Long-term bepridil monotherapy for angina pectoris.
The long-term efficacy of bepridil as once-a-day monotherapy was studied in 19 men with stable angina pectoris. After 2 weeks of single-blind placebo therapy and a 12-week parallel placebo-controlled, dose-response study, each patient received open-label bepridil. After a dose-titration period of 3 months, patients received bepridil (100 to 400 mg once a day, mean 290 mg) for 24 months. The response to treatment was assessed by patient diaries and serial treadmill exercise testing 24 hours after dose administration, every 3 months. Only 2 patients were released from the study due to therapeutic failure. Compared with placebo, 3 months of bepridil therapy resulted in a significant reduction in the weekly frequency of angina from 10.3 +/- 9.1 to 1.8 +/- 3.5 (p less than 0.002) and nitroglycerin consumption from 5.0 +/- 5.4 to 1.4 +/- 2.3 (p less than 0.01). In addition, there was a simultaneous significant increase in the walking time to angina from 5.2 +/- 2.3 to 7.9 +/- 2.6 minutes (p less than 0.001) and total exercise time from 7.1 +/- 2.2 to 8.8 +/- 1.9 minutes (p less than 0.001). These favorable effects were sustained throughout the 24 months of the study. Although resting QTc interval was prolonged by 36 to 42 ms (p less than 0.001) during bepridil therapy, ventricular dysrhythmias were not observed immediately before or during exercise testing and were not manifested by symptoms. Neurologic and gastrointestinal side effects of mild to moderate severity were observed, but none required discontinuation of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)


Antitumor Potential of Annona muricata Linn. An Edible and Medicinal Plant in Mexico: In Vitro, In Vivo, and Toxicological Studies.
Annona muricata (Am) is a plant used in traditional Mexican medicine to treat cancer. In this study, ethanol extracts of Am collected in Acapulco and Tecpan from Guerrero state were evaluated orally on Balb/c mice inoculated with 4T1 cells, for cytotoxic activity (CA) on 4T1 cells, in brine shrimp lethality assay (BSLA), and for acute oral toxicity in mice. In addition, ethanol extracts were subjected to high-performance liquid chromatography (HPLC) with diode array detection. Results showed that the extracts collected in December in Acapulco (AcDe) and Tecpan (TeDe) exhibited the most significant antitumor and cytotoxic activity. In the BSLA, the most important effect was observed in the extracts from Acapulco and Tecpan collected in June (AcJu) and August (TeAg), respectively. The samples from Acapulco (AcJu, and AcAg) and Tecpan (TeJu and TeAg) showed the highest toxicity. The analysis of the extracts, AcDe and TeDe, by HPLC revealed that flavonoids, rutin, narcissin, and nicotinflorin were the major components. These findings suggest that extracts from Am collected in Acapulco and Tecpan in the month of December may be an important source to obtain flavonoid glycosides with anticancer potential specifically against breast cancer. This also supports the use of Am to treat cancer in Mexican traditional medicine.


Microsatellite markers for the relictual dove tree, Davidia involucrata (Cornaceae).
Microsatellite markers were developed for the dove tree, Davidia involucrata (Cornaceae), a Tertiary relict currently endemic to China, to investigate its population genetics and phylogeography. Using the Fast Isolation by AFLP of Sequences Containing repeats (FIASCO) protocol, nine polymorphic microsatellite loci were identified and screened in 44 individuals from three wild populations of D. involucrata. The number of alleles per locus ranged from two to three, while the observed heterozygosity and expected heterozygosity ranged from 0.0000 to 0.6000 and from 0.0000 to 0.6323, respectively. These new microsatellite loci will facilitate further studies of the population genetics and phylogeography of D. involucrata, as well as of the evolutionary history of the plant and other Tertiary relicts endemic to East Asia.


Clinical and laboratory associations of severity in a Sri Lankan cohort of patients with serologically confirmed leptospirosis: a prospective study.
Leptospirosis results in significant morbidity and mortality. This study elucidates markers of severity in a cohort of Sri Lankan patients. Patients presenting to three healthcare institutions in the Western province of Sri Lanka with leptospirosis serological confirmed by the microscopic agglutination test (MAT) were included. Prospective data regarding demographic, clinical and laboratory parameters was extracted. Univariate associations and subsequent multivariate logistic regression models were constructed. The study included 232 patients, with 68.5% (159) demonstrating severe disease. Significant associations of severe disease at a significance level of p<0.05 were fever >38.8°C on presentation, age >40 years, muscle tenderness, tachycardia on admission, highest white cell count >12 350/mm(3) and <7900/mm(3), highest neutrophil percentage >84%, haemoglobin >11.2 g/dL and <10.2 g/dL, packed cell volume (PCV) >33.8% and <29.8%, lowest platelet count <63 500/mm(3), highest alanine transaminase (ALT) >70 IU/L and hyponatremia with sodium <131 mEq/L. On multivariate analysis, PCV <29.8% (p=0.011; OR 3.750; CI: 1.394-10.423), ALT >70 IU/L (p=0.044; OR 2.639; CI: 1.028-6.774) and hyponatremia <131 mEq/L (p=0.019; OR 6.413; CI: 1.353-30.388) were independent associations of severe disease. Severity associations were demonstrated with both clinical and laboratory parameters. There is a need for novel biomarkers for prediction of severity in leptospirosis.


Ascertaining of age by Raman spectroscopic analysis of apical dentin - A forensic study.
Age estimation in forensics employ various methods of which Raman microspectroscopy provides a noninvasive method by assessing various parts of dentin. The aim of this study is to ascertain the age of carious tooth using Raman spectra of apical dentin and to correlate the similarity of the spectra in a defined age group. Teeth of known age from Indian population (n=48) and morphology (incisors, canine, premolars, molars) indicated for extraction due to caries were allocated into four groups, i.e., Group A (21-30 years), Group B (31-40 years), Group C (41-50 years) and Group D (51-60 years). Teeth were sectioned and the apical 2 mm of dentin was examined by a Raman microspectroscopy machine for spectra from 400 cm-1 to 1500 cm-1, and peak at phosphate group at 963 cm-1 was taken for statistical analysis. The data were analyzed using IBM SPSS version 20.0. Pearson's correlation to test the strength of linear relation of the spectra of the teeth within an age group showed an "r" value approaching 1. One-way ANOVA to test the difference between means of spectrum values obtained between the four age groups was statistically significant at P < 0.05. Raman spectroscopic analysis of apical dentin of teeth affected by caries can also be used to estimate the age and the Raman spectra obtained differed for different age groups, and the same can be advocated as an alternative method to ascertain age in forensic dentistry.


MRI-guided biopsy in inflammatory myopathy: initial results.
The purpose of this report is to describe our initial experience with techniques employing magnetic resonance imaging (MRI) to guide the choice of muscle to be biopsied in patients suspected of having inflammatory myopathy. Five patients with a clinical diagnosis of inflammatory myopathy (IM) were studied. Four were imaged prior to biopsy. Four had repeated examinations, either immediately following biopsy or to evaluate disease progression. Use of MRI to localize muscle lesions was associated with abnormal pathologic findings in all cases, including histopathologic demonstration of lymphocyte infiltration in three cases of idiopathic polymyositis; nonspecific myopathic changes were seen in one patient with probable dermatomyositis and in one patient with chronic inflammatory polyneuropathy and high serum creatine kinase levels (> 45,000 IU/ml). The precise location of the area sampled by biopsy was visible in only one of four postbiopsy images. MRI shows promise in identifying pathologic muscle in patients suspected of having one of the inflammatory myopathies; however, further refinement of localization techniques may be needed to optimize histopathologic diagnoses.


Pelvic floor disorders in postpartum adolescents in the Western Amazon: a cross-sectional study.
To analyze the postpartum pelvic floor disorders (PFD) and mode of delivery among adolescents, late adolescents, and young women from Western Amazon. Cross-sectional study was carried out in the urban area of Western Amazon in the city of Rio Branco, Acre, Brazil, from October 2016 to February 2017. This is a convenience sample of women up to 30 years who completed six months postpartum, separated in three groups according to maternal age: adolescents (age ≤19 years), late adolescents (20-24 years), and young women (25-30 years). Participants were home interviewed and answered Pelvic Floor Distress Inventory-20 (PFDI-20). Delivery clinical data were collected from patient's medical records. In total, 285 participants were interviewed: 41 adolescents, 103 late adolescents, and 141 young women. After controlling for confounding factors, prevalences of PFD were higher in the adolescents' group compared with the young women's group (urinary incontinence [UI], prevalence ratio [PR] = 1.75, 95% CI 1.14-2.69; urge urinary incontinence [UUI], PR = 1.88, 95% CI 1.02-3.47; stress urinary incontinence, PR = 2.00, 95% CI 1.11-3.62; fecal incontinence [FI], PR = 4.40, 95% CI 1.36-14.27). PFDI-20 scores also presented higher values in the adolescent group (Pelvic Organ Prolapse Distress Inventory [POPDI], PR = 2.02, 95% CI 1.49-2.75; urinary distress inventory [UDI], PR = 2.09, 95% CI 1.47-2.98; PFDI, PR = 2.12, 95% CI 1.47-2.98). Analyzing the influence of cesarean section, adolescents have higher prevalence of UI (PR = 1.84, 95% CI 1.04-3.26, P=0.037), UUI (PR = 2.36, 95% CI 1.03-5.40, P=0.042), and FI (PR = 4.09, 95% CI 1.21-13.81, P=0.023). In addition, POPDI (PR = 2.15, 95% CI 1.60-2.89, P<0.001), UDI (PR = 2.25, 95% CI 1.61-3.16, P<0.001), and PFDI (PR = 2.27, 95% CI 1.68-3.08, P<0.001) scores are also higher among adolescents where the baby is born by cesarean section. Adolescents present higher prevalence and symptoms of PFD; furthermore, cesarean delivery has a greater negative influence on the pelvic floor of adolescents when compared with young women. This reinforces the importance of PFD investigation among the adolescent population, mainly in developing countries which have high rates of adolescent pregnancy and cesarean section.


