-reactivity or differential variant growth rates. Using a mathematical model based only on known infection variables, we show that order in trypanosome infections can be explained more parsimoniously by a simpler combination of two key parasite-intrinsic factors: differential activation rates of parasite variant surface glycoprotein (VSG) genes and density-dependent parasite differentiation. The model outcomes concur with empirical evidence that several variants are expressed simultaneously and that parasitaemia peaks correlate with VSG genes within distinct activation probability groups. Our findings provide a possible explanation for the enormity of the recently sequenced VSG silent archive and have important implications for field transmission.


The COVID-19 Pandemic and Internal Labour Migration in India: A 'Crisis of Mobility'.
This paper examines the impact of COVID-19 pandemic on migration. The rapid spread of the pandemic caught countries across the world off guard, resulting in widespread lockdowns that clamped down on mobility, commercial activities and social interactions. In India, the pandemic precipitated a severe 'crisis of mobility', with migrant labourers in many major cities seeking to return to their hometowns. Their desperate attempts to return home by any means available rendered the lockdown ineffective in several areas, prompting clashes with authorities, last-minute policy relief and, eventually, the arrangement of transport measures. This paper aims to shed light on the vulnerability of India's internal migrants in terms of their mobility, gender and mental health. In addition, it critically analyses the limitations of public policy in addressing migrants and suggests recommendations for the way ahead.


Warning symptoms and family history in children and young adults with sudden cardiac arrest.
Children and young adults with undiagnosed cardiovascular disorders at risk for sudden death may have warning symptoms or significant family history that is detectable through screening. The objective of this study was to determine the prevalence of warning symptoms and family history in a cohort of children and young adults who suffered sudden cardiac arrest (SCA). A retrospective survey investigating warning symptoms and family history of cardiovascular disease was completed by families with a child or young adult who suffered SCA. Eighty-seven of 146 families (60%) returned a completed survey. The SCA victims were an average age of 16 years (range, <5-29 years), 69% male, and 68% white. Seventy-two percent of SCA victims were reported by their parents to have at least one cardiovascular symptom before SCA, with fatigue (44%) and near-syncope/lightheadedness (30%) the two most common. Twenty-four percent of SCA victims had one or more (average 2.6; range, 1 to 10) events of syncope or unexplained seizure that remained undiagnosed as a cardiac disorder before SCA. Parents reported that cardiovascular symptoms first occurred, on average, 30 months (range, 19 to 71 months) before SCA; a symptom was brought to the attention of the child's physician in 41% of cases. Twenty-seven percent of families reported a family member had suffered sudden death before age 50 because of a heart condition. Many children and young adults who suffered SCA are reported to have cardiac symptoms or a family history of premature cardiac death. Syncope and unexplained seizure activity are distinct events but often go unrecognized as ominous signs of underlying cardiovascular disease. Physician education and increased public awareness regarding cardiovascular warning signs in the young may improve early detection of those at risk and prevent tragedies.


Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.
Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).


Chemometric analysis of integrated FTIR and Raman spectra obtained by non-invasive exfoliative cytology for the screening of oral cancer.
FTIR spectroscopy and Raman spectroscopy of biological analytes are increasingly explored as screening tools for early detection of cancer. In the present study, an integrated analysis of the FTIR and Raman spectra obtained from exfoliated cells is adopted to improve discrimination of normal, pre-cancerous and cancerous conditions. Multiple spectra were obtained from 13 normal, 13 pre-cancer and 10 cancer patients in both modes. Compared to normal patients, significant differences were observed at 1550, 1580, 1640, 2370, 2330, 2950-3000 and 3650-3750 cm-1 (FTIR) and 520, 640, 785, 827, 850, 935, 1003, 1175, 1311 cm-1 and 1606 cm-1 (Raman) vibrations of the other two. The increase in DNA, protein and lipid content with malignancy was more clearly elucidated by examining both spectra. Principal component analysis (PCA)-linear discriminant analysis (LDA) with 10-fold cross validation of the FTIR and Raman spectral data sets showed efficient discrimination between normal and pathological conditions while overlapping was seen between the two pathologies. The PCA-LDA model of the dual spectra yielded a classification accuracy of 98% in comparison with either FTIR (85%) or Raman (82%) in a spectrum-wise comparison. In the patient-wise approach (mean of all spectra from a patient), the overall classification efficiency was 73%, 80% and 87% for FTIR, Raman and integrated spectral approaches respectively. Moreover, the efficiency of the integrated FTIR-Raman PCA-LDA model as a prediction tool was tested to screen susceptible individuals (11 cigarette smokers) using the dual spectra acquired from these individuals. The study presents proof-of-concept for adopting a large-scale, follow-up trial of the approach for mass screening purposes.


