Reproductive effects in birds exposed to pesticides and industrial chemicals.
Environmental contamination by agricultural chemicals and industrial waste disposal results in adverse effects on reproduction of exposed birds. The diversity of pollutants results in physiological effects at several levels, including direct effects on breeding adults as well as developmental effects on embryos. The effects on embryos include mortality or reduced hatchability, failure of chicks to thrive (wasting syndrome), and teratological effects producing skeletal abnormalities and impaired differentiation of the reproductive and nervous systems through mechanisms of hormonal mimicking of estrogens. The range of chemical effects on adult birds covers acute mortality, sublethal stress, reduced fertility, suppression of egg formation, eggshell thinning, and impaired incubation and chick rearing behaviors. The types of pollutants shown to cause reproductive effects include organochlorine pesticides and industrial pollutants, organophosphate pesticides, petroleum hydrocarbons, heavy metals, and in a fewer number of reports, herbicides, and fungicides. o,p'-DDT, polychlorinated biphenyls (PCBs), and mixtures of organochlorines have been identified as environmental estrogens affecting populations of gulls breeding in polluted "hot spots" in southern California, the Great Lakes, and Puget Sound. Estrogenic organochlorines represent an important class of toxicants to birds because differentiation of the avian reproductive system is estrogen dependent.


A new applicator design for endocavitary brachytherapy of cancer in the nasopharynx.
In attempting to improve local tumor control by higher doses of radiation, there has been a resurgence of interest in the implementation of brachytherapy in the management of primary and recurrent cancers of the nasopharynx. Brachytherapy with its steep dose fall-off is of particular interest because of the proximity of critical dose limiting structures. Recent developments in brachytherapy, such as the introduction of pulsed-dose-rate and high-dose-rate computerized afterloaders, have encouraged further evolution of brachytherapy techniques. We have designed an inexpensive, re-usable and flexible silicone applicator, tailored to the shape of the soft tissues of the nasopharynx, which can be used with either low-dose-rate brachytherapy or high (pulsed)-dose-rate remote controlled afterloaders. This Rotterdam nasopharynx applicator proved to be easy to introduce, patient friendly and can remain in situ for the duration of the treatment (2-6 days). The design, technique of application and the first consecutive 5 years of clinical experience in using this applicator are presented.


Presence of infectious agents and co-infections in diarrheic dogs determined with a real-time polymerase chain reaction-based panel.
Infectious diarrhea can be caused by bacteria, viruses, or protozoan organisms, or a combination of these. The identification of co-infections in dogs is important to determine the prognosis and to plan strategies for their treatment and prophylaxis. Although many pathogens have been individually detected with real-time polymerase chain reaction (PCR), a comprehensive panel of agents that cause diarrhea in privately owned dogs has not yet been established. The objective of this study was to use a real-time PCR diarrhea panel to survey the frequencies of pathogens and co-infections in owned dogs attended in a veterinary hospital with and without diarrhea, as well the frequency in different countries. Feces samples were tested for canine distemper virus, canine coronavirus, canine parvovirus type 2 (CPV-2), Clostridium perfringens alpha toxin (CPA), Cryptosporidium spp., Giardia spp., and Salmonella spp. using molecular techniques. In total, 104 diarrheic and 43 control dogs that were presented consecutively at a major private veterinary hospital were included in the study. Overall, 71/104 (68.3%) dogs with diarrhea were positive for at least one pathogen: a single infection in 39/71 dogs (54.9%) and co-infections in 32/71 dogs (45.1%), including 21/32 dogs (65.6%) with dual, 5/32 (15.6%) with triple, and 6/32 (18.8%) with quadruple infections. In the control group, 13/43 (30.2%) dogs were positive, all with single infections only. The most prevalent pathogens in the diarrheic dogs were CPA (40/104 dogs, 38.5%), CPV-2 (36/104 dogs, 34.6%), and Giardia spp. (14/104 dogs, 13.5%). CPV-2 was the most prevalent pathogen in the dual co-infections, associated with CPA, Cryptosporidium spp., or Giardia spp. No statistical difference (P = 0.8374) was observed in the duration of diarrhea or the number of deaths (P = 0.5722) in the presence or absence of single or co-infections. Diarrheic dogs showed a higher prevalence of pathogen infections than the controls. Whereas the healthy dogs had only single infections, about half the diarrheic dogs had co-infections. Therefore, multiple pathogens should be investigated in dogs presenting with diarrhea. The effects of multiple pathogens on the disease outcomes remain unclear because the rate of death and the duration of diarrhea did not seem to be affected by these factors.


Pregnancy differentially regulates the collagens types I and III in left ventricle from rat heart.
The pathologic cardiac remodeling has been widely documented; however, the physiological cardiac remodeling induced by pregnancy and its reversion in postpartum are poorly understood. In the present study we investigated the changes in collagen I (Col I) and collagen III (Col III) mRNA and protein levels in left ventricle from rat heart during pregnancy and postpartum. Col I and Col III mRNA expression in left ventricle samples during pregnancy and postpartum were analyzed by using quantitative PCR. Data obtained from gene expression show that Col I and Col III in left ventricle are upregulated during pregnancy with reversion in postpartum. In contrast to gene expression, the protein expression evaluated by western blot showed that Col I is downregulated and Col III is upregulated in left ventricle during pregnancy. In conclusion, the pregnancy differentially regulates collagens types I and III in heart; this finding could be an important molecular mechanism that regulates the ventricular stiffness in response to blood volume overload present during pregnancy which is reversed in postpartum.


HIV treatment as prevention: how scientific discovery occurred and translated rapidly into policy for the global response.
In 2011 interim results of HIV Prevention Trials Network study 052, a National Institutes of Health study designed to test the effectiveness of antiretroviral treatment against the spread of HIV, were reported. These results showed that in a stable relationship in which one member of the couple was infected with HIV, treatment of the infected partner with antiretroviral drugs, combined with couples counseling and condom use, resulted in a 96 percent reduction in sexual transmission of HIV-1. This finding led to the use of antiretroviral treatment as a cornerstone of HIV prevention. Independent advisory committees of the President's Emergency Plan for AIDS Relief (PEPFAR) and the World Health Organization (WHO) have since issued analyses that set the stage for broader use of antiretroviral agents in treatment and prevention. This article describes the separate PEPFAR and WHO recommendations and outlines the design of prospective new trials to test how best to maximize the benefits of early treatment for prevention.


Bibliometric analysis of extracorporeal shock wave therapy for tendinopathy.
Extracorporeal shock wave therapy (ESWT) is a mature, conservative treatment modality for tendinopathy. Although many relevant studies have been conducted, systematic bibliometric studies are lacking. This study aimed to identify trends and hotspots in the treatment of tendinopathy using ESWT. A literature search was conducted on ESWT for tendinopathy using the Web of Science Core Collection with a search period of 2002 to 2022. Of 559 identified studies, 276 met the inclusion criteria and were analyzed using CiteSpace software. The results showed that from 2002 to 2022, the publication rate of literature on ESWT for tendinopathy was generally increasing. Research hotspots, such as tendinopathy and calcific rotator cuff deposits, began earlier but continued to receive scholarly attention. Research on animal models and molecular mechanisms has progressed slowly in this field. The combined or comparative effectiveness of injectable and supplement-based treatments with ESWT is a popular research topic. Pain management in patients with tendinopathy has received considerable attention. Simultaneously, more clinical indicators of energy levels and pulse parameters during ESWT are needed to provide more scientific and accurate treatment for patients.


P-N bond length alterations monitored by infrared absorption and Fourier transform Raman spectroscopy in combination with density functional theory calculations.
Fourier transform (FT) Raman and infrared spectroscopy in combination with density functional theory calculations have been applied to the vibrational characterization of the dimeric zinc diphenylphosphanyl(trimethylsilyl)amide complex [(Me3Si)2NZnPh2PNSiMe3]2 and the ortho-metallated species [Li(o-C6H4PPh2NSiMe3)]2 x Et2O in relation to their parent starting materials diphenylphosphanyl (trimethylsilyl)amine Ph2P-N(H)SiMe3 and iminophosphorane Ph3P=NSiMe3. The spectroscopic changes evidenced in the spectra were correlated with the structural parameters in order to provide insight as to what extent the P-N bond is affected by the coordination to the metal center. The employment of density functional theory (DFT) calculations in addition to these spectroscopic methods offers the possibility of predicting whether the Lewis-basic imido nitrogen atom is involved in coordination not only in the solid state, but also in the gas phase.


Cefiderocol.
Cefiderocol is a new siderophore cephalosporin with potent in vitro activity against gram-negative bacilli including Enterobacterales that produce all kinds of carbapenemases and non-fermenting Gram-negative with difficult-to-treat resistance. As a β-lactam, its efficacy is optimized in extended-perfusion and requires dose adjustment in renal dysfunction and hyperclearance. Its efficacy has been validated in three clinical trials, one of them in the treatment of hospital-acquired pneumonia and ventilator-associated pneumonia. The clinical trial aimed at difficult-to-treat gram-negatives achieved the clinical and microbiological target, but the increase in mortality observed in the cefiderocol arm makes it necessary to demonstrate efficacy in real clinical practice. Cefiderocol is a good option among the new β-lactams for the treatment of pneumonia caused by Gram-negative bacilli carbapenem-resistant.


Critical factors governing the difference in antizyme-binding affinities between human ornithine decarboxylase and antizyme inhibitor.
Both ornithine decarboxylase (ODC) and its regulatory protein, antizyme inhibitor (AZI), can bind with antizyme (AZ), but the latter has a higher AZ-binding affinity. The results of this study clearly identify the critical amino acid residues governing the difference in AZ-binding affinities between human ODC and AZI. Inhibition experiments using a series of ODC mutants suggested that residues 125 and 140 may be the key residues responsible for the differential AZ-binding affinities. The ODC_N125K/M140K double mutant demonstrated a significant inhibition by AZ, and the IC(50) value of this mutant was 0.08 µM, three-fold smaller than that of ODC_WT. Furthermore, the activity of the AZ-inhibited ODC_N125K/M140K enzyme was hardly rescued by AZI. The dissociation constant (K(d)) of the [ODC_N125K/M140K]-AZ heterodimer was approximately 0.02 µM, which is smaller than that of WT_ODC by approximately 10-fold and is very close to the K(d) value of AZI_WT, suggesting that ODC_N125K/M140K has an AZ-binding affinity higher than that of ODC_WT and similar to that of AZI. The efficiency of the AZI_K125N/K140M double mutant in the rescue of AZ-inhibited ODC enzyme activity was less than that of AZI_WT. The K(d) value of [AZI_K125N/K140M]-AZ was 0.18 µM, nine-fold larger than that of AZI_WT and close to the K(d) value of ODC_WT, suggesting that AZI_K125N/K140M has an AZ-binding affinity lower than that of AZI_WT and similar to that of ODC. These data support the hypothesis that the differences in residues 125 and 140 in ODC and AZI are responsible for the differential AZ-binding affinities.