Continuous de novo synthesis of neurosteroids is required for normal synaptic transmission and plasticity in the dentate gyrus of the rat hippocampus.
Both in vivo and in vitro studies have shown that neurosteroids promote learning and memory by modulating synaptic functions in the hippocampus. However, we do not know to what degree endogenously synthesized neurosteroids contribute to the hippocampal synaptic functions. Cytochrome P450scc is the enzyme that converts cholesterol to pregnenolone (PREG), which is required for the biosynthesis of all other neurosteroids. To investigate the physiological roles of endogenous neurosteroids in synaptic functions, we electrophysiologically examined the effects of aminoglutethimide (AG), a selective inhibitor of P450scc, on the synaptic transmission and plasticity in the dentate gyrus of rat hippocampal slices. The application of AG (100 μM) decreased the slope of the field excitatory postsynaptic potentials (fEPSPs) in granule cells by 20-30% in 20 min through the modulation of postsynaptic AMPA receptors, while it did not affect the presynaptic properties, including the paired-pulse ratio and the probability of glutamate release from presynaptic terminals. The AG-induced depression was nearly completely rescued by exogenously applied 500 nM PREG or by 1 nM dehydroepiandrosterone sulfate (DHEAS), one of the neurosteroids synthesized from PREG, suggesting that the AG-induced depression was caused by the loss of DHEAS. AG also reduced NMDA receptor activity, and suppressed high-frequency stimulation (HFS)-induced long-term potentiation (LTP). These findings provide novel evidence that the endogenous neurosteroids locally synthesized in the brain are required to maintain the normal excitatory synaptic transmission and plasticity in the dentate gyrus of the rat hippocampus.


Analyzing the function of the insert region found between the α and β-subunits in the eukaryotic nitrile hydratase from Monosiga brevicollis.
The functional roles of the (His)17 region and an insert region in the eukaryotic nitrile hydratase (NHase, EC 22.214.171.124) from Monosiga brevicollis (MbNHase), were examined. Two deletion mutants, MbNHaseΔ238-257 and MbNHaseΔ219-272, were prepared in which the (His)17 sequence and the entire insert region were removed. Each of these MbNHase enzymes provided an α2β2 heterotetramer, identical to that observed for prokaryotic NHases and contains their full complement of cobalt ions. Deletion of the (His)17 motif provides an MbNHase enzyme that is ∼55% as active as the WT enzyme when expressed in the absence of the Co-type activator (ε) protein from Pseudonocardia thermophila JCM 3095 (PtNHaseact) but ∼28% more active when expressed in the presence of PtNHaseact. MbNHaseΔ219-272 exhibits ∼55% and ∼89% of WT activity, respectively, when expressed in the absence or presence of PtNHaseact. Proteolytic cleavage of MbNHase provides an α2β2 heterotetramer that is modestly more active compared to WT MbNHase (kcat = 163 ± 4 vs 131 ± 3 s-1). Combination of these data establish that neither the (His)17 nor the insert region are required for metallocentre assembly and maturation, suggesting that Co-type eukaryotic NHases utilize a different mechanism for metal ion incorporation and post-translational activation compared to prokaryotic NHases.


Photoionization microscopy.
We present the first experimental results of a technique called photoionization microscopy. Photoelectrons ejected in threshold photoionization of Xe are detected in a velocity map imaging apparatus, and interferences between various trajectories by which the electron moves from the atom to the detector are observed. The structure of the interference pattern, which contains the transverse component of the electronic wave function, evolves smoothly with the excess energy above the saddle point. The main observed features are interpreted within the framework of the semiclassical approximation.


The effect of uptake by adrenergic nerve terminals on the sensitivity of arterial vessels to topically applied noradrenaline.
1. Direct observations were made of the rat mesenteric vasculature in vivo. They showed a gradual increase in the sensitivity to topically applied noradrenaline from the larger arteries to the precapillary arterioles which was paralleled by a gradual decrease in the density of the adrenergic innervation. 2. Both cocaine and chronic denervation increased the sensitivity to noradrenaline of the innervated arterial vessels, approximately in proportion to the density to their innervation. They did not affect the sensitivity of the non-innervated precapillary arterioles. 3. It is concluded that the sensitivity gradient to topically applied noradrenaline results mainly from the uptake of the applied catecholamine by the perivascular nerve terminals.


Shifts of microbial community and metabolic function during food wastes and waste activated sludge co-fermentation in semi-continuous-flow reactors: Effects of fermentation substrate and zero-valent iron.
The effects of food wastes (FW) composition and zero-valent iron (ZVI) on the volatile fatty acids (VFAs) generation, bacterial community succession and related metabolic functions during long-term FW and waste activated sludge (WAS) co-fermentation were investigated. The VFAs production in the carbohydrate-enriched reactor was approximately 3.0-folds of that in FW reactor. The ZVI contributed to the VFAs promotion by 3.6- and 6.7-folds in carbohydrate-enriched and FW reactors, respectively. Firmicutes (20.1-74.7%), Actinobacteria (0.9-26.3%), Bacteroidetes (3.4-65.7%), and Proteobacteria (9.1-28.5%) were the main bacteria in different fermentation reactors, and they were closely associated with the fermentation substrates and ZVI. Further analysis demonstrated that the key metabolic capacity (i.e. amino acid, carbohydrate and energy metabolism) and the genetic expressions of enzymes (i.e. fabA, fabZ, accA and accB) involved in VFAs generation were also related to FW composition, and were improved by the ZVI, which accounted for the significant VFAs promotion.


The first state-level public health program for obstructive airway disease in India: An early field-level evaluation.
Chronic obstructive pulmonary disease (COPD) is the second leading cause of mortality in India; however, there are no programs for COPD in India at primary care level. Kerala became the first state in India to implement a program at primary care for COPD, called the Step Wise Approach to Airway Syndrome program. The objective of the study was to evaluate and document the implementation status of a program for obstructive airway disease (OAD) in Trivandrum district of Kerala state in India and compare the treatment characteristics of patients with OAD seeking care from the centers implementing and not implementing this program for OADs. A cross-sectional study was done as early evaluation of a program for OAD implemented in Kerala state, India, from October 2018 to February 2019. A reflection of the health-seeking behavior due to better facilities at the FHCs. There was no difference in the hospital visits or emergency department visits between the two groups. However, there was a statistically significant difference in the average number of visits per patient to health center for taking injectable drugs and visits for nebulization. Forty-nine (94%) of the COPD and 36 (100%) of the asthma patients underwent spirometry from implementing center itself. A higher proportion of patients receiving care from implementing centers (30.9%) never had to buy inhalers from outside. This is the first time that a public health programme for chronic respiratory disease management at primary care level was evaluated in India. The study has provided valuable insights on the need for strengthening the training for health care providers as well as patient education in bringing about a change in patient attitudes.


Seasonal pattern of bovine fasciolosis in the Kafue and Zambezi catchment areas of Zambia.
In order to establish seasonality of bovine fasciolosis in the Southern province of Zambia, 288 cattle were examined at slaughter at Turnpike slaughter slab for 1 year. The examination involved liver inspection and coprological examination. Liver condemnation rates were relatively high at the beginning of both the cold dry season and the rainy season (May/June and December, respectively). All cattle, regardless of age, had higher fluke abundances in the post-rainy season (39.1% young and 42.1% adult) while the lowest rates were in the hot dry season (13.3% young and 14.3% adult). On coprological examination, the highest abundance was in the post-rainy season (45.0%) and the lowest in the cold dry season (24.9%). From November (end of dry season) to February/March (end of rains), more fluke eggs were found than in any other period. The distribution of fluke eggs was significantly different (p<0.001) among the four seasons. Identified associations were: egg counts were highest in post-rainy (mean abundance=146) and lowest in cold dry season (mean abundance=118) at 95% confidence (CI 0.64-1.25). Differences in abundance observed according to origin, sex and age of cattle were not significant on both methods. Based on these results, it may be concluded that Fasciola gigantica was present throughout the year in cattle in Zambia but the abundance was highest in the post-rainy season and lowest in the cold dry season.


A Comparison of 2,845 Head and Neck Injuries in Various Martial Arts.
The primary purpose of this study is to estimate and compare the frequencies, types, and hospital admission rates of head and neck injuries in subjects who practice different martial art fighting styles, including karate, kung fu, kickboxing, taekwondo, judo, and jiu jitsu. The investigators designed and implemented a 20-year cross-sectional study using the National Electronic Injury Surveillance System database. Information related to head and neck martial art injuries from January 2000 through December 2019 was included in this study. Study variables were obtained from both patient demographics and injury characteristics (date of injury, diagnosis, body part, type of martial art, and disposition). Patient and injury characteristics were compared through χ2 and independent sample tests. Taekwondo was the most likely type of martial art to lead to a head injury (P < .01), whereas jiu jitsu (P < .01) and judo (P < .01) were most likely to cause neck injuries. The type of martial art was not significantly associated with admission rates (P = .190); however, patients with head injuries were more likely to be admitted relative to patients who did not suffer head injuries (P < .05). Moreover, injuries secondary to judo were more likely to result in admissions relative to that of all other martial arts (P < .05). Judo was the most severe martial art during this time period as it led to the highest rate of hospital admissions. Karate injuries are most likely to occur in younger populations of fighters under the age of 18 years.


Barcoding in the dark? A critical view of the sufficiency of zoological DNA barcoding databases and a plea for broader integration of taxonomic knowledge.
The functionality of standard zoological DNA barcoding practice (the identification of unknown specimens by comparison of COI sequences) is contingent on working barcode databases with sufficient taxonomic coverage. It has already been established that the main barcoding repositories, NCBI and BOLD, are devoid of data for many animal groups but the specific taxonomic coverage of the repositories across animal biodiversity remains unexplored. Here, I shed light on this mystery by contrasting the number of unique taxon labels in the two databases with the number of currently recognized species for each animal phylum. The numbers reveal an overall paucity of COI sequence data in the repositories (15.13% total coverage across the recognized biodiversity on Earth, and 20.76% average taxonomic coverage for each phylum) and, more importantly, bear witness to the idleness towards numerous phyla, rendering current barcoding efforts either ineffective or inaccurate. The importance of further integrating taxonomic expertise into barcoding practice is briefly discussed and some guidelines, previously mentioned in the barcoding literature, are suggested anew. Finally, the asserted values concerning the taxonomic coverage in barcoding databases for Animalia are contrasted with those of Plantae and Fungi.