CDX2 and villin are useful markers of intestinal metaplasia in the diagnosis of Barrett esophagus.
The identification of intestinal metaplasia (IM) in the esophagus is necessary for the selection of patients with Barrett esophagus (BE) for surveillance. We studied 108 esophageal biopsy and resection specimens, clinically diagnosed as BE, and stained them for CDX2, villin, HepPar-1, and cytokeratin (CK) 7 to investigate sensitivity for identifying IM. H&E-stained sections showed definite goblet cells in 94 cases. CDX2 and villin were positive in all 94 cases. Of 38 cardia- and 9 fundic-type mucosa samples associated with BE, 13 (34%) and 0 (0%) displayed CDX2 positivity and 21 (55%) and 1 (11%) displayed villin positivity, respectively. HepPar-1 was positive in 54 (57%) of 94 cases with IM and negative in the associated cardia- and fundic-type mucosa. A full-thickness CK7 staining pattern was present in 90 (96%) of samples with IM and 22 (58%) and 0 (0%) of the associated cardia- and fundic-type mucosa, respectively. None of 20 control samples of morphologically normal gastric mucosa stained for CDX2 or villin. CDX2 and villin are sensitive markers for early-stage IM and can supplement the histologic identification of this premalignant condition in the esophagus.


Hypo-activity screening in school setting; examining reliability and validity of the Teacher Estimation of Activity Form (TEAF).
It is well established that physical activity during childhood contributes to children's physical and psychological health. The aim of this study was to test the reliability and validity of the Hebrew version of the Teacher Estimation of Activity Form (TEAF) questionnaire as a screening tool among school-aged children in Israel. Six physical education teachers completed TEAF questionnaires of 123 children aged 5-12 years, 68 children (55%) with Typical Development (TD) and 55 children (45%) diagnosed with Developmental Coordination Disorder (DCD). The Hebrew version of the TEAF indicates a very high level of internal consistency (α = .97). There were no significant gender differences. Significant differences were found between children with and without DCD attesting to the test's construct validity. Concurrent validity was established by finding a significant high correlation (r = .76, p < .01) between the TEAF and the Movement-ABC mean scores within the DCD group. The TEAF demonstrated acceptable reliability and validity estimates. It appears to be a promising standardized practical tool in both research and practice for describing information about school-aged children's involvement in physical activity. Further research is indicated with larger samples to establish cut-off scores determining what point identifies hypo activity in striated age groups. Furthermore, the majority of the participants in this study were boys, and further research is needed to include more girls for a better understanding of the phenomena of hypo activity.