The effect of photoisomerization on the enzymatic hydrolysis of polymeric micelles bearing photo-responsive azobenzene groups at their cores.
The design of stable polymeric micelles that can respond to specific stimuli is crucial for the development of smart micellar nanocarriers that can release their active cargo selectively at the target site, thus diminishing the therapeutic limitations due to non-selective damage to healthy tissues. Here we report the design and synthesis of photo- and enzyme-responsive amphiphilic PEG-dendron hybrids bearing one, two or four enzymatically cleavable azobenzene end-groups. These dual-responsive hybrids can respond to light through the reversible isomerization of the azobenzene end-groups from the non-polar trans isomer to the highly polar cis isomer and vice versa, upon UV and visible irradiation, respectively. The high structural precision of these hybrids, which emerges from the dendritic architecture, enabled a detailed study of the photoisomerization of the azobenzene end-groups with high molecular resolution. Remarkably, although the transition from trans-to-cis led to a significant increase in the polarity of the micellar cores, the micelles remained stable. Our kinetic studies show that although the trans isomer is a better substrate for the activating enzyme, the UV induced formation of the cis azobenzene end-groups led to significant acceleration of the enzymatic hydrolysis of the end-groups. These results provide strong indication that the enzyme cannot reach the core of the micelles and instead the end-groups have to leave the hydrophobic core in order to be exposed on the micelle's surface or even leave the micelle in order to allow their cleavage by the activating enzymes.


Human screams occupy a privileged niche in the communication soundscape.
Screaming is arguably one of the most relevant communication signals for survival in humans. Despite their practical relevance and their theoretical significance as innate [1] and virtually universal [2, 3] vocalizations, what makes screams a unique signal and how they are processed is not known. Here, we use acoustic analyses, psychophysical experiments, and neuroimaging to isolate those features that confer to screams their alarming nature, and we track their processing in the human brain. Using the modulation power spectrum (MPS [4, 5]), a recently developed, neurally informed characterization of sounds, we demonstrate that human screams cluster within restricted portion of the acoustic space (between ∼30 and 150 Hz modulation rates) that corresponds to a well-known perceptual attribute, roughness. In contrast to the received view that roughness is irrelevant for communication [6], our data reveal that the acoustic space occupied by the rough vocal regime is segregated from other signals, including speech, a pre-requisite to avoid false alarms in normal vocal communication. We show that roughness is present in natural alarm signals as well as in artificial alarms and that the presence of roughness in sounds boosts their detection in various tasks. Using fMRI, we show that acoustic roughness engages subcortical structures critical to rapidly appraise danger. Altogether, these data demonstrate that screams occupy a privileged acoustic niche that, being separated from other communication signals, ensures their biological and ultimately social efficiency.


Fatal methyldopa-associated granulomatous hepatitis and myocarditis.
A 78-year-old woman developed spiking fever of obscure etiology while receiving long term therapy with methyldopa and died suddenly seven days after admission to the hospital. Autopsy showed widespread granulomas in the liver, spleen, lymph nodes and bone marrow, interstitial myocarditis with granulomatous features and renovascular vasculitis. Eosinophils were prominent in the granulomas and in the myocardium consistent with a drug-induced cell mediated hypersensitivity reaction presumably triggered by methyldopa. The need for a careful drug history in fever of obscure etiology is emphasized.


Objective cough frequency in Idiopathic Pulmonary Fibrosis.
Cough is a common presenting symptom in patients with Idiopathic Pulmonary Fibrosis (IPF). This study measured cough rates in IPF patients and investigated the association between cough and measures of health related quality of life and subjective cough assessments. In addition, IPF cough rates were related to measures of physiological disease severity and compared to cough rates in health and other respiratory conditions. Nineteen IPF patients, mean age 70.8 years +/- 8.6, five female (26.3%) were studied. Subjects performed full pulmonary function testing, 24 hour ambulatory cough recordings, completed a cough related quality of life questionnaire (Leicester Cough Questionnaire) and subjectively scored cough severity with a visual analogue scale. Ambulatory cough recordings were manually counted and reported as number of coughs per hour. The 24hr cough rates were high (median 9.4, range 1.5-39.4), with day time rates much higher than night time (median 14.6, range 1.9-56.6 compared to 1.9, range 0-19.2, p = 0.003). Strong correlations were found between objective cough frequency and both the VAS (day r = 0.80, p < 0.001, night r = 0.71, p = 0.001) and LCQ (r = -0.80, p < 0.001), but not with measures of pulmonary function. Cough rates in IPF were higher than healthy subjects (p < 0.001) and asthma patients (p < 0.001) but similar to patients with chronic cough (p = 0.33). This study confirms objectively that cough is a major, very distressing and disabling symptom in IPF patients. The strong correlations between objective cough counts and cough related quality of life measures suggest that in IPF patient's, perception of cough frequency is very accurate.


Usage of sphingosine kinase isoforms in mast cells is species and/or cell type determined.
FcεRI engagement in mast cells (MCs) induces the activation of two distinct sphingosine kinase isoforms (SphK1 and SphK2) to produce sphingosine-1-phosphate, a mediator essential for MC responses. Whereas embryonic-derived SphK2-null MCs showed impaired responses to Ag, RNA silencing studies on other MC types indicated a dominant role for SphK1. Given the known functional heterogeneity of MCs, we explored whether the reported differences in SphK1 or SphK2 usage could be reflective of phenotypic differences between MC populations. Using lentiviral-based short hairpin RNA to silence SphK1 or SphK2, we found that SphK2 is required for murine MC degranulation, calcium mobilization, and cytokine and leukotriene production, irrespective of the tissue from which the MC progenitors were derived, the stage of MC granule maturity, or the conditions used for differentiation. This finding was consistent with the lack of a full allergic response in SphK2-null mice challenged to undergo passive cutaneous anaphylaxis. A redundant role for both SphKs was uncovered, however, in chemotaxis toward Ag in all MC types tested and in TNF-α production in certain MC types. In contrast, human MC responses were dependent only on SphK1, associating with a more robust expression of this isoform and a more varied representation of SphK variants relative to murine MCs. The findings show that the function of SphK1 and SphK2 can be interchangeable in MCs; however, an important determinant of SphK isoform usage is the species of origin and an influencing factor, the tissue from which MCs may be derived and/or their differentiation state.


Correlates of readiness to receive Chlamydia screening among 2 populations of youths.
To assess young people's preferences for Chlamydia testing venues and methods, attitudes about testing, sex differences among these variables, and their predictive associations with young people's readiness for screening. Survey. National Job Training site and Department of Youth Services site. One hundred fifty male and 150 female youths from the National Job Training site and 150 male youths from the Department of Youth Services site. Modifiable predictors of stage of readiness for Chlamydia screening. Modifiable variables associated with increasing readiness for Chlamydia screening included the following: (1) among males in the Department of Youth Services group, perceived likelihood of ever having a Chlamydia infection; (2) among males from the National Job Training site, lack of condom use as a risk factor for Chlamydia infection and perception of untreated Chlamydia infection as dangerous; and (3) among females from the National Job Training site, belief that a partner could have a Chlamydia infection and fewer perceived social consequences of Chlamydia testing. Interventions targeted at sex-specific modifiable variables may help reduce undiagnosed Chlamydia infection among sexually active youth.


The fear of awful smell: risk perceptions among farmers in Vietnam using wastewater and human excreta in agriculture.
Vietnamese farmers' health-risk awareness, knowledge, and practices related to their use of wastewater and human excreta was investigated in an anthropological study by a multidisciplinary team in peri-urban Hanoi and Nghe An Province. Farmers identified health risks associated with their use of excreta and wastewater, but they viewed these as unavoidable risks related to production. They perceived the health risks as different for the use of wastewater and human feces. They perceived health risks from wastewater as non-serious because it remained on the skin and only caused skin problems, but they considered health risks from non-composted smelly feces serious because it entered the body through 'polluted' air. Most farmers were more aware of threats to health from 'dirt' entering the domestic environment than of the health risks during their work. The concept of 'dirt' should be separated from understanding of germs, viruses, and parasites so that it is understood that things that carrying health risks cannot always be identified by their 'dirtiness' or smell. Farmers mainly considered hygiene and health as women's issues. Men's responsibility for the health and hygiene of the family should therefore be emphasized.


[An overview of 5 years of disciplinary measures imposed on psychiatrists].
The primary goal of disciplinary law is to enhance medical care by learning from mistakes and taking preventive measures. Disciplinary law affects the individual big (Healthcare Professionals Act) registered professionals. Furthermore, it is about quality control of professional practice.
 AIM: To draw lessons from the individual judgments of disciplinary law for psychiatrists as a group.
 METHOD: Collecting information from the annual reports of the disciplinary boards and collecting sanctioned individual verdicts on psychiatrists from the Regional and Central Disciplinary Board of Health Care over a period of 5 years.
 RESULTS: Psychiatrists received complaints about their actions relatively more often than other doctors and other big registered professionals. Over a 5-year period, 75 'warnings' and 3 'reprimands' were imposed, and 19 psychiatrists were subject to a work-limiting measure. The incorrect preparation of a report or statement was relatively often a reason for a sanctioned complaint.
 CONCLUSION: Awareness through the analysis of disciplinary complaints at the psychiatrist's group level can offer opportunities for preventive measures and improve the quality of care.


Monitoring the behaviour of 4-ketocyclophosphamide versus cyclophosphamide during capillary gas chromatography by mass spectrometry.
Capillary Gas Chromatography (CGC) is capable of determining underivatized cyclophosphamide (CPA) using SCOT OV 275 columns. Then CPA is subjected to in situ degradation resulting in formation of a cyclization product which can be determined selectively in biological fluids. In routine bioanalysis however cyclization products of CPA metabolites might interfere, e.g. 4-keto CPA. In the present study possible formation of cyclization products of 4-keto CPA similar to CPA was monitored by Mass Spectrometry. Cyclization of 4-keto CPA in situ was demonstrated to occur, resulting in a product similar to that of CPA. Both cyclization products could be determined selectively and it appeared that in situ cyclization of 4-keto CPA was negligible (less than 5%), probably owing to extra stabilization of the CPA metabolite by keto-enol tautomerism as has been demonstrated by NMR.