Chick embryo chorioallantoic membrane as a suitable in vivo model to evaluate drug delivery systems for cancer treatment: A review.
Cancer represents a significant public health problem. More than 18.1 million people are annually diagnosed with cancer and 9.6 million die mainly due to metastatic disease. Chemotherapy has been one of the main cancer treatment modalities; however, most of the chemotherapeutic agents are non-specific, exhibiting several toxic side effects, which compromises the patient's quality of life. Therefore, it is necessary to search for new therapeutic alternatives, using for example, drug delivery systems (DDS) to target cancer cells, increasing the selectivity of chemotherapeutic drugs. This approach is promising; however, it is crucial to evaluate the biological performance of the systems. Although mammalian models continue to be explored for clinical applications, they are time-consuming and very restrictive from the ethical and legal perspectives. Hence, the chick embryo chorioallantoic membrane (CAM) has been shown to be a suitable in vivo model since it allows a more appropriate model for the study of drugs and/or DDS performance than in vitro tests. Thereby, this article revises the recent advances of DDS for cancer therapy, evaluating the feasibility of the CAM model.


Molecular mechanism of extinction of liver-specific functions in mouse hepatoma x rat fibroblast hybrids: extinction of the albumin gene.
Hybrids formed by the fusion of mouse hepatoma (BWTG3) and rat fibroblast (JF1) cells exhibit the extinction of mouse albumin and alpha-fetoprotein synthesis. Karyotype analyses suggest that all parental chromosomes are present in the hybrids. The extinction, therefore, of mouse hepatocyte genes is attributed to the inhibitory action of the rat genome. In these studies, we show that these hybrids possess and express the mouse beta-glucuronidase gene (which is encoded on the same chromosome as the mouse albumin and alpha-fetoprotein gene), and we present data of Southern blot analysis which demonstrate that such hybrids have indeed retained both mouse and rat albumin DNA sequences. In addition, using mouse albumin cDNA, we have shown by cDNA-RNA reassociation kinetics that albumin mRNA is virtually absent in these hybrids. We conclude from these studies that the extinction of albumin synthesis involves a mechanism which results in the loss of cytoplasmic albumin mRNA.


L-type Ca2+ channel modulation by dihydropyridines potentiates kappa-opioid receptor agonist induced acute analgesia and inhibits development of tolerance in rats.
The effect of 1,4-dihydropyridine (DHP) calcium channel blockers (CCBs), nimodipine (NIM) and lercanidipine (LDP) on the analgesic response of selective kappa-opioid receptor agonists, U50,488H, PD117,302 and U69,593 was determined in male Sprague-Dawley rats using the tail-flick test. The effect of NIM on development of tolerance to U50,488H-induced analgesia and the status of brain DHP-sensitive Ca(2+) channel (L-type) binding sites in both U50,488H-naive and tolerant rats was determined using the highly selective DHP radioligand, [(3)H]PN200-110. Tolerance was induced by injecting U50,488H (25 mg/kg, i.p.) twice daily for 4 days. Intraperitoneal (i.p.) injection of kappa-opioid receptor agonists produced a dose-dependent acute analgesic response. NIM (1 mg/kg; i.p.) and LDP (0.3 mg/kg; i.p.) used in the study produced no tail-flick analgesia. Administration of NIM and LDP (15 min prior) significantly potentiated the analgesia produced by three kappa-opioid receptor agonists. Tolerance developed completely to the analgesic effect induced by U50,488H (25 mg/kg, i.p.) administered on the 5th day. NIM (1 mg/kg, i.p.) twice daily for 4 days not only completely inhibited the development of tolerance to analgesic response but also significantly potentiated it (supersensitivity). There was a significant up-regulation of DHP binding sites (B(max): +41%) in whole brain membranes of tolerant rats when compared to vehicle treated naive rats, implicating increased influx of Ca(2+) through L-type channels in kappa-opioid tolerance. U50,488H (25 mg/kg, i.p.) and NIM (1 mg/kg, i.p.) twice daily for 4 days also resulted in an equivalent up-regulation of DHP binding sites (+36%) as that of U50,488H alone. These results strongly suggest a functional role of L-type Ca(2+) channels in the regulation of pain sensitivity, mechanism of kappa-opioid analgesia and expression of tolerance.


Research in Atrial Fibrillation: A Scientometric Analysis Using the Novel Web Application SciPE.
This study sought to determine the quantity and quality of publications in AF research using large-scale scientometric data analyses. Research in atrial fibrillation (AF) has increased over time. The increasing number of research papers makes it harder to identify relevant research work. All 21,603 publications from 1945 to 2018 were retrieved from Web of Science and analyzed regarding geographical distribution of scientific output and international research cooperation. The total number of AF publications has significantly increased since the millennium change, from 3,063 (14.2%) in 1945 to 1999 to 18,540 (85.8%) publications in 2000 to 2018. AF research grew 10-fold compared with overall medical research since 1990 (ratio of AF publications to all publications: 0.02% (n = 99 of 410,701) in 1990 vs. 0.2% (n = 1,967 of 1,172,649) in 2018; p < 0.05). Quantitatively, the United States contributed 25.9% of AF research, followed by Japan (8.0%), Germany (7.8%), China (7.3%), and the United Kingdom (5.9%). In the all-time modified h-index, the United States ranked first (13.3% of all nations), followed by Canada (8.5%) and the United Kingdom (6.3%). In relation to population, Denmark was the best-rated nation, with the lowest number of inhabitants per publication (11,457), followed by Sweden (18,426) and the Netherlands (25,749), and per modified h-index (90,746), followed by Sweden (170,602) and the Netherlands (218,203). Measuring publications per research institute, Denmark again ranked first, with 19.2 publications per institute, followed by Italy (14.9) and Sweden (13.8). An intensive cooperation between nations was apparent. This study showed an increase in publication activity in AF research. The United States was the leading country in quantity of research efforts. Related to population and research institutes, Denmark ranked first.


The 2018 Bioinformatics Open Source Conference (GCCBOSC 2018).
In 2018, the annual Bioinformatics Open Source Conference was held for the first time in conjunction with the Galaxy Community Conference, as an experiment to see if we could reach people in the bioinformatics community who aren't part of the audience attracted by ISMB. Held in June 2018 at Reed College in Portland, Oregon, GCCBOSC (Galaxy Community Conference and Bioinformatics Open Source Conference) attracted over 300 participants from around the world. The meeting started with two days of training, followed by two days of talks and poster/demo sessions (with some joint and some parallel sessions). The joint sessions included well-received keynote talks by Tracy Teal, Fernando Pérez and Lucia Peixoto, as well as a panel discussion about documentation and training. After the main meeting, many attendees stayed for up to four additional collaboration days, an extended version of the Codefests that have been held in conjunction with previous BOSCs. GCCBOSC was a successful experiment. The organizers concluded that the best way to serve the broadest community of potential BOSC attendees will be to partner some years with the International Society for Computational Biology (ISMB) and others with GCC.


Feasibility and relevance of global expression profiling of gene transcripts in serum from breast cancer patients using whole genome microarrays and quantitative RT-PCR.
Previous studies, by ourselves and others, have indicated that gene transcripts are detectable extracellularly. Advancing on this work, in order to investigate the feasibility of analysing global gene expression profiles and so the possibility in the future of identifying panels of circulating mRNA biomarkers that may be diagnostic, prognostic or predictive for cancer, here we performed the first whole genome microarray analysis of human serum. RNA was isolated from pre-surgery serum and corresponding breast tumour and normal tissue biopsies, and from post-surgery and normal control serum. Specimens were examined using Affymetrix whole genome microarrays and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Of the 54,675 mRNAs/variants analysed, approximately 8% and 45% were called Present in serum and breast tissue specimens, respectively. Differentially expressed genes were identified for each group of specimens analysed. Analysis, by qRT-PCR, of 3 selected transcripts further indicated that the nucleic acids detected were mRNA, not DNA. mRNAs are apparently present in serum and their global detection and identification can be successfully achieved using microarray technologies. The potential implication of this novel finding is that using microarrays it may be possible to identify a panel of extracellular mRNAs that are diagnostic, prognostic and/or predictive of outcome for cancer patients.


Endoscopic management of choledochal cyst.
Choledochal cyst is an uncommon anomaly of the biliary tract. Experience with this disorder, with emphasis on the role of ERCP in management, is presented. All pertinent data for 13 patients with choledochal cyst seen between 1987 and 1998 were reviewed, retrospectively. Cholangitis, either alone or associated with other findings, was the main presenting feature (69.23% of patients). Bilobar Caroli's disease was the most common cyst type (46.15% of patients). ERCP was diagnostic alone in 46.15% of patients and therapeutic in 53.85%. Choledochal cyst is a complex condition that requires early diagnosis. Long-term management remains controversial, and guidelines for treatment require revision. Whether interventional ERCP will obviate the need for surgery or alter the malignant potential of the disorder remains uncertain.


Transplantation of insulin-producing cells from umbilical cord mesenchymal stem cells for the treatment of streptozotocin-induced diabetic rats.
Although diabetes mellitus (DM) can be treated with islet transplantation, a scarcity of donors limits the utility of this technique. This study investigated whether human mesenchymal stem cells (MSCs) from umbilical cord could be induced efficiently to differentiate into insulin-producing cells. Secondly, we evaluated the effect of portal vein transplantation of these differentiated cells in the treatment of streptozotocin-induced diabetes in rats. MSCs from human umbilical cord were induced in three stages to differentiate into insulin-producing cells and evaluated by immunocytochemistry, reverse transcriptase, and real-time PCR, and ELISA. Differentiated cells were transplanted into the liver of diabetic rats using a Port-A catheter via the portal vein. Blood glucose levels were monitored weekly. Human nuclei and C-peptide were detected in the rat liver by immunohistochemistry. Pancreatic β-cell development-related genes were expressed in the differentiated cells. C-peptide release was increased after glucose challenge in vitro. Furthermore, after transplantation of differentiated cells into the diabetic rats, blood sugar level decreased. Insulin-producing cells containing human C-peptide and human nuclei were located in the liver. Thus, a Port-A catheter can be used to transplant differentiated insulin-producing cells from human MSCs into the portal vein to alleviate hyperglycemia among diabetic rats.