Mitochondrial import and processing of rat liver carnitine palmitoyltransferase II defines the amino terminus of the mature protein. Possibility of differential modification of the rat and human isoforms.
[35S]Methionine-labeled porcine heart citrate synthase (used here as a positive control) and rat liver carnitine palmitoyltransferase II (CPT II) were generated by in vitro transcription and translation of their cDNA constructs in appropriate Bluescript plasmids. Each product was imported into rat liver mitochondria in an energy-dependent manner to yield an immunoprecipitable protein of smaller size that comigrated with the corresponding purified enzyme. The size shift occurring with citrate synthase was consistent with the removal of the postulated 27-amino acid leader peptide. To determine the amino terminus of mature CPT II, [35S]methionine- or [3H]leucine-labeled material (after import and processing) was subjected to Edman degradation, followed by counting of the radioactivity released on each cycle. The results established that the precursor targeting peptide was cleaved between leucine 25 and serine 26 in the previously deduced amino acid sequence. Taken in conjunction with the recent report of Finocchiaro et al. (Finocchiaro, G., Taroni, F., Rocchi, M., Martin, A. L., Colombo, I., Tarelli, G. T., and DiDonato, S. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 661-665), the present results establish three key points concerning the rat and human forms of CPT II. First, it appears that in both species the initial translation product contains 658 amino acids and, upon mitochondrial import, is reduced in length by 25 residues through cleavage at an identical site. Second, the difference in electrophoretic mobility between the two mature proteins (documented earlier) presumably reflects either anomalous behavior of one of them on polyacrylamide gels or differential covalent modification. Finally, the recent suggestion by Brady et al. (Brady, P. S., Liu, J. S., Park, E. A., Hanson, R. W., and Brady, L. J. (1991) FASEB J. 5, A817) that our CPT II cDNA construct is incomplete in the 5'-coding region is refuted.


Epidemiology, transmission dynamics and control of SARS: the 2002-2003 epidemic.
This paper reviews current understanding of the epidemiology, transmission dynamics and control of the aetiological agent of severe acute respiratory syndrome (SARS). We present analyses of data on key parameters and distributions and discuss the processes of data capture, analysis and public health policy formulation during the SARS epidemic are discussed. The low transmissibility of the virus, combined with the onset of peak infectiousness following the onset of clinical symptoms of disease, transpired to make simple public health measures, such as isolating patients and quarantining their contacts, very effective in the control of the SARS epidemic. We conclude that we were lucky this time round, but may not be so with the next epidemic outbreak of a novel aetiological agent. We present analyses that help to further understanding of what intervention measures are likely to work best with infectious agents of defined biological and epidemiological properties. These lessons learnt from the SARS experience are presented in an epidemiological and public health context.


Under Pressure: The Chronic Effects of Lower-Body Compression Garment Use during a 6-Week Military Training Course.
Background: Previous studies have shown that compression garments may aid recovery in acute settings; however, less is known about the long-term use of compression garments (CG) for recovery. This study aimed to assess the influence of wearing CG on changes in physical performance, subjective soreness, and sleep quality over 6 weeks of military training. Methods: Fifty-five officer-trainees aged 24 ± 6 y from the New Zealand Defence Force participated in the current study. Twenty-seven participants wore CG every evening for 4−6 h, and twenty-eight wore standard military attire (CON) over a 6-week period. Subjective questionnaires (soreness and sleep quality) were completed weekly, and 2.4 km run time-trial, maximum press-ups, and curl-ups were tested before and after the 6 weeks of military training. Results: Repeated measures ANOVA indicated no significant group × time interactions for performance measures (p > 0.05). However, there were small effects in favour of CG over CON for improvements in 2.4 km run times (d = −0.24) and press-ups (d = 0.36), respectively. Subjective soreness also resulted in no significant group × time interaction but displayed small to moderate effects for reduced soreness in favour of CG. Conclusions: Though not statistically significant, CG provided small to moderate benefits to muscle-soreness and small benefits to aspects of physical-performance over a 6-week military training regime.


Altered miRNAs expression profiling in sperm of mice induced by fluoride.
The reproductive toxicity of fluoride has become a major concern in the world. Fluoride can decrease the abilities of sperm capacitation, hyperactivation, chemotaxis, acrosome reaction and fertilization, but the studies on the responses of sperm small noncoding RNAs (sncRNAs), especially miRNAs, to fluoride exposure are lacking. miRNAs are demonstrated to influence sperm quality and male fertility by regulating gene expression at post-transcriptional levels or translational repression. The objective of this study is to analyze miRNA profiling in sperm of mice administrated with 25 and 100 mg L(-1) sodium fluoride (NaF) for 60 d using high-throughput sequencing technology. Along with reduced sperm concentration, survival, motility, and mitochondrial membrane potential, 31 differentially expressed known miRNAs were identified in fluoride groups, compared with the control group. 671 predicted target genes against the 16 altered miRNAs were mainly involved in protease inhibitor activity, apoptosis, ubiquitin mediated proteolysis, and signaling pathways of calcium, JAK-STAT, MAPK, p53, Wnt, which were proved to be directly related to sperm quality. These findings suggested that the altered sperm miRNAs could be potential biomarkers for fluoride reproductive toxicity.