The Role of Circular RNAs in Male Infertility and Reproductive Cancers: A Narrative Review.
Infertility is a global health problem affecting about 15% of all couples, of which 50% are due to male infertility. Although the etiology of infertility is known in most infertile men, idiopathic male infertility remains a challenge. Therefore, there is a need for novel diagnostic methods to detect the underlying mechanisms and develop appropriate therapies. Recent studies have focused on the role of non-coding RNAs (ncRNAs) in male infertility. Circular RNAs (CircRNAs), a type of ncRNAs, are found to play a key role in the development of some pathological conditions, including cardiovascular diseases, diabetes, cancers, autoimmune diseases, etc. Several studies have reported the presence of CircRNAs and their target genes in the human reproductive system. In addition, their expression in testicular tissues, sperm cells, and seminal fluid has been identified. Abnormal expression of CircRNAs has been associated with azoospermia and asthenozoospermia in infertile men. The present narrative review provides a brief description of the role of CircRNAs in spermatogenic cells, male infertility, and reproductive cancers. In addition, some CircRNAs have been identified as potential biomarkers for disease detection and treatment.


Sub-cloning of the wild-type proAB region of the Escherichia coli genome.
The genes proA and proB encoding the first two enzymes of the proline biosynthetic sequence in Escherichia coli were subcloned from a ColE1 hybrid plasmid containing 23.3 kilobases of genomic DNA. proA and proB are contiguous and constitute a single operon transcribed in the direction proB-proA. The pro operon is contiguous with the gene phoE. Hybridization experiments showed no homology between proAB of E. coli and the other regions of the E. coli genome or with the DNA of several other bacterial species.


Clinical Integration of a Smartphone App for Patients With Chronic Pain: Retrospective Analysis of Predictors of Benefits and Patient Engagement Between Clinic Visits.
Although many pain-related smartphone apps exist, little attention has been given to understanding how these apps are used over time and what factors contribute to greater compliance and patient engagement. This retrospective analysis was designed to help identify factors that predicted the benefits and future use of a smartphone pain app among patients with chronic pain. An app designed for both Android and iOS devices was developed by Brigham and Women's Hospital Pain Management Center (BWH-PMC) for users with chronic pain to assess and monitor pain and communicate with their providers. The pain app offered chronic pain assessment, push notification reminders and communication, personalized goal setting, relaxation sound files, topics of interest with psychological and medical pain management strategies, and line graphs from daily assessments. BWH-PMC recruited 253 patients with chronic pain over time to use the pain app. All subjects completed baseline measures and were asked to record their progress every day using push notification daily assessments. After 3 months, participants completed follow-up questionnaires and answered satisfaction questions. We defined the number of completed daily assessments as a measure of patient engagement with the pain app. The average age of participants was 51.5 years (SD 13.7, range 18-92), 72.8% (182/253) were female, and 36.8% (78/212) reported the low back as their primary pain site. The number of daily assessments ranged from 1 to 426 (average 62.0, SD 49.9). The app was easy to introduce among patients, and it was well accepted. Those who completed more daily assessments (greater patient engagement) throughout the study were more likely to report higher pain intensity, more activity interference, and greater disability and were generally overweight compared with others. Patients with higher engagement with the app rated the app as offering greater benefit in coping with their pain and expressed more willingness to use the app in the future (P<.05) compared with patients showing lower engagement. Patients completing a small number of daily assessments reported less pain intensity, less daily activity interference, and less pain-related disability on average and were less likely to use the two-way messaging than those who were more engaged with the pain app (P<.05). Patients with chronic pain who appeared to manage their pain better were less likely to report benefits of a smartphone pain app designed for chronic pain management. They demonstrated lower patient engagement in reporting their daily progress, in part, owing to the perceived burden of regularly using an app without a perceived benefit. An intrinsically different pain app designed and targeted for individuals based on early identification of user characteristics and adapted for each individual would likely improve compliance and app-related patient engagement.


On-Farm Multi-Environment Evaluation of Selected Cassava (Manihot esculenta Crantz) Cultivars in South Africa.
Cassava is an important starchy root crop grown globally in tropical and subtropical regions. The ability of cassava to withstand difficult growing conditions and long-term storability underground makes it a resilient crop, contributing to food and nutrient security. This study was conducted to evaluate the performance and adaptability of exotic cassava cultivars across different environments in South Africa and to recommend genotypes for cultivation. A total of 11 cassava cultivars were evaluated at six on-farm sites, using a randomized complete block design with three replications. There were highly significant (p < 0.001) variations between genotypes, environments, and their interaction for all yield and yield-related traits studied. This indicates the need to test the genotypes in multiple environments before effective selection and commercialization can be undertaken. MSAF2 and UKF4 showed the overall best performances for most of the traits, whilst UKF9 (49.5%) and P1/19 (48.5%) had the highest dry matter yield. UKF4 (102.7 t ha−1) had the highest yield and greatest root yield stability across environments. MSAF2 did not perform consistently across environments because it was highly susceptible to cassava mosaic disease (CMD). MSAF2 could be used as a donor parent to generate novel clones with large numbers of marketable roots, and high fresh root yields, if the other parent can provide effective resistance to CMD. Based on genotype and environmental mean, Mabuyeni (KwaZulu-Natal), Mandlakazi (Limpopo), and Shatale (Mpumalanga) were found to be better environments for cassava cultivation and testing. This study is a pioneer in cassava research using multiple environments in South Africa. It provides baseline information on the performance of currently available cassava clones, their adaptation to multiple sites, the identification of suitable test sites, and information on current genetic resources for a future breeding program.


Recommendations from an international consensus conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer.
The use of neoadjuvant systemic therapy (NST) for the treatment of primary breast cancer has constantly increased, especially in trials of new therapeutic regimens. In the 1980 s, NST was shown to substantially improve breast-conserving surgery rates and was first typically used for patients with inoperable locally advanced or inflammatory breast cancer. Investigators have since also used NST as an in vivo test for chemosensitivity by assessing pathologic complete response. Today, by using pathologic response and other biomarkers as intermediate end points, results from trials of new regimens and therapies that use NST are aimed to precede and anticipate the results from larger adjuvant trials. In 2003, a panel of representatives from various breast cancer clinical research groups was first convened in Biedenkopf to formulate recommendations on the use of NST. The obtained consensus was updated in two subsequent meetings in 2004 and 2006. The most recent conference on recommendations on the use of NST took place in 2010 and forms the basis of this report.


Tau Antibody Targeting Pathological Species Blocks Neuronal Uptake and Interneuron Propagation of Tau in Vitro.
The clinical progression of Alzheimer disease (AD) is associated with the accumulation of tau neurofibrillary tangles, which may spread throughout the cortex by interneuronal tau transfer. If so, targeting extracellular tau species may slow the spreading of tau pathology and possibly cognitive decline. To identify suitable target epitopes, we tested the effects of a panel of tau antibodies on neuronal uptake and aggregation in vitro. Immunodepletion was performed on brain extract from tau-transgenic mice and postmortem AD brain and added to a sensitive fluorescence resonance energy transfer-based tau uptake assay to assess blocking efficacy. The antibodies reduced tau uptake in an epitope-dependent manner: N-terminal (Tau13) and middomain (6C5 and HT7) antibodies successfully prevented uptake of tau species, whereas the distal C-terminal-specific antibody (Tau46) had little effect. Phosphorylation-dependent (40E8 and p396) and C-terminal half (4E4) tau antibodies also reduced tau uptake despite removing less total tau by immunodepletion, suggesting specific interactions with species involved in uptake. Among the seven antibodies evaluated, 6C5 most efficiently blocked uptake and subsequent aggregation. More important, 6C5 also blocked neuron-to-neuron spreading of tau in a unique three-chamber microfluidic device. Furthermore, 6C5 slowed down the progression of tau aggregation even after uptake had begun. Our results imply that not all antibodies/epitopes are equally robust in terms of blocking tau uptake of human AD-derived tau species.


Epidemiology and genetic diversity of Taenia asiatica: a systematic review.
Taenia asiatica has made a remarkable journey through the scientific literature of the past 50 years, starting with the paradoxical observation of high prevalences of T. saginata-like tapeworms in non-beef consuming populations, to the full description of its mitochondrial genome. Experimental studies conducted in the 1980s and 1990s have made it clear that the life cycle of T. asiatica is comparable to that of T. saginata, except for pigs being the preferential intermediate host and liver the preferential location of the cysts. Whether or not T. asiatica can cause human cysticercosis, as is the case for Taenia solium, remains unclear. Given the specific conditions needed to complete its life cycle, in particular the consumption of raw or poorly cooked pig liver, the transmission of T. asiatica shows an important ethno-geographical association. So far, T. asiatica has been identified in Taiwan, South Korea, Indonesia, the Philippines, Thailand, south-central China, Vietnam, Japan and Nepal. Especially this last observation indicates that its distribution is not restricted to South-East-Asia, as was thought so far. Indeed, the molecular tools developed over the last 20 years have made it increasingly possible to differentiate T. asiatica from other taeniids. Such tools also indicated that T. asiatica is related more closely to T. saginata than to T. solium, feeding the debate on its taxonomic status as a separate species versus a subspecies of T. saginata. Furthermore, the genetic diversity within T. asiatica appears to be very minimal, indicating that this parasite may be on the verge of extinction. However, recent studies have identified potential hybrids between T. asiatica and T. saginata, reopening the debate on the genetic diversity of T. asiatica and its status as a separate species.