Patient-related factors may affect the outcome of neuropsychological rehabilitation in multiple sclerosis.
The aim of this study was to identify factors associated with neuropsychological rehabilitation outcome in patients with multiple sclerosis (MS). Ninety-eight relapsing-remitting MS patients received multimodal neuropsychological intervention (attention retraining, teaching compensatory strategies, psychoeducation, psychological support, and homework assignments) conducted once a week in 60-minute sessions during thirteen consecutive weeks. The evaluated factors included: 1) patient-related (baseline objective and subjective cognitive performance, mood, fatigue, as well as demographic factors); 2) illness-related (duration and severity of the disease); and 3) intervention-related factors (amount of computer-based attention exercises and homework assignments, therapist's evaluation of the benefit, and therapist). Patient-related factors affected rehabilitation outcome, whereas illness- and intervention-related factors did not. The results showed that especially MS patients with male gender and more severe attentional deficits benefitted from the intervention. Patient-related factors may affect neuropsychological rehabilitation outcome in MS.


Correlation between Acanthosis Nigricans Scoring Chart (ANSC) and narrowband reflectance spectrophotometer in assessing severity of acanthosis nigricans.
There is a lack of standardized tool to monitor treatment outcome of acanthosis nigricans. To meet this end, we developed the Acanthosis Nigricans Scoring Chart (ANSC) that evaluates skin color (score range of 1-8) and skin texture (score range of 1-6), which adds up to a total ANSC score (score range of 2-14). We aimed to determine the correlation of ANSC to narrowband reflectance spectrophotometry and to evaluate its reliability. A cross-sectional study was conducted in adult acanthosis nigricans patients. Two raters independently graded participants using ANSC twice, in which scores were correlated to readings from Mexameter MX18. Intra- and interrater reliability were also evaluated via intraclass correlation coefficient (ICC). Participants had mean (sd) melanin and erythema indices of 615.8 (176.2) and 451.4 (53.4), respectively. Mean (sd) total ANSC score was 9.43 (2.43). The total ANSC score and skin color subdomain demonstrated strong correlations (r > 0.6) with spectrophotometric results, whereas skin texture showed a moderate correlation (r = 0.4-0.6). Total ANSC score generally had excellent intra- and interrater reliabilities (ICC > 0.85). The total ANSC score and its subdomains strongly correlate with spectrophotometer and demonstrate excellent reliability in assessing acanthosis nigricans.


Treatment outcome and its attributes in TB-HIV co-infected patients registered under Revised National TB Control Program: a retrospective cohort analysis.
DOTS treatment has shown to be effective in TB patients with or without HIV infection although there have been some conflicting evidence. This may be due to various factors associated with HIV-TB co-infection and its treatment. Thus the present study was planned to study the outcome of DOTS and factors associated with same in TB-HIV co-infected patients. A retrospective cohort analysis was done. 886 TB-HIV co-infected patients who were registered under RNTCP were the subjects. Data from RNTCP was obtained on diagnosis of TB, HIV and TB therapy and some attributes. Average cure rate for NSP TB-HIV co-infected patients was 72% compared with 83% of total NSP registered patients (P < 0.001). Death rate in NSP TB-HIV co-infected patients was 16% (P < 0.001). In non-NSP TB-HIV co-infected patients, success rate was 80%. Death rate was significantly higher i.e. 12% in non-NSP TB-HIV co-infected cases as compared with 6% in total registered patients. Death rate was 19% in RT TB-HIV co-infected patients while 11% in all registered RT cases (P < 0.001). In TB-HIV co-infected patients paediatric patients, patients with extra pulmonary TB and new patients without any history of previous treatment had a higher chance of success at treatment. Patients with Pulmonary TB had higher chance of death. Success rate was significantly lower and death rate was significantly higher among the TB-HIV co-infected cohort with age, type of TB and history of previous treatment affecting the success rate of treatment and type of TB affecting the death rate.


Development and validation of a model to predict the risk of recurrence in patients with laryngeal squamous cell carcinoma after total laryngectomy.
Recurrence is still the main obstacle to the survival of laryngeal squamous cell carcinoma (LSCC) patients who have undergone a total laryngectomy. Previous models for recurrence prediction in patients with LSCC were based on pathological information, while the role of easily accessible inflammatory markers in the prognosis of LSCC patients has rarely been reported. This study sought to develop and validate a model to predict the risk of recurrence in LSCC patients who underwent total laryngectomy. A total of 204 LSCC patients who underwent a total laryngectomy were included in this retrospective cohort study. Demographics, pathology, and inflammatory markers of patients were collected. All the patients were randomly divided into a training set and a test set at a ratio of 4:1. Patients were followed up for 3 years after surgery or until death occurred during this period. The random-forest method was used to develop a predictive model. The performance of the model was evaluated by calculating the area under the receiver operating characteristic (ROC) curve (AUC) with the 95% confidence interval (CI), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Of the 204 LSCC patients, 56 (27.45%) patients had a recurrence. The random-forest prediction model was an all-factor model, and the most important predictors of the model were the albumin/globulin ratio (AGR), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR), with proportions of 0.121, 0.100, and 0.092, respectively. The AUCs of the model in predicting the recurrence of LSCC in the training set and the test set were 0.960 (95% CI, 0.931-0.989) and 0.721 (95% CI, 0.716-0.726), respectively. The sensitivity, specificity, accuracy, PPV, and NPV of the model in the test set were 0.750 (95% CI, 0.505-0.995), 0.690 (95% CI, 0.521-0.858), 0.707 (95% CI, 0.568-0.847), 0.500 (95% CI, 0.269-0.921), and 0.870 (95% CI, 0.732-1.000), respectively. A model to predict the risk of recurrence in LSCC patients who have undergone a total laryngectomy was established, and inflammatory markers AGR, NLR, and PLR play an important role in the predictive model.


Modification of the double-disk test for detection of enterobacteriaceae producing extended-spectrum and AmpC beta-lactamases.
Detection of extended-spectrum beta-lactamases (ESBLs) in AmpC-producing Enterobacteriaceae is problematic. A modification of the double-disk test (MDDT) has been developed for successful detection of ESBLs in gram-negative bacilli producing well-characterized beta-lactamases as well as 212 clinical isolates of Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, and Citrobacter freundii. MDDT accurately differentiated between ESBL producers and derepressed chromosomal AmpC mutants. MDDT provides a cost-effective alternative approach for clinical microbiology laboratories for routine susceptibility testing with simultaneous detection of ESBLs in enterobacteriaceae.


A region on the human thyrotropin receptor which can induce antibodies that inhibit thyrotropin-mediated activation of in vitro thyroid cell function also contains a highly immunogenic epitope.
Autoantibodies to the thyrotropin receptor (TSHr) bind to the extracellular domain of the TSHr (ETSHr) and either stimulate or inhibit thyroid cell function and/or growth. In order to investigate the regulation and the specificity of the immune response to the TSHr, our laboratory recently produced recombinant human ETSHr protein by using the baculovirus expression system. In the present study, we used the recombinant ETSHr protein, a panel of overlapping synthetic peptides derived from the TSHr, and polyclonal rabbit antibodies produced against recombinant ETSHr and synthetic peptides to define a highly immunogenic region (aa 352-388) of the TSHr. Moreover, we used competitive inhibition studies to identify a dominant epitope (aa 367-372) within this region to which ETSHr antibodies react. This immunodominant epitope lies within a region unique to the TSHr when compared to the other glycoprotein hormone receptors. These data, together with the earlier observation that antibodies against aa region 357-372 can inhibit thyrotropin (TSH)-mediated activation of thyroid cells in culture, show that aa 367-372 represents, an immunodominant epitope within a functionally important region which is unique to the TSHr. Therefore, this region may play an important role in the induction or modulation of the specific immune response against the TSHr.


Aspergillus nidulans UDP-galactopyranose mutase, encoded by ugmA plays key roles in colony growth, hyphal morphogenesis, and conidiation.
Growing resistance to current anti-fungal drugs is spurring investigation of new targets, including those in fungal wall metabolism. Galactofuranose (Galf) is found in the cell walls of many fungi including Aspergillus fumigatus, which is currently the most prevalent opportunistic fungal pathogen in developed countries, and A. nidulans, a closely-related, tractable model system. UDP-galactopyranose mutase (UGM) converts UDP-galactopyranose into UDP-Galf prior to incorporation into the fungal wall. We deleted the single-copy UGM sequence (AN3112.4, which we call ugmA) from an A. nidulans nkuADelta strain, creating ugmADelta. Haploid ugmADelta strains were able to complete their asexual life cycle, showing that ugmA is not essential. However, ugmADelta strains had compact colonial growth, which was associated with substantially delayed and abnormal conidiation. Compared to a wildtype morphology strain, ugmADelta strains had aberrant hyphal morphology, producing wide, uneven, highly-branched hyphae, with thick, relatively electron-dense walls as visualized by transmission electron microscopy. These effects were partially remediated by growth on high osmolarity medium, or on medium containing 10 microg/mL Calcofluor, consistent with Galf being important in cell wall structure and/or function.


Shedding Light on the Photophysics and Photochemistry of I-Motifs Using Quantum Mechanical Calculations.
I-motifs are non-canonical DNA structures formed by intercalated hemiprotonated (CH·C)+ pairs, i.e., formed by a cytosine (C) and a protonated cytosine (CH+), which are currently drawing great attention due to their biological relevance and promising nanotechnological properties. It is important to characterize the processes occurring in I-motifs following irradiation by UV light because they can lead to harmful consequences for genetic code and because optical spectroscopies are the most-used tools to characterize I-motifs. By using time-dependent DFT calculations, we here provide the first comprehensive picture of the photoactivated behavior of the (CH·C)+ core of I-motifs, from absorption to emission, while also considering the possible photochemical reactions. We reproduce and assign their spectral signatures, i.e., infrared, absorption, fluorescence and circular dichroism spectra, disentangling the underlying chemical-physical effects. We show that the main photophysical paths involve C and CH+ bases on adjacent steps and, using this basis, interpret the available time-resolved spectra. We propose that a photodimerization reaction can occur on an excited state with strong C→CH+ charge transfer character and examine some of the possible photoproducts. Based on the results reported, some future perspectives for the study of I-motifs are discussed.