Antineutrophil cytoplasmic antibodies in chronic liver diseases: prevalence, titre, specificity and IgG subclass.
Antineutrophil cytoplasmic antibodies are reported in patients with chronic liver disease, but controversy exists about their prevalence and specificity. We aimed to find the prevalence and specificity of antineutrophil cytoplasmic antibodies in chronic liver diseases by determination of antineutrophil cytoplasmic antibody titre and IgG subclass. One hundred and eight-four sera were studied: 63 primary sclerosing cholangitis, 28 autoimmune hepatitis, 34 primary biliary cirrhosis, 12 alcoholic liver disease, five large duct obstruction, four haemochromatosis, one chronic cholestatic syndrome, one cryptogenic cirrhosis and 36 normal individuals. Antineutrophil cytoplasmic antibodies were detected on alcohol-fixed neutrophils using an alkaline phosphatase technique. The IgG subclass of antineutrophil cytoplasmic antibodies was determined using monoclonal antibodies: HP 6001 for IgG1, HP 6002 for IgG2, HP 6050 for IgG3 and SK 44 for IgG4 (Sigma Immunochemicals). Antineutrophil cytoplasmic antibodies were detected in 65% of primary sclerosing cholangitis patients at a serum dilution of 1:5, dropping to 49% at 1:50. For autoimmune hepatitis, antineutrophil cytoplasmic antibodies were detected in 49% at 1:5, dropping to 11% at 1:50. Only 6% of primary biliary cirrhosis patients were antineutrophil cytoplasmic antibody-positive at 1:5, dropping to 3% at 1:50. All other controls were antineutrophil cytoplasmic antibody negative at 1:5. The presence of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis correlated with involvement of the intra- and extrahepatic biliary tree (p = 0.016, Fisher's exact test), but no other clinical parameters. Determination of the IgG subclass of antineutrophil cytoplasmic antibody in 33 primary sclerosing cholangitis and 11 autoimmune hepatitis patients revealed a predominance of IgG1 in both groups (94% and 82% of all IgG antineutrophil cytoplasmic antibodies, respectively), with a similar distribution of IgG2, IgG3 and IgG4 antineutrophil cytoplasmic antibodies between the groups. Antineutrophil cytoplasmic antibodies are specific to the autoimmune liver diseases, particularly primary sclerosing cholangitis and autoimmune hepatitis. Titres are highest in primary sclerosing cholangitis, with a diagnostic sensitivity of 49% and specificity of 89% at 1:50, making it a useful serological marker for this disease. The lack of correlation with any marker of activity and the association of antineutrophil cytoplasmic antibody with extent of biliary tract involvement suggest that antineutrophil cytoplasmic antibodies arises as a result of the disease or related process rather than being a cause of it. The detection of antineutrophil cytoplasmic antibodies in autoimmune hepatitis, together with a similar IgG subclass distribution of primary sclerosing cholangitis and autoimmune hepatitis antineutrophil cytoplasmic antibodies, may reflect similar mechanisms of immune regulation and a possible overlap syndrome. Future identification of the antigens against which this antineutrophil cytoplasmic antibody are directed should help to clarify this point, as well as allowing the development of a more sensitive and specific serological test for diagnostic purposes.