Evaluation of Risk Factors for Clostridium difficile Infection Based on Immunochromatography Testing and Toxigenic Culture Assay.
In recent years, the diagnostic method of choice for Clostridium difficile infection (CDI) is a rapid enzyme immunoassay in which glutamate dehydrogenase (GDH) antigen and C. difficile toxin can be detected (C. diff Quik Chek Complete; Alere Inc.) (Quik Chek). However, the clinical significance remains unclear in cases that demonstrate a positive result for GDH antigen and are negative for toxin. In this study, we used the Quik Chek test kit on fecal samples, with an additional toxin detection step using a toxigenic culture assay for the aforementioned cases. CDI risk factors were assessed among the 3 groups divided by the Quik Chek test results. The study involved 1,565 fecal samples from patients suspected to have CDI who were hospitalized during the period of April 2012 to March 2014. The 3 groups were defined as follows: both GDH antigen positive and toxin positive (by Quik Chek test) (toxin-positive [TP] group, n = 109), both GDH antigen and toxin negative (toxin-negative [TN] group, n = 111), and positive only for GDH antigen but toxin positive with subsequent toxigenic culture (toxigenic culture [TC] group, n = 72). The gender, age, number of hospitalization days, white blood cell (WBC) counts, serum albumin levels, body mass index (BMI), fecal consistency, and use of antibacterials and proton pump inhibiters (PPIs) were analyzed. The positive rate for the fecal direct Quik Chek test was 7.0% (109/1,565 cases). However, toxigenic culture assays using the Quik Chek test for only the GDH-antigen-positive/toxin-negative samples were 35.3% positive (72/204 cases). As a result, the true positive rate for C. difficile toxin detection was estimated to be 11.6% (181/1,565 cases). Moreover, significant differences (P < 0.05) in the number of hospitalization days (>50 days), WBC counts (>10,000 WBCs/μl), and use of PPIs comparing the TN, TP, and TC groups, were observed. The odds ratios (ORs) for the development of CDI were 1.61 (95% confidence interval [CI], 0.94 to 2.74) and 2.98 (95% CI, 1.59 to 5.58) for numbers of hospitalization days, 2.16 (95% CI, 1.24 to 3.75) and 2.24 (95% CI, 1.21 to 4.14) for WBC counts, and 9.03 (95% CI, 4.9 to 16.6) and 9.15 (95% CI, 4.59 to 18.2) for use of PPIs in the TP and TC groups, respectively. These findings demonstrated that the use of PPIs was a significant risk factor for CDI development. Moreover, antibacterials such as carbapenems, cephalosporins, and fluoroquinolones were demonstrated to be risk factors. In conclusion, identification of the TC group of patients is thought to be important, as this study demonstrates that this group bears the same high risk of developing CDI as the TP group.


A robotic test of proprioception within the hemiparetic arm post-stroke.
Proprioception plays important roles in planning and control of limb posture and movement. The impact of proprioceptive deficits on motor function post-stroke has been difficult to elucidate due to limitations in current tests of arm proprioception. Common clinical tests only provide ordinal assessment of proprioceptive integrity (eg. intact, impaired or absent). We introduce a standardized, quantitative method for evaluating proprioception within the arm on a continuous, ratio scale. We demonstrate the approach, which is based on signal detection theory of sensory psychophysics, in two tasks used to characterize motor function after stroke. Hemiparetic stroke survivors and neurologically intact participants attempted to detect displacement- or force-perturbations robotically applied to their arm in a two-interval, two-alternative forced-choice test. A logistic psychometric function parameterized detection of limb perturbations. The shape of this function is determined by two parameters: one corresponds to a signal detection threshold and the other to variability of responses about that threshold. These two parameters define a space in which proprioceptive sensation post-stroke can be compared to that of neurologically-intact people. We used an auditory tone discrimination task to control for potential comprehension, attention and memory deficits. All but one stroke survivor demonstrated competence in performing two-alternative discrimination in the auditory training test. For the remaining stroke survivors, those with clinically identified proprioceptive deficits in the hemiparetic arm or hand had higher detection thresholds and exhibited greater response variability than individuals without proprioceptive deficits. We then identified a normative parameter space determined by the threshold and response variability data collected from neurologically intact participants. By plotting displacement detection performance within this normative space, stroke survivors with and without intact proprioception could be discriminated on a continuous scale that was sensitive to small performance variations, e.g. practice effects across days. The proposed method uses robotic perturbations similar to those used in ongoing studies of motor function post-stroke. The approach is sensitive to small changes in the proprioceptive detection of hand motions. We expect this new robotic assessment will empower future studies to characterize how proprioceptive deficits compromise limb posture and movement control in stroke survivors.


Combined intervention with education and progressive muscle relaxation on quality of life, functional disability, and positive symptoms in patients with acute schizophrenia.
To explore the effects of combined intervention with education and progressive muscle relaxation (PMR) on quality of life (QoL), functional disability, and positive symptoms of patients with acute schizophrenia. This randomized controlled study took place in an acute schizophrenia ward in Changsha, China. Sixty-four patients with acute schizophrenia were randomly assigned to four groups: control, education, PMR, and education plus PMR. QoL was assessed with the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form. Functional disability was assessed with the Sheehan Disability Scale. Severity of positive schizophrenia symptoms was assessed with the Scale for the Assessment of Positive Symptoms. All patients were evaluated at baseline (within 72 hours before the interventions) and at the end of weeks 5 (when the interventions ended) and week 15 (a 10-week follow-up after the interventions). The sociodemographic and clinical characteristics of all four study groups were similar at baseline. Repeated-measures analysis of variance showed significant differences among the interventions in improving QoL, functional disability, and positive symptoms over time in the patients. Education and PMR alone resulted in sustained improvement of QoL during the intervention period and a 10-week follow-up but had no significant effects on functional disability or positive schizophrenia symptoms. In contrast, combined intervention with education and PMR showed better effects on improving QoL than did education or PMR alone throughout the 15-week study. It also statistically significantly improved functional disability and positive schizophrenia symptoms during the intervention period and led to sustained improvement of functional disability during the 10-week follow-up. A combined intervention with education and PMR is effective in improving QoL, functional disability, and positive symptoms in patients with acute schizophrenia. The combined intervention model could be a new paradigm of adjunctive treatment for acute schizophrenia.


Agricultural Water Quality in Cold Climates: Processes, Drivers, Management Options, and Research Needs.
Cold agricultural regions are important sites of global food production. This has contributed to widespread water quality degradation influenced by processes and hydrologic pathways that differ from warm region analogues. In cold regions, snowmelt is often a dominant period of nutrient loss. Freeze-thaw processes contribute to nutrient mobilization. Frozen ground can limit infiltration and interaction with soils, and minimal nutrient uptake during the nongrowing season may govern nutrient export from agricultural catchments. This paper reviews agronomic, biogeochemical, and hydrological characteristics of cold agricultural regions and synthesizes findings of 23 studies that are published in this special section, which provide new insights into nutrient cycling and hydrochemical processes, model developments, and the efficacy of different potentially beneficial management practices (BMPs) across varied cold regions. Growing evidence suggests the need to redefine optimum soil phosphorus levels and input regimes in cold regions to allow achievement of water quality targets while still supporting strong agricultural productivity. Practices should be considered through a regional and site-specific lens, due to potential interactions between climate, hydrology, vegetation, and soils, which influence the efficacy of nutrient, crop, water, and riparian buffer management. This leads to differing suitability of BMPs across varied cold agricultural regions. We propose a systematic approach (""), to achieve water quality objectives in variable and changing climates, which combines nutrient transport process onceptualization, nderstanding BMP functions, redicting effects of variability and change, onsideration of producer input and agronomic and environmental tradeoffs, practice daptation, nowledge mobilization, and valuation of water quality improvement.


Predicting Metabolic Syndrome by Visceral Adiposity Index, Body Roundness Index and a Body Shape Index in Adults: A Cross-Sectional Study from the Iranian RaNCD Cohort Data.
The use of anthropometric indices is one of the new and low-cost diagnostic methods of metabolic syndrome (MetS). The present study aimed to determine optimal cutoff points for the visceral adiposity index (VAI), body roundness index (BRI), and a body shape index (ABSI) in the prediction of MetS. This cross-sectional study was performed on 10,000 individuals aged from 35 to 65 years, recruited in Ravansar Non-Communicable Diseases (RaNCD) cohort study, in the west region of Iran, in 2019. MetS was defined according to International Diabetes Federation (IDF) criteria. The receiver operating characteristic (ROC) curve analysis was used to assess predictive anthropometric indices and determine optimal cutoff values. The optimal cutoff points for VAI were 4.11 (AUC: 0.82; 95% CI: 0.81-0.84) in men and 4.28 (AUC: 0.86; 95% CI: 0.85-0.87) in women to prediction of MetS. The optimal cutoff points for BRI were 4.75 (AUC: 0.75; 95% CI: 0.74-0.77) in men and 6.17 (AUC: 0.62; 95% CI: 0.61-0.64) in women to prediction of MetS. The optimal cutoff points for ABSI were 0.12 (AUC: 0.49; 95% CI: 0.47-0.51) in men and 0.13 (AUC: 0.49; 95% CI: 0.47-0.51) in women to prediction of MetS. The risk of MetS in men and women with a VAI higher than the optimal cutoff point was, respectively, 9.82 and 11.44 times higher than that in those with a VAI lower than the cutoff point. Although VAI might not be very cost-beneficial compared to IDF, our study showed VAI is a better predictor of MetS than BRI in adults. ABSI was not a suitable predictor for MetS.


Potential role of the cellular allergen stimulation test (CAST) in diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis.
Allergic bronchopulmonary aspergillosis (ABPA) is a severe complication in cystic fibrosis (CF), which is difficult to identify because of overlapping unspecific diagnostic features with common CF-manifestations. The cellular allergen stimulation test (CAST) is used in diagnosis of allergic and pseudoallergic reactions. This assay is based on the determination of sulfidoleukotrienes, which are produced by allergen-stimulated basophils in vitro. The potential role of CAST in diagnosis of ABPA was evaluated in this study. The CAST assay was applied in 27 CF-patients including eight subjects with positive clinical and serological signs of ABPA. Additional to the Nelson-criteria for diagnosis of ABPA specific IgE against recombinant Aspergillus antigens (rAsp f 1, 2, 3, 4, and 6) were assessed. The CAST results were positive in all ABPA-patients and in five controls without any sign of ABPA except positive specific IgE against Aspergillus fumigatus (sensitivity of 100%, specificity of 74%). Specific IgE against rAsp f 4 and/or f 6 were positive in six of the eight ABPA-patients, but not in the controls. Positive CAST results, total serum IgE > 500 U/ml and positive IgE antibodies against rAsp f 4 and/or f 6 were only found in ABPA-patients (specificity of 100%). The CAST assay on its own includes high sensitivity with lower specificity. For the discrimination of ABPA from sensitization to Aspergillus, the CAST, the highly elevated total serum IgE and rAsp in combination are potential auxiliary diagnostic parameters.


Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway beta-agonist paradox.
beta-adrenergic receptors (betaARs) relax airway smooth muscle and bronchodilate, but chronic beta-agonist treatment in asthma causes increased sensitivity to airway constriction (hyperreactivity) and is associated with exacerbations. This paradox was explored using mice with ablated betaAR genes (betaAR-/-) and transgenic mice overexpressing airway smooth muscle beta2AR (beta2AR-OE) representing two extremes: absence and persistent activity of airway betaAR. Unexpectedly, betaAR-/- mice, lacking these bronchodilating receptors, had markedly decreased bronchoconstrictive responses to methacholine and other Gq-coupled receptor agonists. In contrast, beta2AR-OE mice had enhanced constrictive responses. Contraction to permeabilization with beta-escin was unaltered by gene ablation or overexpression. Inositol phosphate accumulation by Gq-coupled M3-muscarinic, thromboxane-A2, and 5-HT2 receptors was desensitized in airway smooth muscle cells from betaAR-/- mice and sensitized in cells from beta2AR-OE mice. Thus, betaAR antithetically regulates constrictive signals, affecting bronchomotor tone/reactivity by additional means other than direct dilatation. Studies of signaling elements in these pathways revealed the nodal point of this cross talk as phospholipase C-beta1, whose expression was altered by betaAR in a direction and magnitude consistent with the physiologic and cellular responses. These results establish a mechanism of the beta-agonist paradox and identify a potential asthma modifier gene (phospholipase C-beta1), which may also be a therapeutic target in asthma when chronic beta-agonists are required.


[Detection of narcotic-containing packages in "body-packers" using imaging procedures. Studies in vitro and in vivo].
The increase in narcotic smuggling through swallowing small packages ("body packing") has created problems in detection and in avoiding acute intoxication. Five such cases are reported. Experiments have been carried out in vitro in order to investigate how such narcotic packages could best be shown by radiological examination, by CT or by MRT.


Clickable NAD analogues for labeling substrate proteins of poly(ADP-ribose) polymerases.
Poly(ADP-ribose) polymerases (PARPs) catalyze the transfer of multiple adenine diphosphate ribose (ADP-ribose) units from nicotinamide adenine dinucleotide (NAD) to substrate proteins. There are 17 PARPs in humans. Several PARPs, such as PARP-1 and Tankyrase-1, are known to play important roles in DNA repair, transcription, mitosis, and telomere length maintenance. To better understand the functions of PARPs at a molecular level, it is necessary to know what substrate proteins PARPs modify. Here we report clickable NAD analogues that can be used to label PARP substrate proteins. The clickable NAD analogues have a terminal alkyne group which allows the conjugation of fluorescent or affinity tags to the substrate proteins. Using this method, PARP-1 and tankyrase-1 substrate proteins were labeled by a fluorescent tag and visualized on SDS-PAGE gel. Using a biotin affinity tag, we were able to isolate and identify a total of 79 proteins as potential PARP-1 substrates. These include known PARP-1 substrate proteins, including histones and heterogeneous nuclear ribonucleoproteins. About 40% of the proteins were also identified in recent proteomic studies as potential PARP-1 substrates. Among the identified potential substrates, we further demonstrated that tubulin and three mitochondrial proteins, TRAP1 (TNF receptor-associated protein 1), citrate synthase, and GDH (glutamate dehydrogenase 1), are substrates of PARP-1 in vitro. These results demonstrate that the clickable NAD analogue is useful for labeling, in-gel detection, isolation, and identification of the substrate proteins of PARPs and will help to understand the biological functions of PARPs.


Cell-to-cell binding induced by different lectins.
The cell-to-cell binding induced by concanavalin A (Con A) and the lectins from wheatgerm, soybean, and waxbean has been analyzed by measuring the ability of single cells to bind to lectin-coated cells immobilized on nylon fibers. The cells used were lymphoma, myeloid leukemia, and normal fibroblast cells. With all lectins, cell-to-cell binding was inhibited if both cells were prefixed with glutaraldehyde. However, in most cases cell-to-cell binding was enhanced when only the lectin-coated cell was prefixed. With normal fibroblasts, treatment of either one or both cells with trypsin enhanced the cell-to-cell binding induced by Con A and the wheatgerm lectin. Neuraminidase, which increases the number of receptors for soybean agglutinin, increased cell-to-cell binding only if both cells were treated. Although cell-to-cell binding induced by the lectins from soybean and wheatgerm could be partially reversed by the appropriate competitive saccharide inhibitor, binding induced by Con A could not be reversed. The experiments indicate that cell-to-cell binding induced by a lectin can be prevented by an insufficient density of receptors for the lectin, insufficient receptor mobility, or induced clustering of receptors. These effects can explain the differences in cell-to-cell binding and agglutination observed with different cell types and lectins. They also suggest that cell-to-cell binding induced by different lectins with a variety of cell types is initiated by a mechanism involving the alignment of complementary receptors on the colliding cells for the formation of multiple cell-to-lectin-to-cell bridges.


2-D DIGE identification of differentially expressed heterogeneous nuclear ribonucleoproteins and transcription factors during neural differentiation of human embryonic stem cells.
Neural stem cells (NSC) are progenitors that can give rise to all neural lineages. They are found in specific niches of fetal and adult brains and grow in vitro as non-adherent colonies, the neurospheres. These cells express the intermediate filament nestin, commonly considered an NSC marker. NSC can be derived as neurospheres from human embryonic stem cells (hESC). The mechanisms of cellular programming that hESC undergo during differentiation remain obscure. To investigate the commitment process of hESC during directed neural differentiation, we compared the nuclear proteomes of hESC and hESC-derived neurospheres. We used 2-D DIGE to conduct a quantitative comparison of hESC and NSC nuclear proteins and detected 1521 protein spots matched across three gels. Statistical analysis (ANOVA n = 3 with false discovery correction) revealed that only 2.1% of the densitometric signal was significantly changed. The ranges of average ratios varied from 1.2- to 11-fold at a statistically significant p-value <0.05. MS/MS identified 15 regulated proteins previously shown to be involved in chromatin remodeling, mRNA processing and gene expression regulation. Notably, three members of the heterogeneous nuclear ribonucleoprotein family (AUF-1, and FBP-1 and FBP-2) register a 54, 70 and 99% increased expression, highlighting them as potential markers for NSC in vitro derivation. By contrast, Cpsf-6 virtually disappears with differentiation with an 11-fold drop in NSC, highlighting this protein as a novel marker for undifferentiated ESC.


Baroreceptor reflex cardiovascular control in mongrel dogs and racing greyhounds.
The open-loop carotid sinus baroreflex control of arterial pressure-flow relations were compared in mongrel dogs and racing greyhounds (GH) anesthetized with alpha-chloralose. The carotid sinuses were bilaterally isolated and perfused under controlled pressure. Pulsatile pressure and flow were simultaneously measured in the ascending aorta, the celiac, superior mesenteric, left renal, and right iliac arteries. Open-loop set point values of mean arterial pressure were higher in GH before and after vagotomy. Reflex gains were similar before vagotomy but lower in GH after vagotomy. The overall range of control of arterial pressure was the same before vagotomy but smaller in GH after vagotomy. The variation of mean arterial pressure with mean carotid sinus pressure in GH was shifted toward higher pressure levels similar to resetting. The overall effects of vagotomy on carotid sinus baroreceptor reflex responses were smaller in GH. Operating point values of regional resistance were generally smaller in GH. Operating point sensitivities of regional resistance were the same except for the iliac bed, which was more sensitive in GH. These results document significant regional differences in the baroreceptor control of regional hemodynamics between mongrels and greyhounds that could contribute to altered responses especially to "hypertensive" perturbations.


Transient Receptor Potential Canonical (TRPC) Channels as Modulators of Migration and Invasion.
Calcium (Ca2+) is perhaps the most versatile signaling molecule in cells. Ca2+ regulates a large number of key events in cells, ranging from gene transcription, motility, and contraction, to energy production and channel gating. To accomplish all these different functions, a multitude of channels, pumps, and transporters are necessary. A group of channels participating in these processes is the transient receptor potential (TRP) family of cation channels. These channels are divided into 29 subfamilies, and are differentially expressed in man, rodents, worms, and flies. One of these subfamilies is the transient receptor potential canonical (TRPC) family of channels. This ion channel family comprises of seven isoforms, labeled TRPC1-7. In man, six functional forms are expressed (TRPC1, TRPC3-7), whereas TRPC2 is a pseudogene; thus, not functionally expressed. In this review, we will describe the importance of the TRPC channels and their interacting molecular partners in the etiology of cancer, particularly in regard to regulating migration and invasion.


Suppression of human melanoma metastasis following introduction of chromosome 6 is independent of NME1 (Nm23).
Metastasis is suppressed more than 95% following microcell-mediated transfer of a single copy of neomycin-tagged human chromosome 6 (neo6) into the human melanoma cell lines C8161 and MelJuSo. Concomitant with metastasis suppression is upregulation of NME1 (Nm23-H1) mRNA and protein expression. The purposes of this study were to determine whether NME1 expression was responsible for metastasis suppression in neo6/melanoma hybrids, and whether genes on chromosome 6 regulate NME1. Using neo6/C8161 cells, transfection of CAT reporter constructs linked to the NME1 promoter failed to consistently induce CAT. Therefore, it does not appear that genes on chromosome 6 directly control transcription of NME1. Transfection and overexpression of NME1 in MelJuSo, under the control of the CMV promoter, resulted in 40-80% inhibition of lung metastasis following i.v. inoculation of 2 x 10(5) cells. Only one transfectant of C8161 subclone 9 (C8161cl.9) cells was suppressed for metastasis. Control transfections with pCMVneo or pSV2neo did not suppress metastasis in either cell line. Taken together, these data suggest that NME1 can reduce metastatic potential of some human melanoma cells; but, this inhibitory activity appears to be independent of the metastasis suppression following introduction of chromosome 6 into C8161 and MelJuSo human melanoma cell lines.


[Effect of antithrombin-III (AT-III) on intestinal epithelium changes related to obstructive icterus: experimental study in rats].
Bacterial translocation leading to sepsis is increased by obstructive jaundice(OJ). Antithrombin III (ATIII) mediates the promotion of prostaglandin release, an inhibitor of leucocyte activation and downregulator of many proinflammatory cytokines. We investigated the effect of ATIII on histopatology and villus morphology of small intestine. We designed an experimental study with 40 rats who were divided into four groups. The first one (control, n = 10) received saline, the second (n = 10) included normal rats who received ATIII, the third group (n = 10) was rats with OJ (ligation of common bile duct), and the fourth group included OJ rats receiving AT-III. AT-III (100 UI/kg intraperitoneally) was started at the third day following bile duct ligation and repeated for 5 days. At the 8 day, rats were scarified and ileum was analysed. Histopathological assessments were performed, using a grading scheme ranging from 0 to 10 (Chui et al). Median histological score was found to be 2 in group 1, 1.71 in group 2, 5.43 in group 3 and 2.71 in group 4. The difference between group 3 and 4 was statistically significant. Mucosal thicknesses and villus lengths were found significantly lower in OJ group. Mucosal thicknesses and villus lengths were significantly preserved in jaundiced + AT-III group. ATIII demonstrated a salutary effect on the histopathological changes caused by the OJ and prevented the adverse effects on histopathological and morphological parameters in ileal mucosa.