A Randomized Controlled Trial of an Outpatient Protocol for Transitioning Children from Tube to Oral Feeding: No Need for Amitriptyline.
To assess the role of amitriptyline in the effectiveness of an outpatient protocol for weaning medically complicated children from tube to oral feeding. Twenty-one children seen in multidisciplinary outpatient feeding teams across 4 sites were recruited to a randomized placebo-controlled trial of a 6-month outpatient treatment protocol with behavioral, oral-motor, nutrition, and medication components. All of the children who completed the 6-month program (73%) were weaned to receive only oral feeding, regardless of group assignment. The transition from tube to oral feeding resulted in decreases in body mass index percentile and pain, some improvements in quality of life, and no statistically significant changes in cost. Amitriptyline is not a key component of this otherwise effective outpatient, interdisciplinary protocol for weaning children from tube to oral feeding. ClinicalTrials.gov: NCT01206478.


Do laypeople recognize youth as a risk factor for false confession? A test of the 'common sense' hypothesis.
In a survey of confession experts, 94% agreed that youth is a risk factor for false confession, but only 37% felt that jurors understand this. To date, no study has tested the latter by comparing laypeople's perceptions of juvenile and adult suspects. To address this gap, Experiment 1 participants read a lengthy (i.e. interrogation and confession) or abridged (i.e. confession-only) transcript of an ostensibly juvenile or adult suspect's interrogation. Transcript length affected perceived pressure but not guilt judgments. Suspect age had little effect, with 75% of participants misjudging the juvenile as guilty. Experiment 2 then tested how expert testimony affects judgments of juvenile suspects. Participants read a lengthy or abridged interrogation transcript, with or without testimony from a juvenile confession expert. Expert testimony somewhat impacted guilt judgments but did not influence perceptions of the interrogation. Implications for interrogation practices, trial procedure and future research are discussed.


Differentiation of single-cell organisms according to elongation stages crucial for gene expression efficacy.
We analyzed the interrelation between the efficiency of a gene expression and the nucleotide composition of all protein-coding sequences in 38 unicellular organisms whose complete genomic sequences are known. These organisms comprise 37 prokaryotic (29 eubacteria and eight archaebacteria) and one eukaryotic (yeast) species. We demonstrated that frequency analysis of gene codon composition fails to reflect adequately the gene expression efficiency of all these organisms. We constructed a measure, the elongation efficiency index, that considers simultaneously the information on codon frequencies and the degree of mRNA local self-complementarity. This measure recognizes the ribosome-coding genes as highly expressed in all the unicellular organisms studied. According to our analysis, these species fall into five groups differentiated by the process that makes the key contribution to the elongation rate.


Comparison of color fundus photographs and fundus autofluorescence images in measuring geographic atrophy area.
To assess the agreement between color fundus photographs (CFP) and fundus autofluorescence (FAF) images when measuring geographic atrophy (GA) area and reproducibility of measurements between graders. Frequency and disagreement types were also determined. Eyes with GA secondary to age-related macular degeneration had CFP and FAF imaging on the same day. Seventy-two eyes from 72 patients were included in the analysis. Three graders calculated GA area using digital imaging software. Main outcome measures included agreement between graders for GA area on both FAF and CFP and agreement between both imaging modalities. The intraclass correlation for the 3 graders for FAF images was 0.99 (95% confidence interval, 0.98-0.99). For CFP, it was 0.96 (95% confidence interval, 0.94-0.97). The intraclass correlation between imaging modalities for Graders 1, 2, and 3 were 0.93, 0.85, and 0.87, respectively. Sensitivities to detect involvement of fovea (CFP, 86-97%; FAF, 72-93%) and specificities to detect sparing of fovea (CFP, 74-76%; FAF, 59-88%) overlapped between imaging modalities. Both CFP and FAF imaging are reliable for measuring GA area. Interobserver agreement was slightly higher for FAF images. Although the high agreement between modalities suggests that either would be appropriate for measuring GA area, using both may be the best approach for following GA progression.


An aminocaproic acid-grafted chitosan derivative with superior antibacterial and hemostatic properties for the prevention of secondary bleeding.
Uncontrolled bleeding is one of the leading causes of human mortality. Existing hemostatic materials or techniques cannot meet the clinical requirements for safe and effective hemostasis. The development of novel hemostatic materials has always been of great interest. Chitosan hydrochloride (CSH), a derivative of chitin, is extensively used on wounds as an antibacterial and hemostatic agent. However, the formation of intra- or intermolecular hydrogen bonds between hydroxyl and amino groups limits its water solubility and dissolution rate and affects its effectiveness in promoting coagulation. Herein, we covalently grafted aminocaproic acid (AA) to the hydroxyl and amino groups of CSH via ester and amide bonds, respectively. The solubility of CSH in water (25 °C) was 11.39 ± 0.98 % (w/v), whereas the AA-grafted CSH (CSH-AA) reached 32.34 ± 1.23 % (w/v). Moreover, the dissolution rate of CSH-AA in water was 6.46 times higher than that of CSH. Subsequent studies proved that CSH-AA is non-toxic, biodegradable, and has superior antibacterial and hemostatic properties to CSH. Additionally, anti-plasmin activity can be exerted by the dissociated AA from the CSH-AA backbone, which can help to lessen secondary bleeding.


Selective facilitation of the serotonin(1B) receptor causes disorganization of thalamic afferents and barrels in somatosensory cortex of rat.
Alteration of serotonin (5-HT) levels influences developing thalamocortical afferents (TCAs) in primary somatosensory cortex (SI) of rats and mice. The 5-HT(1B) receptor, present on TCAs during the first postnatal week, may be involved in these effects. The present study asked whether administration of 5-nonyloxytriptamine (NNT), a selective 5-HT(1B) receptor agonist, affects TCA organization in rat SI. Littermates were injected five times daily (5x/day), with either 0.1 mg/kg NNT or vehicle from birth to postnatal day 6 (P-6). Animals were killed on P-6, and their brains were processed for high-performance liquid chromatography (HPLC), cytochrome oxidase (CO) histochemistry, cresyl violet, or demonstration of TCAs by placement of 1,1'-dioctadecyl-3,3,3'' 3'-tetra-methylindocarbocyanine perchlorate (Di-I) on thalamocortical radiations. At P-6, NNT treatment decreased 5-HT levels slightly compared with controls, although this difference was not statistically significant. In NNT-treated rats, the Di-I-labeled vibrissae-related pattern showed a range of effects, from fusion of patches related to mystacial vibrissae in treated animals to a less distinct vibrissae-related pattern in SI barrelfield compared with controls. Staining for CO and Nissl stain in layer IV of SI showed a similar range of abnormalities. These results indicate that the agonist action of NNT at the 5-HT(1B) receptor causes TCA disorganization in rat barrel field cortex in the absence of elevated 5-HT.


Childbirth Education Prior to Pregnancy? Survey Findings of Childbirth Preferences and Attitudes Among Young Women.
The childbirth preferences and attitudes of young women prior to pregnancy (N = 758) were explored in a cross-sectional survey. Sources of influential childbirth information and self-reported childbirth learning needs were described. Young women's attitudes about childbirth, including the degree of confidence in coping with a vaginal birth, whether birth is considered a natural event, and expectations of labor pain were associated with their mode of birth preference. Conversations with friends and family were the most influential source of childbirth information. Gaps in knowledge about pregnancy and birth were identified. An improved understanding of women's preferences and attitudinal profiles can inform the structure and content of educational strategies that aim to help the next generation of maternity care consumers participate in informed decision making.


Topical psoralen photochemotherapy (PUVA) and superficial radiotherapy in the treatment of chronic hand eczema.
The therapeutic efficacy of conventional superficial radiotherapy and topical psoralen photochemotherapy (topical PUVA) administered over a 6 week period was compared in a double-blind study of 21 patients with chronic bilateral constitutional hand eczema. One hand was treated with conventional superficial radiotherapy and the other with topical 8-methoxy-psoralen and long-wave ultraviolet light (topical PUVA). Significantly better clinical improvement was seen in superficial radiotherapy treated hands over topical PUVA treated hands after 6 weeks of treatment, but this difference was not maintained at 9 or 18 weeks. There was no significant difference in symptom severity between the two treatments after 6 weeks, but superficial radiotherapy produced significantly more symptomatic improvement at 9 and 18 weeks. Superficial radiotherapy is a less time consuming procedure than topical PUVA and leads to more rapid improvement.


Ultrastructural and immunocytochemical characterization of ameloblast-enamel adhesion at maturation stage in amelogenesis in Macaca fuscata tooth germ.
Maturation-stage ameloblasts are firmly bound to the tooth enamel by a basal lamina-like structure. The mechanism underlying this adhesion, however, remains to be fully clarified. The goal of this study was to investigate the mechanism underlying adhesion between the basal lamina-like structure and the enamel in monkey tooth germ. High-resolution immunogold labeling was performed to localize amelotin and laminin 332 at the interface between ameloblasts and tooth enamel. Minute, electron-dense strands were observed on the enamel side of the lamina densa, extending into the degrading enamel matrix to produce a well-developed fibrous layer (lamina fibroreticularis). In un-demineralized tissue sections, mineral crystals smaller than those in the bulk of the enamel were observed adhering to these strands where they protruded into the surface enamel. Immunogold particles reactive for amelotin were preferentially localized on these strands in the fibrous layer. On the other hand, those for laminin 332 were localized solely in the lamina densa; none were observed in the fibrous layer. These results suggest that the fibrous layer of the basal lamina-like structure is partly composed of amelotin molecules, and that these molecules facilitate ameloblast-enamel adhesion by promoting mineralization of the fibrous layer during the maturation stage of amelogenesis.


Sensorimotor deficits produced by phenytoin and chlorpromazine in unanesthetized cats.
Unanesthetized adult cats were evaluated for suprasegmental reflex activity and motor skills before and after administration of chlorpromazine (0.0625--0.5 mg/kg) alone and in combination with phenytoin (20 mg/kg). The greatest deficits were seen in the tests of balance and corrdination in which half the animals failed to match their control responses after administration of chlorpromazine and phenytoin. The impairment was most noticeable with the most stringent test (walking a 4 cm wide beam), and the effects of the two drugs were additive. Although there was no effect of either drug on muscle strength, the two drugs in combination depressed the animals' motivational state, making them less willing to work against imposed loads. Neither drug, alone or in combination, altered responses to the flexor reflex, blind placing, the hopping response or visually aided placing. It is concluded that the effects of chlorpromazine and phenytoin on motor control are selective for the CNS loci which control balance and coordination. Although the two drugs produce additive responses, the deficits occur only at doses which are well above those needed for clinical efficacy and thus may not pose a problem in their long term clinical use.