Variants in nicotinic receptors and risk for nicotine dependence.
A recent study provisionally identified numerous genetic variants as risk factors for the transition from smoking to the development of nicotine dependence, including an amino acid change in the alpha5 nicotinic cholinergic receptor (CHRNA5). The purpose of this study was to replicate these findings in an independent data set and more thoroughly investigate the role of genetic variation in the cluster of physically linked nicotinic receptors, CHRNA5-CHRNA3-CHRNB4, and the risk of smoking. Individuals from 219 European American families (N=2,284) were genotyped across this gene cluster to test the genetic association with smoking. The frequency of the amino acid variant (rs16969968) was studied in 995 individuals from diverse ethnic populations. In vitro studies were performed to directly test whether the amino acid variant in the CHRNA5 influences receptor function. A genetic variant marking an amino acid change showed association with the smoking phenotype (p=0.007). This variant is within a highly conserved region across nonhuman species, but its frequency varied across human populations (0% in African populations to 37% in European populations). Furthermore, functional studies demonstrated that the risk allele decreased response to a nicotine agonist. A second independent finding was seen at rs578776 (p=0.003), and the functional significance of this association remains unknown. This study confirms that at least two independent variants in this nicotinic receptor gene cluster contribute to the development of habitual smoking in some populations, and it underscores the importance of multiple genetic variants contributing to the development of common diseases in various populations.


Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice.
Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.


The influence of internship training experience on Kenyan and Ugandan doctors' career intentions and decisions: a qualitative study.
Medical internship is a key period for doctors' individual career planning and also a transition period for the broader labour market. We aimed to understand the complex set of factors influencing the career intentions and decisions of junior doctors, post-internship in Kenya and Uganda. We conducted semi-structured interviews with 54 junior medical officers and 14 consultants to understand doctors' internship experiences and subsequent employment experiences. We analysed the data using a mix of a direct content approach, informed by an internship experience and career intentions framework developed primarily from high-income country literature, alongside a more inductive thematic analysis. Echoing the internship experience and career intentions framework, we found that clinical exposure during internship, work-life balance, aspects of workplace culture such as relationships with consultants and other team members, and concerns over future job security and professional development all influenced Kenyan and Ugandan doctors' career preferences. Additionally, we added a new category to the framework to reflect our finding that interns might want to 'fill a health system gap' when they choose their future careers, based on what they witness as interns. However, often career intentions did not match career and employment decisions due to specific contextual factors, most importantly a shortage of job opportunities. We have shown how internship experiences shape medical doctors' career intentions in Kenya and Uganda and highlighted the importance of job availability and context in influencing doctors' career choices.


Carriage and fecal counts of cefotaxime M-producing Escherichia coli in pigs: a longitudinal study.
Current knowledge on extended-spectrum beta-lactamases (ESBLs) in animals is based largely on cross-sectional studies and qualitative data. The aim of this longitudinal study was to elucidate carriage proportions and fecal counts of ESBL-producing Escherichia coli in pigs during the production cycle. At each of three ESBL-positive single-sited farrow-to-finisher pig farms (farms A, B, and C) included in the study, individual fecal samples were taken from 17 to 20 sows 1 week before farrowing and from 2 piglets of each sow's litter four times from birth to slaughter (as piglets, weaners, and finishers). Cefotaxime (CTX)-resistant coliforms in feces were counted on MacConkey agar containing 2 μg/ml CTX and characterized for the presence of ESBL-encoding genes by PCR and sequencing. CTX-M-positive pigs were detected in all age groups at farms A (bla(CTX-M-9) group, compatible with bla(CTX-M-14/17)) and B (bla(CTX-M-1) group, compatible with bla(CTX-M-1/61)), whereas only three weaners were positive at farm C (bla(CTX-M-1) group, compatible with bla(CTX-M-1/61)). A significant decrease in carriage was detected during the production cycle, with on average 50% carriage immediately after birth, 58% just before weaning, 29% during weaning, and 12% during finishing. The observed reduction in numbers of CTX-M-positive pigs was accompanied by a significant reduction in mean fecal counts of CTX-resistant coliforms from ~10(7) CFU/g in piglets to ~10(3) CFU/g in finishers (P < 0.001). These findings provide novel information about the epidemiology of ESBLs at the farm level and have important implications for assessments of risks of meat contamination during slaughter.