Weakly Supervised Learning for Categorization of Medical Inquiries for Customer Service Effectiveness.
With the growing unstructured data in healthcare and pharmaceutical, there has been a drastic adoption of natural language processing for generating actionable insights from text data sources. One of the key areas of our exploration is the Medical Information function within our organization. We receive a significant amount of medical information inquires in the form of unstructured text. An enterprise-level solution must deal with medical information interactions via multiple communication channels which are always nuanced with a variety of keywords and emotions that are unique to the pharmaceutical industry. There is a strong need for an effective solution to leverage the contextual knowledge of the medical information business along with digital tenants of natural language processing (NLP) and machine learning to build an automated and scalable process that generates real-time insights on conversation categories. The traditional supervised learning methods rely on a huge set of manually labeled training data and this dataset is difficult to attain due to high labeling costs. Thus, the solution is incomplete without its ability to self-learn and improve. This necessitates techniques to automatically build relevant training data using a weakly supervised approach from textual inquiries across consumers, healthcare professionals, sales, and service providers. The solution has two fundamental layers of NLP and machine learning. The first layer leverages heuristics and knowledgebase to identify the potential categories and build an annotated training data. The second layer, based on machine learning and deep learning, utilizes the training data generated using the heuristic approach for identifying categories and sub-categories associated with verbatim. Here, we present a novel approach harnessing the power of weakly supervised learning combined with multi-class classification for improved categorization of medical information inquiries.


Syntheses, structure diversity and properties of complexes with 4-acyl pyrazolone salicylidene hydrazide derivatives.
Five new complexes [Zn(HL(1))(OAc)(CH(3)CH(2)OH)] (1), [Cd(2)(HL(1))(2)(OAc)(2)(CH(3)CH(2)OH)(2)] (2), [Cu(6)(L(1))(6)] (3) (H(2)L(1) = N-(1-phenyl-3-phenmethyl-4-phenylethylene-pyrazolone-5)-salicylidene hydrazide, OAc = acetate anion), {[Zn(L(2))(CH(3)OH)]·(CH(3)OH)}(n) (4) (H(2)L(2) = N-(1-phenyl-3-phenmethyl-4-ethylene-pyrazolone-5)-salicylidene hydrazine), [Cu(L(3))](n) (5) (H(2)L(3) = N-(1-phenyl-3-phenmethyl-4-benzylidene-pyrazolone-5)-salicylidene hydrazide) have been synthesized and characterized by chemical and spectroscopic techniques. Complexes 1-3 feature mononuclear, dinuclear and rare hexanuclear structures, respectively. The different molecular structures and different coordination modes of H(2)L(1) in complexes 1-3 indicate that the coordination geometry of the metal atoms have a remarkable impact on the structure of these complexes. Complexes 4 and 5 have 1D chain structures. Comparing complexes 4 and 1 or 5 and 3, it can be concluded that the substituents at the 4-position of the ligands have a significant effect on the structure of the resulting complexes. It is worth noting that N(2) atoms of the pyrazolyl ring play an important role in building the two-dimensional networks for 1 and 2 by hydrogen bonds, a novel hexanuclear unit for 3, and the 1D polymer chain for 4 and 5 by bridging bonds. Complexes 1, 2 and 4 show strong fluorescent behavior in the solid state. The magnetic property of complex 3 shows the presence of intramolecular antiferromagnetic exchange (J = -8.63 cm(-1)).


Rate of positive depression screenings among Marshallese patients with diabetes in Northwest Arkansas.
The lifetime risk of developing depression is 16.6%, however the risk is 2-fold in patients with diabetes. The rate of diabetes is much higher for the Marshallese than the general US population, with a prevalence ranging from 25% to 50%, however the prevalence of depression is not well defined among this minority group. The primary objective of this study was to obtain the rate of positive depression screenings, using the Patient Health Questionnaire-2 (PHQ-2), among adult Marshallese patients with diabetes. A retrospective chart review was performed for Marshallese adults receiving care in a student-led clinic in Northwest Arkansas. Marshallese adults with a documented PHQ-2 score and a diagnosis of type 1 or 2 diabetes, as outlined by the American Diabetes Association, were included. Demographic information was obtained from the medical records. The data were analyzed using descriptive statistics. The study included 96 patients. Ten patients scored a 3 or higher on the PHQ-2, indicating a positive screen. Of these, scores ranged from 3 to 6, with the majority of patients scoring 4 (N = 6). The average hemoglobin A1C for patients with a positive PHQ-2 score was 10.5%. This project identified a rate of 10.4% of patients with a positive PHQ-2 from the study sample. This finding is similar to the prevalence of depression for the general US population, however it is lower than rates cited in the literature for patients diagnosed with diabetes. Future studies should use Native Marshallese community health workers and focus groups to develop a multistep approach to obtain a culturally appropriate, translated tool with high sensitivity for patient response.


DIALYSIS OF SLEEP AND WAKING FACTORS IN BLOOD OF THE RABBIT.
Dialysis of cerebral venous blood was performed on rabbits during sleep induced by electrical stimulation of the hypnogenic thalamic system or during sustained wakefulness elicited by stimulation of the activating reticular system. The injection of dialysate from a sleeping donor elicited in a normal recipient a moderate sleep which did not differ from normal sleep according to the behavior of the animal and the pattern of the electroencephalogram. The action of the dialysate obtained from sleeping donors was significantly different from that obtained from control donors after sham-stimulation of the thalamus. Injection of dialysate from alert donors elicited a behavioral and electrographic arousal with rhinodiencephalic activation symptoms. These results suggest that dialyzable humoral factors play a role in the mediation of sleep and wakeleness.


Residual activity of benzyl benzoate against Dermatophagoides pteronyssinus (Acari: Pyroglyphidae).
The residual effect of a commercial spray containing 2.0% benzyl benzoate against Dermatophagoides pteronyssinus was evaluated in the laboratory. Filter papers treated with benzyl benzoate were dried for 2 hours and placed in Petri dishes. Adult mites were then added and mortality was assessed following 24 hour contact and at succeeding 4 weeks intervals up to week 28 post-treatment using the same treated filter papers. There was 100% mortality at 24 hours post-treatment, declining progressively to 71% by week 28. Probit analysis estimated a median lethal time (LT50) of 59 weeks.


Prevalence and predictors of adverse events in older surgical patients: impact of the present on admission indicator.
to examine the effects of the present on admission (POA) indicator on the prevalence of and factors associated with postsurgical adverse events in older patients. this is a secondary data analysis of 82,898 surgical patients aged 65 years or older in 252 acute care hospitals in California in 2004. Four adverse events were counted using the Agency for Healthcare Research and Quality's Patient Safety Indicator (PSI) definitions with and without using the POA indicator. We also examined the effects of the POA indicator on the relationships between patient- and hospital-level factors and adverse events, using generalized linear mixed models. the use of the POA indicator resulted in a marked reduction in the estimated rates of all 4 adverse event rates. Adjustment for POA conditions also influenced factors associated with adverse events. Compared with those with newly occurring adverse events only, admissions with only POA conditions were more likely to be admitted through the emergency department, be unplanned, and belong to patients with one or more preceding admissions or those with multiple admissions within the same year. adverse event rates estimated from discharge abstracts using PSI methodology could be overstated when the POA indicator was not used. The POA indicator could influence predictors of adverse events. Studies on geriatric safety and outcomes using large administrative data sets should consider using the POA indicator. Further studies are needed on how to determine POA conditions.


Asymmetry of language activation relates to regional callosal morphology following early cerebral injury.
The anatomical factors underlying reorganization of language representation are yet to be elucidated, although correlations between asymmetric structures and language lateralization have been identified. Previous research has implicated the corpus callosum in the development of language lateralization. This study examined the relationship between callosal morphology and language asymmetry, using letter fluency functional magnetic resonance imaging, in 13 patients with focal epilepsy and 8 healthy controls. Regional callosal thickness was determined without relying on a priori delineation of callosal segments. We predicted that language asymmetry measured by fMRI activation laterality scores would be correlated with regional callosal thickness in both groups. However, only the degree of language activation asymmetry was significantly correlated with callosal thickness in the isthmus and the midbody of patients, and there was a significant interaction between the groups with respect to callosal thickness and language activation asymmetry. These data suggest that callosal pathways may be important for language reorganization in the context of early cerebral injury.


Genomic nucleotide-based distance analysis for delimiting old world monkey derived herpes simplex virus species.
Herpes simplex viruses form a genus within the alphaherpesvirus subfamily, with three identified viral species isolated from Old World monkeys (OWM); Macacine alphaherpesvirus 1 (McHV-1; herpes B), Cercopithecine alphaherpesvirus 2 (SA8), and Papiine alphaherpesvirus 2 (PaHV-2; herpes papio). Herpes B is endemic to macaques, while PaHV-2 and SA8 appear endemic to baboons. All three viruses are genetically and antigenically similar, with SA8 and PaHV-2 thought to be avirulent in humans, while herpes B is a biosafety level 4 pathogen. Recently, next-generation sequencing (NGS) has resulted in an increased number of published OWM herpes simplex genomes, allowing an encompassing phylogenetic analysis. In this study, phylogenetic networks, in conjunction with a genome-based genetic distance cutoff method were used to examine 27 OWM monkey herpes simplex isolates. Genome-based genetic distances were calculated, resulting in distances between lion and pig-tailed simplex viruses themselves, and versus herpes B core strains that were higher than those between PaHV-2 and SA8 (approximately 14 and 10% respectively). The species distance cutoff was determined to be 8.94%, with the method recovering separate species status for PaHV-2 and SA8 and showed that lion and pig-tailed simplex viruses (vs core herpes B strains) were well over the distance species cutoff. We propose designating lion and pig-tailed simplex viruses as separate, individual viral species, and that this may be the first identification of viral cryptic species.