Factors associated with waiting time for surgery.
To explore the factors associated with waiting times for surgery in public hospitals. Three major acute care public hospitals in one Area Health Service. 691 adult patients entered onto the computerised booking list between 16 and 22 November 1994, and then between 16 January and 12 February 1995, were interviewed prospectively and followed up over a minimum of 18 months. Data were obtained from the Area Health Service's computerised booking system and patient self-report. Relevant surgical specialty, urgency rating, employment status and health insurance status were significantly associated with waiting time. Age, hospital, sex, country of birth, education, marital status and holding a Health Care Card were not significantly associated with waiting time. Self-reported health status (as measured by the SF-36) was not associated with waiting time for surgery. Waiting time for surgery was not simply determined by how urgently patients need surgery, but also by the type of surgery needed and patient's employment and health insurance status. The extent of disability experienced by patients, as measured by the SF-36, was not reflected in waiting times for surgery.


Examining Test Cutoffs to Optimize Diagnosis of Latent Tuberculosis Infection in People Born Outside the United States.
Rationale: Detection of latent tuberculosis infection (LTBI) in persons born in high tuberculosis (TB) incidence countries living in low TB incidence countries is key to TB elimination in low-incidence countries. Optimizing LTBI tests is critical to targeting treatment. Objectives: To compare the sensitivity and specificity of tuberculin skin test (TST) and two interferon-γ release assays at different cutoffs and of a single test versus dual testing. Methods: We examined a subset (N = 14,167) of a prospective cohort of people in the United States tested for LTBI. We included non-U.S.-born, human immunodeficiency virus-seronegative people ages 5 years and older with valid TST, QuantiFERON-TB Gold-in-Tube (QFT), and T-SPOT.TB (TSPOT) results. The sensitivity/specificity of different test cutoffs and test combinations, obtained from a Bayesian latent class model, were used to construct receiver operating characteristic (ROC) curves and assess the area under the curve (AUC) for each test. The sensitivity/specificity of dual testing was calculated. Results: The AUC of the TST ROC curve was 0.81 (95% credible interval (CrI), 0.78-0.86), with sensitivity/specificity at cutoffs of 5, 10, and 15 mm of 86.5%/61.6%, 81.7%/71.3%, and 55.6%/88.0%, respectively. The AUC of the QFT ROC curve was 0.89 (95% CrI, 0.86-0.93), with sensitivity/specificity at cutoffs of 0.35, 0.7, and 1.0 IU/mL of 77.7%/98.3%, 66.9%/99.1%, and 61.5%/99.4%. The AUC of the TSPOT ROC curve was 0.92 (95% CrI, 0.88-0.96) with sensitivity/specificity for five, six, seven, and eight spots of 79.2%/96.7%, 76.8%/97.7%, 74.0%/98.6%, and 71.8%/99.5%. Sensitivity/specificity of TST-QFT, TST-TSPOT, and QFT-TSPOT at standard cutoffs were 73.1%/99.4%, 64.8%/99.8%, and 65.3%/100%. Conclusion: Interferon-γ release assays have a better predictive ability than TST in people at high risk of LTBI.


Assessment of sun-safety education behavior via spectrophotometric evaluation: A preliminary study.
Biases inherent in self-assessment of sun exposure and sun-safe behavior may lead to inaccurate conclusions about the effectiveness of sun-safety educational programs. We aimed to compare self-reports to objective measures of sun exposure, when examining the effectiveness of passive versus active educational interventions. From May to June 2018, 73 participants recruited at a dermatology clinic were sequentially assigned to receive sun-safety education through one of 3 modes: interactive online module, video, or no education. A baseline Sun Exposure and Behavior Inventory (SEBI) questionnaire was administered, and spectrophotometric measurements of sun-exposed and sun-protected areas were taken and reported in the CIE L*a*b* color space. Participants were followed 4-8 and 16 weeks after the initial visit where the SEBI was re-administered, and serial measurements of skin color were taken. The change in SEBI scores and L*a*b values, as calculated by the individual typology angle (ITA°), was analyzed. There was a significant increase in skin darkening in all the groups at 4-8 and 16 weeks follow-up. There was no statistically significant difference between the groups in the magnitude of color change. However, subjectively at 4-8 weeks post-intervention, participants in the interactive module and video groups had significantly improved self-reported SEBI scores compared to control (p < .05, Kruskal-Wallis). By 16 weeks, only the interactive module group showed significant improvement in SEBI scores compared to control (p < .05, ANOVA). In determining the effectiveness of sun-safety programs, spectrophotometric evaluation of sun-induced skin pigmentation can allow for a more complete evaluation of self-reported sun exposure and sun-protective behavior.


Characterisation of Anopheles strains used for laboratory screening of new vector control products.
Insecticides formulated into products that target Anopheles mosquitos have had an immense impact on reducing malaria cases in Africa. However, resistance to currently used insecticides is spreading rapidly and there is an urgent need for alternative public health insecticides. Potential new insecticides must be screened against a range of characterized mosquito strains to identify potential resistance liabilities. The Liverpool School of Tropical Medicine maintains three susceptible and four resistant Anopheles strains that are widely used for screening for new insecticides. The properties of these strains are described in this paper. WHO tube susceptibility bioassays were used for colony selection and to screen for resistance to the major classes of public health insecticides. Topical and tarsal contact bioassays were used to produce dose response curves to assess resistance intensity. Bioassays with the synergist piperonyl butoxide were also performed. Taqman™ assays were used to screen for known target site resistance alleles (kdr and ace-1). RT-qPCR was used to quantify expression of genes associated with pyrethroid resistance. Pyrethroid selection pressure has maintained resistance to this class in all four resistant strains. Some carbamate and organophosphate resistance has been lost through lack of exposure to these insecticide classes. The Anopheles gambiae (sensu lato) strains, VK7 2014, Banfora M and Tiassalé 13 have higher levels of pyrethroid resistance than the An. funestus FUMOZ-R strain. Elevated expression of P450s is found in all four strains and the 1014F kdr mutation is present in all three An. gambiae strains at varying frequencies. Tarsal contact data and overexpression of CYP4G16 and SAP2 suggest penetration barriers and/or sequestration also confer resistance in Banfora M. Continual selection with deltamethrin has maintained a stable pyrethroid-resistant phenotype over many generations. In conjunction with a standardized rearing regime, this ensures quality control of strains over time allowing for robust product comparison and selection of optimal products for further development. The identification of multiple mechanisms underpinning insecticide resistance highlights the importance of screening new compounds against a range of mosquito strains.


Analysis of ceftazidime and related compounds by micellar electrokinetic chromatography.
A micellar electrokinetic chromatographic method for the separation and quantification of ceftazidime, its delta2-isomer and pyridine (two ceftazidime related impurities) was developed and validated. Optimised conditions were obtained using an electrolyte system consisting of 25 mM sodium tetraborate, at pH 9.2, and 75 mM sodium dodecylsulphate. A limit of detection of 0.2 microg ml(-1) and a limit of quantitation of 0.6 microg ml(-1) were estimated for pyridine and delta2-isomer: this means that levels of < 0.1% of pyridine and delta2-isomer in ceftazidime can be determined. Calibration curves for all analytes were linear over the studied ranges with correlation coefficients >0.999. Good reproducibility for migration times and corrected peak areas were achieved (RSD % 0.3 and 1.0, respectively). The results demonstrate that the method is reproducible, accurate and appropriate for ceftazidime assay in pharmaceutical samples.


Hemiarthroplasty in high risk elderly patient under epidural anesthesia with 0.75% ropivacaine-fentanyl versus 0.5% bupivacaine-fentanyl: Clinical trial.
Anesthetic management of elderly patients is a challenge as aging makes them more susceptible to hemodynamic fluctuations during regional anesthesia. This study was aimed to compare the clinical efficacy of epidural 0.75% ropivacaine fentanyl (RF)- with 0.5% bupivacaine-fentanyl (BF) for hemiarthroplasty in high-risk elderly patients. Sixty elderly consented patients of either sex with American Society of Anesthesiologist ASA II and III, scheduled for elective hemiarthroplasty were randomized into two Groups of 30 patients to receive epidural study solution of 15 mL of 0.75% Ropivacaine or 0.5% Bupivacaine with 1 mL fentanyl (50 μg). The hemodynamic variability with onset and duration of sensory and motor blocks were recorded. The adequacy and quality of surgical anesthesia were assessed. The post-epidural nausea and vomiting, shivering, respiratory parameters, or any other side effects were also recorded. There was no difference in the demographic profile between groups. The mean onset time to achieve sensory block to the T10 dermatome was rapid in the Group BF (12.4±6.9 vs. 17.5±3.7 min in Group RF). The mean time to achieve motor block was 17.5±3.4 min in Group BF versus 21.7±7.8 min in Group RF. The intraoperative hemodynamic fluctuations showed statistically significant differences between groups. The pruritis was observed in five patients but post-epidural shivering, nausea, vomiting, respiratory depression, or urinary retention were not observed in any patient. Epidural 0.75% Ropivacaine with fentanyl showed better clinical profile as compared to 0.5% Bupivacaine with fentanyl for hemiarthroplasty in elderly patients.


Falsely elevated D-dimer partially caused by heterophilic antibodies: A case report.
Plasma D-dimer is a screening marker for thrombosis and hemostasis disorders. Falsely elevated D-dimer may result in misdiagnosis and potentially invasive investigations. Therefore, identifying falsely elevated D-dimer is of great value in laboratory practice. D-dimer is determined by immunoassay and vulnerable to heterophilic antibody interference. Here, we reported a case of falsely elevated D-dimer partially caused by heterophilic antibodies. Dilution test, polyethylene glycol precipitation, heterophilic blocking reagent and method comparison were used to identify the heterophilic antibody interference. All these methods, except for the heterophilic blocking reagent, revealed the existence of heterophilic antibody interference. Polyethylene glycol precipitation failed to reduce the D-dimer to its reference interval. Therefore, we conclude that the falsely elevated D-dimer is partially caused by heterophilic antibody interference.