The diagnosis of postprandial hypoglycemia.
Our observation that hypoglycemia, often self-diagnosed by our patients, was seldom confirmed led the authors to establish norms for the glucose tolerance test. We first obtained values for 650 patients who were entirely free from symptoms before and during testing. The median nadir in this group was 64 mg/dl. Ten percent of the patients had plasma glucose nadirs of 47 mg/dl or below and 2.5% had values of 39 mg/dl or less. Utilizing these values in combination with clinical criteria, we confirmed hypoglycemia after glucose load in 16 (median nadir 39.5 mg/dl) of 118 patients presenting with this diagnosis, and only 5 of the 16 were hypoglycemic after their usual meals. The other 102 patients, whose many complaints were unrelated to measured plasma glucose levels, had nadirs similar to those of the control group. Placebo tests performed on 14 nonhypoglycemic patients provoked symptoms (recorded by the patients themselves) and they considered indicative of hypoglycemia. Some accepted other diagnoses after we demonstrated that their symptoms occurred when they were normoglycemic. Since nadirs of hypoglycemics and control subjects overlap, we conclude that accurate diagnosis of hypoglycemia requires that symptoms develop concurrently with low blood sugar and that they are absent at other times. Low plasma glucose must be considered only one of the criteria in diagnosing functional hypoglycemia along with a relationship between food intake, timing of symptoms, correlation of symptoms and low glucose levels, and reproducibility of test results.


Telomere length of anterior crucial ligament after rupture: similar telomere length in injured and noninjured ACL portions.
The regeneration of ligaments following injury is a slow process compared to the healing of many other tissues and the underlying mechanisms remain unknown. The purpose of the study was to evaluate the proliferative potential of ligaments by assessing telomere length within three distinct parts of human anterior cruciate ligament (ACL) obtained during ACL reconstruction: the macroscopically injured proximal part and macroscopically noninjured mid- and distal portions in eight subjects (age 28 ± 8 years). The mean telomere length in ACL was within normal range of values usually reported for other tissues indicating that the endogenous machinery responsible for the proliferative potential of ligament is not implicated in its poor healing capacity. The three ACL parts showed similar mean TRF lengths (distal part: 11.5 ± 0.8 kbp, mid-portion: 11.8 ± 1.2 kbp, proximal part: 11.9 ± 1.6 kbp) and there was no relationship between mean telomere length in ACL and the healing duration after rupture. This implies that despite the occurrence of ligament repair including a phase of intense cell proliferation the proliferative potential of ruptured ACL is not impaired. This knowledge is important for scientists and clinicians aiming to understand the mechanisms behind the low healing capacity of ligament.


Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.
The impact of nonrheumatic atrial fibrillation, hypertension, coronary heart disease, and cardiac failure on stroke incidence was examined in 5,070 participants in the Framingham Study after 34 years of follow-up. Compared with subjects free of these conditions, the age-adjusted incidence of stroke was more than doubled in the presence of coronary heart disease (p less than 0.001) and more than trebled in the presence of hypertension (p less than 0.001). There was a more than fourfold excess of stroke in subjects with cardiac failure (p less than 0.001) and a near fivefold excess when atrial fibrillation was present (p less than 0.001). In persons with coronary heart disease or cardiac failure, atrial fibrillation doubled the stroke risk in men and trebled the risk in women. With increasing age the effects of hypertension, coronary heart disease, and cardiac failure on the risk of stroke became progressively weaker (p less than 0.05). Advancing age, however, did not reduce the significant impact of atrial fibrillation. For persons aged 80-89 years, atrial fibrillation was the sole cardiovascular condition to exert an independent effect on stroke incidence (p less than 0.001). The attributable risk of stroke for all cardiovascular contributors decreased with age except for atrial fibrillation, for which the attributable risk increased significantly (p less than 0.01), rising from 1.5% for those aged 50-59 years to 23.5% for those aged 80-89 years. While these findings highlight the impact of each cardiovascular condition on the risk of stroke, the data suggest that the elderly are particularly vulnerable to stroke when atrial fibrillation is present.(ABSTRACT TRUNCATED AT 250 WORDS)