Diverse roles for sex hormone-binding globulin in reproduction.
Sex hormone-binding globulin (SHBG) transports androgens and estrogens in blood and regulates their access to target tissues. Hepatic production of SHBG fluctuates throughout the life cycle and is influenced primarily by metabolic and hormonal factors. Genetic differences also contribute to interindividual variations in plasma SHBG levels. In addition to controlling the plasma distribution, metabolic clearance, and bioavailability of sex steroids, SHBG accumulates in the extravascular compartments of some tissues and in the cytoplasm of specific epithelial cells, where it exerts novel effects on androgen and estrogen action. In mammals, the gene-encoding SHBG is expressed primarily in the liver but also at low levels in other tissues, including the testis. In subprimate species, Shbg expression in Sertoli cells is under the control of follicle-stimulating hormone and produces the androgen-binding protein that influences androgen actions in the seminiferous tubules and epididymis. In humans, the SHBG gene is not expressed in Sertoli cells, but its expression in germ cells produces an SHBG isoform that accumulates in the acrosome. In fish, Shbg is produced by the liver but has a unique function in the gill as a portal for natural steroids and xenobiotics, including synthetic steroids. However, salmon have retained a second, poorly conserved Shbg gene that is expressed only in ovary, muscle, and gill and that likely exerts specialized functions in these tissues. The present review compares the production and functions of SHBG in different species and its diverse effects on reproduction.


[Histoplasma capsulatum: isolation from bats in Cuba].
A mycologic-serologic study of 169 bats of species Artibeus jamaicensis parvipos, Brachyphyllanana, Eptesicus fuscus dutertreus, Tadarida brasiliensis muscula and Mormoops blainvillei which were catched in a cave of Havana province is presented. Histoplasma capsulatum were isolated from the lungs, liver and spleen, in four out of the five species studied. All species were serologically negative.


Fixed prosthodontic rehabilitation with a fully digital workflow for a teenage patient with amelogenesis imperfecta: A 2-year follow-up.
Amelogenesis imperfecta is a hereditary disorder that affects the enamel formation of the primary and permanent dentition and has significant consequences because hypersensitivity causes difficulty with oral hygiene, function, self-esteem, and quality of life. Patients diagnosed with amelogenesis imperfecta often require extensive treatment, often at an early age. Prosthodontic intervention of adolescent patients with amelogenesis imperfecta presents specific clinical challenges. This clinical report describes the fixed prosthodontic rehabilitation of a teenage patient with amelogenesis imperfecta by using a fully digital workflow throughout the treatment process, which facilitated functional, biomechanical, esthetic, and sociopsychological improvements.


Exploiting lipid-free tubing passive samplers and embryonic zebrafish to link site specific contaminant mixtures to biological responses.
The Biological Response Indicator Devices Gauging Environmental Stressors (BRIDGES) bio-analytical tool was developed in response to the need for a quantitative technology for assessing the toxicity of environmentally relevant contaminant mixtures. This tool combines passive samplers with the embryonic zebrafish model. When applied in an urban river it effectively linked site specific, bioavailable contaminant mixtures to multiple biological responses. Embryonic zebrafish exposed to extracts from lipid-free passive samplers that were deployed at five locations, within and outside of the Portland Harbor Superfund Megasite, displayed different responses. Six of the eighteen biological responses observed in 941 exposed zebrafish were significantly different between sites. This demonstrates the sensitivity of the bio-analytical tool for detecting spatially distinct toxicity in aquatic systems; bridging environmental exposure to biological response.


Oligonucleotides tethered to a short polyguanylic acid stretch are targeted to macrophages: enhanced antiviral activity of a vesicular stomatitis virus-specific antisense oligonucleotide.
The poor membrane permeability of oligonucleotides is one of the major problems of antisense technology. Here we report the construction of designer oligonucleotides for targeted delivery to macrophages. The oligonucleotides tethered to a 10-mer poly(G) sequence at their 3' ends were recognized by scavenger receptors on macrophages and were taken up about 8- to 10-fold as efficiently as those oligonucleotides that either lacked a poly(G) tail or that contained a 10-mer poly(C) tail instead of the poly(G) tail. The enhanced uptake of poly(G) constructs was inhibited in the presence of poly(G) and other known ligands of the scavenger receptor. The bioefficacy of poly(G)-mediated targeting of antisense oligonucleotides (ANS) was demonstrated by using vesicular stomatitis virus (VSV) as a model system. The ability of ANS directed against the translation initiation site of N protein mRNA of VSV to inhibit virus replication was assessed. The ANS with the 10-mer poly(G) sequences (ANS-G) brought about significant inhibition of VSV replication in J774E cells (a murine monocyte/macrophage cell line) and Chinese hamster ovary (CHO) cell transfectants expressing scavenger receptors. The ANS lacking a 10-mer poly(G) stretch were ineffective. The inhibition of VSV replication due to ANS-G was completely abrogated in the presence of 10-mer poly(G), indicating that the antisense effect of the ANS-G molecule was a consequence of scavenger receptor-mediated enhanced uptake. Importantly, antisense molecules linked exclusively by natural phosphodiester bonds were as bioeffective as those synthesized with a mixed backbone of phosphodiester and phosphorothioate. Taken together, these results suggest that macrophage-directed designer ANS against infective agents may simply be obtained by adding a short stretch of guanylic acid sequence to the desired specific ANS during solid-phase synthesis. This nucleic acid-based strategy, which utilizes homogeneous preparation of ANS, may find applications in directed manipulation of macrophage metabolism for a variety of purposes as well as in therapy of a broad spectrum of macrophage-related disorders amenable to the antisense approach.


[An epidemiological index to assess the nutritional status of children based in a polynomial model of values from Z punctuation for the age in Mexico].
A nutritional status index was built by modeling the mathematical function of the mean Z scores of weight for age, from 60,079 children under five years of age, selected in a probabilistic fashion from the Mexican population. The most precise mathematical model was a fifth degree polynomial. The correlation coefficient was between .937<R<.999. The proposed index is the integral of the polynomial function, which represents the nutritional gap between the observed and the reference population. This model is used to analyze the characteristics of the different study populations. The index shows an improvement of -39.6 to -16.8 at the national level, between the years 1988 and 1999. This improvement is greater in urban (-36-4 to -8.4) than in rural areas (-48.8 in 1989, to -37.7 in 1999). The indigenous rural population of the country showed the highest levels of malnutrition (-54.4), as compared to the non-indigenous rural population (-37.1). In Mexico, City, the index was -5.9 in 1995, which represents an average of extreme nutritional values: -17.3 in the lower socioeconomic strata and 18.0 in the higher strata, the latter suggesting the presence of childhood obesity. This index is useful to estimate the epidemiological burden and the characteristics of malnutrition at early ages, as well as to assess the impact of interventions, without being altered by common biases related to the utilization of malnutrition prevalence values.


Perspectives on emerging zoonotic disease research and capacity building in Canada.
Zoonoses are fundamental determinants of community health. Preventing, identifying and managing these infections must be a central public health focus. Most current zoonoses research focuses on the interface of the pathogen and the clinically ill person, emphasizing microbial detection, mechanisms of pathogenicity and clinical intervention strategies, rather than examining the causes of emergence, persistence and spread of new zoonoses. There are gaps in the understanding of the animal determinants of emergence and the capacity to train highly qualified individuals; these are major obstacles to preventing new disease threats. The ability to predict the emergence of zoonoses and their resulting public health and societal impacts are hindered when insufficient effort is devoted to understanding zoonotic disease epidemiology, and when zoonoses are not examined in a manner that yields fundamental insight into their origin and spread. Emerging infectious disease research should rest on four pillars: enhanced communications across disciplinary and agency boundaries; the assessment and development of surveillance and disease detection tools; the examination of linkages between animal health determinants of human health outcomes; and finally, cross-disciplinary training and research. A national strategy to predict, prevent and manage emerging diseases must have a prominent and explicit role for veterinary and biological researchers. An integrated health approach would provide decision makers with a firmer foundation from which to build evidence-based disease prevention and control plans that involve complex human/animal/environmental systems, and would serve as the foundation to train and support the new cadre of individuals ultimately needed to maintain and apply research capacity in this area.


Characterization of adenylate cyclase-coupled alpha 2-adrenergic receptors in rat renal cortex using [3H]yohimbine.
Alpha 2 adrenergic receptors in rat renal cortex were measured with the antagonist ligand [3H]yohimbine. Renal cortical membranes contained 120 +/- 11.7 (SE) fmoles of binding sites per milligram of protein (n = 9). Their affinity for [3H]yohimbine was 10.4 +/- 0.5 (SE) nM (n = 9) from equilibrium studies and 7.2 +/- 3.3 (n = 4) from kinetic measurements. Alpha-adrenergic agonists and antagonists bound [3H]yohimbine sites with affinities consistent with alpha 2-receptor binding. The slope factors for the binding of all antagonists tested were close to 1, whereas agonists bound with slope factors of less than 1, consistent with the presence of receptors of more than one affinity. The alpha 2-receptors measured with [3H]yohimbine appeared to be coupled to the inhibition of adenylate cyclase. The affinities of alpha-adrenergic catecholamines measured in cyclase inhibition studies were similar to their affinities in binding studies when these were performed under conditions optimal for adenylate cyclase inhibition. Both sodium ion and GTP are required for maximal inhibition of renal cortical adenylate cyclase [Woodcock, E.A., C. I. Johnston, and C.A. Olsson. J. Cyclic Nucleotide Res. 6:261-271, 1980)]. Each of these factors produced a 10- to 20-fold decrease in the binding affinity of epinephrine. Together, a 100- to 200-fold decrease was produced. The concentrations of both sodium ion and GTP required to decrease the affinity of epinephrine were similar to the concentrations required for adenylate cyclase inhibition. This suggested that similar mechanisms were involved in decreasing the affinity of agonists for the alpha 2-receptor and promoting agonist-induced inhibition of adenylate cyclase.


Optimizing Two-level Supersaturated Designs using Swarm Intelligence Techniques.
Supersaturated designs (SSDs) are often used to reduce the number of experimental runs in screening experiments with a large number of factors. As more factors are used in the study, the search for an optimal SSD becomes increasingly challenging because of the large number of feasible selection of factor level settings. This paper tackles this discrete optimization problem via an algorithm based on swarm intelligence. Using the commonly used E(s2) criterion as an illustrative example, we propose an algorithm to find E(s2)-optimal SSDs by showing that they attain the theoretical lower bounds in Bulutoglu and Cheng (2004) and Bulutoglu (2007). We show that our algorithm consistently produces SSDs that are at least as efficient as those from the traditional CP exchange method in terms of computational effort, frequency of finding the E(s2)-optimal SSD and also has good potential for finding D3-, D4- and D5-optimal SSDs.