Influence of phospholipids on the assessment of factor VIII activity.
In view of reported discrepancies between different factor VIII assays, the influence of phospholipids on the performance of one-stage clotting (OS) and chromogenic substrate (CS) assays was evaluated. The B domain deleted recombinant factor VIII, rVIII SQ, two full-length recombinant products and a plasma derived factor VIII concentrate were each diluted into severe haemophilia A plasma and assayed against a plasma standard. The one-stage activity was 50, 80, 75 and 106%, respectively, of the chromogenic result. Variations in the phospholipid concentration did not affect the chromogenic assay, except at very low levels where the apparent activity increased. In contrast, dilution of the phospholipid reagent had a substantial influence on the activity measured by OS assays, especially in the case of rVIII SQ. At low levels of phospholipid, the one-stage activity of rVIII SQ exceeded the chromogenic result. When mixtures of phosphatidylserine (PS) and phosphatidyl-choline (PC) were used as a source of phospholipid, the OS results for rVIII SQ agreed well with the CS activity as long as the content of PS was below 10%, i.e., closer to the physiological level. At higher levels of PS, as in most commercial APTT reagents, the OS activity decreased. When the APTT reagent was replaced by platelets in the OS assay, the results compared well with those obtained by the CS assay for both t-VIII SQ and full-length factor VIII products.


Involvement of temperature sensitive syncytium inducing VSV or defective retroviruses in the development of spongiform encephalopathies.
Various enveloped viruses can induce syncytia in competent cells. Some temperature-sensitive mutants can express the trans-membrane viral G antigen under non-permissive conditions. The G antigen can then migrate at long distances, engulfing thousands of cells without producing any virus. When a temperature-sensitive vesicular stomatitis virus (VSV) infects a sensitive host, and under the condition that the G antigen is expressed, spongiosis can be induced in the central nervous system in the absence of detectable virus multiplication. We postulate that such a mechanism might be observed with various enveloped viruses, as recently illustrated with knock-out mice experimentally infected with defective murine leukemia virus (MULV).


Antibodies to Herpes simplex virus types 1 and 2 in patients with squamous-cell carcinoma of uterine cervix in India.
Antibody activity to Herpes simplex virus type-1 (HSV-1) and type-2 (HSV-2) was measured by the indirect hemagglutination (IHA) test in sera from 124 women with squamous-cell carcinoma of the uterine cervix, 46 women with non-cervical cancer and 116 matched normal women. The type-specific antibodies were assayed by IHA inhibition test. The proportion of cervical cancer cases positive for HSV-2 infection was significantly greater than that of non-cervical cancer cases and matched control women. No difference was observed in the percentages positive for HSV-1 infection among the three study groups. The mean titers of antibodies to HSV-1 as well as HSV-2 were significantly higher than the respective titers in the other two study groups. However, determination of type-specific antibodies did not help in establishing evidence for past infection by HSV-2 in patients with cervical cancer, as no type-specific HSV-2 antibodies were produced in 58% of the cases. The cervical cancer cases were also analysed according to clinical staging (Stages 0 to IV) and histological differentiation of squamous-cell carcinoma. Neither the percentage of positives for HSV-2 infection nor HSV-antibody titers varied, either in clinical staging or in histological differentiation of cervical cancer. These findings suggest that HSV-2 may be related to cervical cancer as an etiological agent but not as a passenger virus of carcinomatous tissue.


Association of beta-defensin-1 gene polymorphisms with Pseudomonas aeruginosa airway colonization in cystic fibrosis.
Lung disease and Pseudomonas aeruginosa (P. aeruginosa) airway colonization represent a major cause of morbidity and mortality in cystic fibrosis (CF). Human beta-defensin (hBD)-1 is believed to play an important role in mucosal innate immunity in the lung. This study aimed to investigate whether three single-nucleotide polymorphisms (SNPs) in the 5'-untranslated region of DEFB1, G-52A, C-44G and G-20A were associated with P. aeruginosa airway colonization in CF. A total of 224 CF patients and 196 control subjects were studied. DEFB1 SNPs were characterized by restriction fragment length polymorphisms. Patients' sputum samples were collected and analyzed by standard methods. Single SNP analysis suggested that CF patients carrying the -52AA and the -20GG genotypes had a higher rate of P. aeruginosa airway colonization than patients homozygous and heterozygous for the -52G and -20A alleles (P=0.01 and P=0.007, respectively). A significant association between the ACG haplotype and chronic P. aeruginosa infection was also identified (odds ratio (95% confidence interval): 3.00 (1.42-6.36), P=0.004). These results indicate that variant alleles in DEFB1 might contribute to the colonization of P. aeruginosa in CF.


Influence of interleukin-6 gene -174G>C polymorphism on development of atherosclerosis: a meta-analysis of 50 studies involving 33,514 subjects.
Increasing epidemiological studies have focused on the associations between interleukin-6 (IL-6) gene -174G>C polymorphism and atherosclerotic diseases, but the results are still controversial. This meta-analysis was designed to identify whether this association exists. PubMed, Embase, Web of Science, Cochrane database, Clinicaltrials.gov and Current Controlled Trials, Chinese Clinical Trial Registry, CBMdisc, CNKI and Google Scholar were searched to get the genetic association studies. The crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the IL-6 gene -174G>C polymorphism and atherosclerosis ( AS ) risk. The subgroup analyses were made on the following: ethnicity, atherosclerotic diseases and source of controls. Finally, 50 studies (15,029 cases and 18,485 controls) were included in this meta-analysis. Overall, no significant association was found between the IL-6 gene -174G>C polymorphism and AS risk (for C allele vs. G allele: OR=1.02, 95% CI=0.94-1.11, p=0.64; for C/C vs. G/G: OR=1.01, 95% CI=0.85-1.21, p=0.88; for C/C vs. C/G+G/G: OR=0.97, 95% CI=0.84-1.12, p=0.68; for C/C+C/G vs. G/G: OR=1.07, 95% CI=0.97-1.17, p=0.18). In the subgroup analyses, significant associations were found between the IL-6 gene -174G>C polymorphism and AS in non-Caucasian group (for CC+CG vs. GG: OR=1.22, 95% CI=1.06-1.41, p=0.005), other atherosclerotic diseases group (for C allele vs. G allele: OR =0.75, 95% CI=0.61-0.93, p=0.008; for C/C vs. G/G: OR=0.56, 95% CI=0.38-0.81, p=0.002; for C/C vs. C/G+G/G: OR=0.60, 95% CI=0.45-0.79, p=0.0004) and population-based group (for C allele vs. G allele: OR=1.09, 95% CI=1.00-1.18, p=0.04; for CC+CG vs. GG: OR=1.15, 95% CI=1.04-1.27, p=0.005). In summary, the present meta-analysis suggests that the IL-6 gene -174G C polymorphism is associated with the susceptibility to AS. However, due to the high heterogeneity in the meta-analysis, the results should be interpreted with caution.


SMRT compounds correct nonsense mutations in primary immunodeficiency and other genetic models.
Within less than 10 years after the realization of the double helix of DNA, the ability of aminoglycosides to influence the misreading or readthrough of premature termination codons was discovered. It took another three decades to clone and sequence disease genes and appreciate the similarity of mutation spectra for most inborn errors. Nonsense mutations once again have become the target of readthrough compounds. In this brief review, we trace the development in our laboratory of the next generation of readthrough agents, small molecule readthrough (SMRT) drug-like chemicals, and assays for comparing their in vitro activity. Possible mechanisms of action and potential clinical applications are considered.


Estimating and testing autocorrelation with small samples: a comparison of the C-statistic to a modified estimator.
Huitema and McKean (Psychological Bulletin, 110, 291-304, 1991) recently showed, in a Monte-Carlo study, that five conventional estimators of first-order autocorrelation perform poorly for small (< 50) sample sizes. They suggested a modified estimator and a test for autocorrelation. We examine an estimator not considered by Huitema and McKean: the C-statistic (Young, Annals of Mathematical Statistics, 12, 293-300, 1941). A Monte-Carlo study of the small sample properties of the C-statistic shows that it performs as well or better than the modified estimator suggested by Huitema and McKean (1991). The C-statistic is also shown to be closely related to the d-statistic of the widely used Durbin-Watson test.


3D QSAR CoMFA/CoMSIA, molecular docking and molecular dynamics studies of fullerene-based HIV-1 PR inhibitors.
For the first time, a set of experimentally reported [60] fullerene derivatives were subjected to the 3D-QSAR/CoMFA and CoMSIA studies. The aim of this study is to propose a series of novel [60] fullerene-based inhibitors with optimal binding affinity for the HIV-1 PR enzyme. The position of the template molecule at the cavity of HIV-1 PR was optimized and 3D QSAR models were developed. Relative contributions of steric/electrostatic fields of the 3D-QSAR/CoMFA and CoMSIA models have shown that steric effects govern the bioactivity of the compounds, but electrostatic interactions play also an important role.The de novo drug design Leapfrog simulations provided a series of novel compounds with predicted improved inhibition effect.


Evaluation of a co-extraction kit for mRNA, miRNA and DNA methylation-based body fluid identification.
Recently, messenger RNA (mRNA), micro RNA (miRNA), and DNA methylation (DNAm) have been reported as novel markers for body fluid identification (BFID). Comprehensive analysis of these markers should be a flexible and reliable BFID method for various types of forensic samples. However, independent extraction of all targets can be difficult depending on the usable amounts of samples. In this study, the applicability of a co-extraction kit for these molecules, the AllPrep DNA/RNA/miRNA Universal Kit (APU), was evaluated by comparing RNA and DNA extracted from blood and saliva stains by the APU with those extracted by standard kits for each molecule and by previously reported methods for mRNA/DNA or miRNA/DNA co-extraction. Electrophoresis using the Bioanalyzer platform and real-time PCR analysis revealed that the APU performed almost equivalently to each standard kit in the quality of RNA or DNA extracted and extraction efficiency of mRNAs, miRNAs, and DNA. Moreover, the APU outperformed the co-extraction methods, especially in RNA integrity and miRNA extraction efficiency. In addition, pyrosequencing revealed that the methylation ratios of DNA extracted by the APU were not different from those extracted by standard DNA extraction kits. Overall, the APU is applicable to comprehensive analysis of mRNA/miRNA/DNAm markers for BFID analysis. Because the DNA eluate can also be used for DNA typing, the APU may be among the best choices for forensic examination of body fluid samples in terms of its flexibility and reliability in BFID and efficiency in sample consumption.