Identification and characterization of cyclic diguanylate signaling systems controlling rugosity in Vibrio cholerae.
Vibrio cholerae, the causative agent of the disease cholera, can generate rugose variants that have an increased capacity to form biofilms. Rugosity and biofilm formation are critical for the environmental survival and transmission of the pathogen, and these processes are controlled by cyclic diguanylate (c-di-GMP) signaling systems. c-di-GMP is produced by diguanylate cyclases (DGCs) and degraded by phosphodiesterases (PDEs). Proteins that contain GGDEF domains act as DGCs, whereas proteins that contain EAL or HD-GYP domains act as PDEs. In the V. cholerae genome there are 62 genes that are predicted to encode proteins capable of modulating the cellular c-di-GMP concentration. We previously identified two DGCs, VpvC and CdgA, that can control the switch between smooth and rugose. To identify other c-di-GMP signaling proteins involved in rugosity, we generated in-frame deletion mutants of all genes predicted to encode proteins with GGDEF and EAL domains and then searched for mutants with altered rugosity. In this study, we identified two new genes, cdgG and cdgH, involved in rugosity control. We determined that CdgH acts as a DGC and positively regulates rugosity, whereas CdgG does not have DGC activity and negatively regulates rugosity. In addition, epistasis analysis with CdgG, CdgH, and other DGCs and PDEs controlling rugosity revealed that CdgG and CdgH act in parallel with previously identified c-di-GMP signaling proteins to control rugosity in V. cholerae. We also determined that PilZ domain-containing c-di-GMP binding proteins contribute minimally to rugosity, indicating that there are additional c-di-GMP binding proteins controlling rugosity in V. cholerae.


Changes in the gene expression profiles of the brains of male European eels (Anguilla anguilla) during sexual maturation.
The vertebrate brain plays a critical role in the regulation of sexual maturation and reproduction by integrating environmental information with developmental and endocrine status. The European eel Anguilla anguilla is an important species in which to better understand the neuroendocrine factors that control reproduction because it is an endangered species, has a complex life cycle that includes two extreme long distance migrations with both freshwater and seawater stages and because it occupies a key position within the teleost phylogeny. At present, mature eels have never been caught in the wild and little is known about most aspects of reproduction in A. anguilla. The goal of this study was to identify genes that may be involved in sexual maturation in experimentally matured eels. For this, we used microarrays to compare the gene expression profiles of sexually mature to immature males. Using a false discovery rate of 0.05, a total of 1,497 differentially expressed genes were identified. Of this set, 991 were expressed at higher levels in brains (forebrain and midbrain) of mature males while 506 were expressed at lower levels relative to brains of immature males. The set of up-regulated genes includes genes involved in neuroendocrine processes, cell-cell signaling, neurogenesis and development. Interestingly, while genes involved in immune system function were down-regulated in the brains of mature males, changes in the expression levels of several receptors and channels were observed suggesting that some rewiring is occurring in the brain at sexual maturity. This study shows that the brains of eels undergo major changes at the molecular level at sexual maturity that may include re-organization at the cellular level. Here, we have defined a set of genes that help to understand the molecular mechanisms controlling reproduction in eels. Some of these genes have previously described functions while many others have roles that have yet to be characterized in a reproductive context. Since most of the genes examined here have orthologs in other vertebrates, the results of this study will contribute to the body of knowledge concerning reproduction in vertebrates as well as to an improved understanding of eel biology.


Interfacial charge rearrangement and intermolecular interactions: Density-functional theory study of free-base porphine adsorbed on Ag(111) and Cu(111).
We employ dispersion-corrected density-functional theory to study the adsorption of tetrapyrrole 2H-porphine (2H-P) at Cu(111) and Ag(111). Various contributions to adsorbate-substrate and adsorbate-adsorbate interactions are systematically extracted to analyze the self-assembly behavior of this basic building block to porphyrin-based metal-organic nanostructures. This analysis reveals a surprising importance of substrate-mediated van der Waals interactions between 2H-P molecules, in contrast to negligible direct dispersive interactions. The resulting net repulsive interactions rationalize the experimentally observed tendency for single molecule adsorption.