An essential splice site mutation (c.317+1G>A) in the TSHR gene leads to severe thyroid dysgenesis.
Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and 2% of cases have familial origin. Our aim in this study was to determine the genetic alterations in two siblings with CH coming from a consanguineous family. Because CH is often inherited in autosomal recessive manner in consanguineous/multicase-families, we first performed genetic linkage studies to all known causative CH loci followed by conventional sequencing of the linked gene. The family showed potential linkage to the TSHR locus, and we detected an essential splice site mutation (c.317+1G>A) in both siblings. RT-PCR analysis confirmed the functionality of the mutation. The mutation was homozygous in the cases whereas heterozygous in carrier parents and an unaffected sibling. Here we conclude that thyroid agenesis in both siblings in this study originates from c.317+1G>A splice site mutation in the TSHR gene, and this study underlines the importance of detailed molecular genetic studies in the definitive diagnosis and classification of CH.


[Optimal Bowel Preparation for Capsule Endoscopy and Device-assisted Enteroscopy].
For improved examination of video capsule endoscopy (VCE) and device-assisted enteroscopy (DAE), bowel preparation is an essential issue. Multiple factors like air bubbles, food material in the small bowel, and gastric and small bowel transit time affect the small bowel visualization quality (SBVQ), diagnostic yield (DY) and cecal completion rate (CR). Bowel preparation with polyethylene glycol (PEG) solution enhances SBVQ and DY, but it has no effect on CR. Bowel preparation with PEG solution 2 L is similar to PEG 4 L in SBVQ, DY, and CR. Bowel preparation with fasting or PEG solution combined with anti-foaming agents like simethicone enhance SBVQ, but it has no effect on CR. Bowel preparation with prokinetics is not commonly recommended. Optimal timing for purgative bowel preparation has yet to be established. However, the studies regarding bowel preparation for DAE are not sufficient. European Society of Gastrointestinal Endoscopy (ESGE) recommends 8-12 hours fasting from solid food and 4-6 hours fasting from liquids prior to the antegrade DAE. For retrograde DAE, colonoscopy preparation regimen is recommended. This article reviews the literature and ESGE, 2013 Korean published guidelines regarding bowel preparation for VCE and DAE, following suggestion for optimal bowel preparation for VCE and balloon enteroscopy.


Preferential decrease in IgG4 anti-citrullinated protein antibodies during treatment with tumour necrosis factor blocking agents in patients with rheumatoid arthritis.
To investigate the dynamics of IgG1 and IgG4 anti-citrullinated protein antibody (ACPA) subclasses during anti-tumour necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA). IgG, IgG1 and IgG4 ACPA levels were determined by ELISA on anti-citrullinated fibrinogen (ACF) and IgG1 : IgG4 ACPA ratios were calculated. A pilot study was performed in 28 ACF-positive patients treated with infliximab for one year. Confirmation of the results was obtained using a cohort of 180 consecutive patients treated with adalimumab for 28 weeks. The median reduction in ACF levels was 31% for total IgG, 29% for IgG1, 40% for IgG4 and 22% for the IgG4 : IgG1 ACF ratio in the infliximab cohort. In adalimumab-treated patients, ACF levels declined 14% for total IgG and IgG1, and 36% for IgG4 ACF; the IgG4 : IgG1 ratio was reduced by 24% (all percentage values p<0.05). The decrease in antibody levels was correlated with the clinical response; European League Against Rheumatism good responders had the greatest decline in antibody levels and this effect was most pronounced for IgG4 (48% reduction). The IgG4 : IgG1 ACF ratio preferentially decreased in patients with adequate therapeutic adalimumab levels. ACPA subclass distribution is modulated by effective anti-inflammatory treatment. The preferential decline of IgG4 ACPA, reflected by the decreased IgG4 : IgG1 ratio, suggests a beneficial effect of anti-TNF treatment on chronic antigenic stimulation by citrullinated proteins. This effect may be directly anti-TNF mediated or the result of effective dampening of the inflammation in the rheumatoid joint.


On quantifying the apparent temperature sensitivity of plant phenology.
Many plant phenological events are sensitive to temperature, leading to changes in the seasonal cycle of ecosystem function as the climate warms. To evaluate the current and future implications of temperature changes for plant phenology, researchers commonly use a metric of temperature sensitivity, which quantifies the change in phenology per degree change in temperature. Here, we examine the temperature sensitivity of phenology, and highlight conditions under which the widely used days-per-degree sensitivity approach is subject to methodological issues that can generate misleading results. We identify several factors, in particular the length of the period over which temperature is integrated, and changes in the statistical characteristics of the integrated temperature, that can affect the estimated apparent sensitivity to temperature. We show how the resulting artifacts can lead to spurious differences in apparent temperature sensitivity and artificial spatial gradients. Such issues are rarely considered in analyses of the temperature sensitivity of phenology. Given the issues identified, we advocate for process-oriented modelling approaches, informed by observations and with fully characterised uncertainties, as a more robust alternative to the simple days-per-degree temperature sensitivity metric. We also suggest approaches to minimise and assess spurious influences in the days-per-degree metric.


Standardizing Opioid Prescriptions to Patients After Ambulatory Oncologic Surgery Reduces Overprescription.
Overprescribing of opioids after surgery contributes to long-term abuse. Evaluating opioid prescription patterns and patient-reported opioid use offers an evidence-based method to identify potential overprescription. This quality improvement initiative aimed to reduce and standardize opioid prescriptions upon discharge from an ambulatory oncologic surgery center and evaluate the effect of this change on patients' subsequent opioid use and reported pain. Between March 2018 and January 2019, consecutive opioid-naïve patients aged ≥ 18 years who underwent robotic or laparoscopic hysterectomy, radical prostatectomy, or partial nephrectomy, or total mastectomy with or without immediate reconstruction were surveyed 7-10 days postoperatively. Data collected in the pre- (n = 551) and post-standardization (n = 480) cohorts included perception of pain relief, opioids prescribed (verified by electronic medical record review) and consumed, and refills received. Pre-standardization, the median opioid prescription at discharge was 20 pills (interquartile range [IQR] 20-28) or 140 oral morphine milligram equivalents (MME) (IQR 100-150). Median opioid consumption was 2 pills (IQR 0-7) or 10 MME (IQR 0-40) among all services. Opioid prescriptions were later standardized to 7, 8, and 10 pills (35, 40, and 75 MME), in the gynecology, urology, and breast services, respectively. The change was not associated with an increase in reported pain. Refill requests increased postintervention across all surgeries from 4.4% to 7.7%, with the largest increase among patients who underwent breast surgery. The number of opioid pills given at discharge to patients undergoing ambulatory or short-stay cancer surgery can safely be reduced.


Ultrasound-guided arterial line catheterization in the critically ill: technique and review.
Arterial line catheterization in the critically ill patient is often an arduous task. Here we identify risk factors in the critical care patient that may predict a more difficult arterial catheter insertion. We also describe our ultrasound technique and review of the literature with regard to location of access, complications, and the use of ultrasound guidance.


Solution-phase vertical growth of aligned NiCo2O4 nanosheet arrays on Au nanosheets with weakened oxygen-hydrogen bonds for photocatalytic oxygen evolution.
Vertical heterojunctions of two-dimensional (2D) semiconducting materials have attracted more and more research interest recently due to their unique optical, electrical, and catalytic properties and potential applications. Although great progress has been made, vertical integration of the layered materials formed by 2D semiconductor nanosheets and 2D plasmatic metal nanosheets remains a huge challenge. Here, we demonstrate for the first time a solution-phase growth of vertical plasmatic metal-semiconductor heterostructures in which aligned NiCo2O4 nanosheet arrays vertically grow on a single Au nanosheet, forming vertically aligned NiCo2O4-Au-NiCo2O4 sandwich-type heterojunctions with hierarchical open channels. Such vertical NiCo2O4-Au-NiCo2O4 heterojunctions can effectively promote the separation and transfer of a photoinduced charge. Density functional theory (DFT) studies and time-resolved transient absorption spectroscopy show that electrons transfer from NiCo2O4 to Au, and the formation of the heterojunction weakens the H-O bond of H2O. Due to the unique structure and superiority of the component, the vertical NiCo2O4-Au-NiCo2O4 heterojunctions exhibit significant activity with an O2 production rate of up to 33 μmol h-1 and long-term stability for photocatalytic water oxidation. We calculated the apparent quantum efficiency (AQE) to be 21.9% for NiCo2O4-Au-NiCo2O4 heterojunctions at the wavelength λ = 450 ± 10 nm, which is higher than that of NiCo2O4 nanosheets (10.9%), Au nanosheets (0.96%) and other photocatalysts. The present study paves the way for the controlled synthesis of novel vertical heterojunctions based on 2D semiconductor nanosheets and 2D metal nanosheets for efficient photocatalysis.


Potential Modulation of Vascular Function by Nitric Oxide and Reactive Oxygen Species Released From Erythrocytes.
The primary role for erythrocytes is oxygen transport that requires the reversible binding of oxygen to hemoglobin. There are, however, secondary reactions whereby the erythrocyte can generate reactive oxygen species (ROS) and nitric oxide (NO). ROS such as superoxide anion and hydrogen peroxide are generated by the autoxidation of hemoglobin. NO can be generated when nitrite reacts with hemoglobin forming an HbNO+ intermediate. Both of these reactions are dramatically enhanced under hypoxic conditions. Within the erythrocyte, interactions of NO with hemoglobin and enzymatic reactions that neutralize ROS are expected to prevent the release of any generated NO or ROS. We have, however, demonstrated that partially oxygenated hemoglobin has a distinct conformation that enhances hemoglobin-membrane interactions involving Band 3 protein. Autoxidation of the membrane bound partially oxygenated hemoglobin facilitates the release of ROS from the erythrocyte. NO release is made possible when HbNO+, the hemoglobin nitrite-reduced intermediate, which is not neutralized by hemoglobin, is bound to the membrane and releases NO. Some of the released ROS has been shown to be transferred to the vasculature suggesting that some of the released NO may also be transferred to the vasculature. NO is known to have a major effect on the vasculature regulating vascular dilatation. Erythrocyte generated NO may be important when NO production by the vasculature is impaired. Furthermore, the erythrocyte NO released, may play an important role in regulating vascular function under hypoxic conditions when endothelial eNOS is less active. ROS can react with NO and, can thereby modulate the vascular effects of NO. We have also demonstrated an inflammatory response due to erythrocyte ROS. This reflects the ability of ROS to react with various cellular components affecting cellular function.