Neutrophil and monocyte phagocytosis in depressed patients.
1. Monocyte and neutrophil phagocytosis was investigated in a group of depressed patients during the active phase of their illness and following recovery. The results were compared with those obtained from a group of schizophrenia and manic patients and with age and sex matched controls. Neutrophil phagocytosis was reduced in all three patient groups during the active phase of the illness but returned to control values on recovery. Monocyte phagocytosis was however increased but while it returned to control values following recovery of the depressed patients, it remained raised in the manic and schizophrenic patients. 2. T-cell replication in response to a mitogen challenge was also investigated in the depressed patients. This was found to be significantly reduced in the depressed patients during the active phase of the illness and remained reduced following their recovery. 3. The results suggest that the changes in phagocytosis and T-cell replication are state and trait markers respectively of depression. 4. A differential white blood cell count revealed that the neutrophil number was increased and the monocytes decreased, in the depressed patients during the active phase of the illness, but returned to normal values on recovery. 5. The factor(s) responsible for the changes in these various aspects of the immune function is unknown. However, evidence is presented that the changes are not due to hypercortisolaemia or to the direct effects of the psychotropic medication on phagocytosis or T-cell replication.


Can home care work be organized to promote health among the workers while maintaining productivity? An investigation into stakeholders' perspectives on organizational work redesign concepts based on the Goldilocks Work principles.
Due to the aging population, the need for home care services is increasing in most Western countries, including Norway. However, the highly physical nature of this job could contribute to make recruiting and retaining qualified home care workers (HCWs) challenging. This issue may be overcome by adopting the Goldilocks Work principles, aiming at promoting workers' physical health by determining a "just right" balance between work demands and recovery periods while maintaining productivity. The aim of this study was to 1) gather suggestions from home care employees on suitable organizational (re)design concepts for promoting HCWs' physical health and 2) have researchers and managers define actionable behavioral aims for the HCWs for each proposed (re)design concept and evaluate them in the context of the Goldilocks Work principles. HCWs, safety representatives, and operation coordinators (n = 14) from three Norwegian home care units participated in digital workshops led by a researcher. They suggested, ranked, and discussed redesign concepts aimed at promoting HCWs' health. The redesign concepts were subsequently operationalized and evaluated by three researchers and three home care managers. Workshop participants suggested five redesign concepts, namely "operation coordinators should distribute work lists with different occupational physical activity demands more evenly between HCWs", "operation coordinators should distribute transportation modes more evenly between HCWs", "Managers should facilitate correct use of ergonomic aids and techniques", "HCWs should use the stairs instead of the elevator", and "HCWs should participate in home-based exercise training with clients". Only the first two redesign concepts were considered to be aligned with the Goldilocks Work principles. A corresponding behavioral aim for a "just right" workload was defined: reduce inter-individual differences in occupational physical activity throughout a work week. Operation coordinators could have a key role in health-promoting organizational work redesign based on the Goldilocks Work principles in home care. By reducing the inter-individual differences in occupational physical activity throughout a work week, HCWs' health may be improved, thus reducing absenteeism and increasing the sustainability of home care services. The two suggested redesign concepts should be considered areas for evaluation and adoption in practice by researchers and home care services in similar settings.


Neutrophil dependence of vascular remodeling after Mycoplasma infection of mouse airways.
Vascular remodeling is a feature of sustained inflammation in which capillaries enlarge and acquire the phenotype of venules specialized for plasma leakage and leukocyte recruitment. We sought to determine whether neutrophils are required for vascular remodeling in the respiratory tract by using Mycoplasma pulmonis infection as a model of sustained inflammation in mice. The time course of vascular remodeling coincided with the influx of neutrophils during the first few days after infection and peaked at day 5. Depletion of neutrophils with antibody RB6-8C5 or 1A8 reduced neutrophil influx and vascular remodeling after infection by about 90%. Similarly, vascular remodeling after infection was suppressed in Cxcr2(-/-) mice, in which neutrophils adhered to the endothelium of venules but did not extravasate into the tissue. Expression of the venular adhesion molecule P-selectin increased in endothelial cells from day 1 to day 3 after infection, as did expression of the Cxcr2-receptor ligands Cxcl1 and Cxcl2. Tumor necrosis factor α (TNFα) expression increased more than sixfold in the trachea of wild-type and Cxcr2(-/-) mice, but intratracheal administration of TNFα did not induce vascular remodeling similar to that seen in infection. We conclude that neutrophil influx is required for remodeling of capillaries into venules in the airways of mice with Mycoplasma infection and that TNFα signaling is necessary but not sufficient for vascular remodeling.


Primary choriocarcinoma of the stomach and pancreas: CT findings.
In this report we present the CT findings of two non-gestational, extragonadal choriocarcinomas, one arising within the stomach and one in the pancreas. These are rare tumours and a pancreatic primary site has not been previously described.


Enrollee characteristics and receipt of colorectal cancer testing in Pennsylvania after adoption of the Affordable Care Act Medicaid expansion.
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer-related death in the U.S. Despite increased CRC screening rates, they remain low among low-income non-older adults, including Medicaid enrollees who are more likely to be diagnosed at advanced stages. Given limited evidence regarding CRC screening service use among Medicaid enrollees, we examined multilevel factors associated with CRC testing among Medicaid enrollees in Pennsylvania after Medicaid expansion in 2015. Using the 2014-2019 Medicaid administrative data, we performed multivariable logistic regression models to assess factors associated with CRC testing, adjusting for enrollment length and primary care services use. We identified 15,439 adults aged 50-64 years newly enrolled through Medicaid expansion. Outcome measures include receiving any CRC testing and by modality. About 32% of our study population received any CRC testing. Significant predictors for any CRC testing include being male, being Hispanic, having any chronic conditions, using primary care services ≤4 times annually, and having a higher county-level median household income. Being 60-64 years at enrollment, using primary care services >4 times annually, and having higher county-level unemployment rates were significantly associated with a decreased likelihood of receiving any CRC tests. CRC testing rates were low among adults newly enrolled in Medicaid under the Medicaid expansion in Pennsylvania relative to adults with high income. We observed different sets of significant factors associated with CRC testing by modality. Our findings underscore the urgency to tailor strategies by patients' racial, geographic, and clinical conditions for CRC screening.


Paxillin is required for cell-substrate adhesion, cell sorting and slug migration during Dictyostelium development.
Paxillin is a key regulatory component of focal adhesion sites, implicated in controlling cell-substrate interactions and cell movement. We analyse the function of a Dictyostelium discoideum paxillin homologue, PaxB, which contains four highly conserved LD and four LIM domains, but lacks two characteristic tyrosine residues, that form the core of vertebrate SH2-binding domains. PaxB is expressed during growth and all stages of development, but expression peaks during slug formation. Using a paxB-gfp knockin strain we show the existence of focal adhesions and characterise their dynamics. During multicellular development PaxB is not only found in focal adhesions at the cell-substrate interface, but also in the tips of filopodial structures predominantly located at the trailing ends of cells. paxB- strains are less adhesive to the substrate, they can aggregate but multicellular development from the mound stage onwards is severely impeded. paxB- strains are defective in proper cell type proportioning, cell sorting, slug migration and form-defective fruiting bodies. Mutation of a conserved JNK phosphorylation site, implicated in the control of cell migration, does not have any major effects on cell sorting, slug migration or morphogenesis in Dictyostelium. PaxB does not appear to function redundantly with its closest relative Lim2 (paxA), which when deleted also results in a mound arrest phenotype. However, analysis of paxA- and paxB- single and double null mutants suggest that PaxB may act upstream of Lim2.


On the use of small artificial pupils to open-loop the accommodation system.
Monocular accommodation responses to stimuli at vergences from 0 to -4.5 D (i.e. effective object-eye distances from infinity to 22 cm) were measured objectively using artificial pupils of 0.5, 0.75, 1.0 and 3.0 mm diameters and a constant retinal illuminance of 7000 td. The slopes of the response/stimulus curves for the 0.75, 1.0 and 3.0 mm pupils agree with those reported previously. The 0.5 mm pupil produced open-loop accommodation, no systematic change in accommodation being observed as the stimulus vergence was varied. However, the response drifted considerably with this pupil diameter.


Investigating evolutionary trends and characteristics of renewable energy research in Africa: a bibliometric analysis from 1999 to 2021.
Several countries across the African continent have been challenged with energy crises for decades. A growing number of studies have identified renewable energy as a sustainable way for Africa to address its persisting energy situation while combating climate change, as the continent has in abundance some of the common renewable energy resources. Little has been reported in the body of literature to quantitatively and qualitatively map the knowledge domain of this growing research field. In the current study, we conduct a bibliometric analysis on research documents extracted from the Web of Science Core Collection to identify trends and characteristics of the knowledge domain related to renewable energy in Africa from 1999 to 2021. Using two different software (VOSviewer and ITgInsight), we report the contribution of journals, countries, institutions, and authors and their collaboration patterns. We also perform co-citation and keyword analysis to identify the intellectual base and central themes of this research field. The results from the study revealed a growing interest in Africa's renewable energy, with about 90% of the total publication from within the last decade. Renewable & Sustainable Energy Reviews was identified as the most productive as well as the most influential journal in this field. The most contributing countries in this field were South Africa, USA, and Algeria. Centre de Developpement Des Energies Renouvelables, a research institute in Algeria, emerged as the most productive and influential institution. The analysis of research hotspots under different categories revealed that "solar energy," "CO2 emissions," and "rural electrification" are the topics that have gained maximum attention over the years. Keyword evolution analysis also identified "economic growth" and "green hydrogen production" as emerging topics that will play a major role in future studies. We conclude our work by providing specific suggestions and strategies to help bridge the gap which exists in the quantity and quality of renewable energy research between Africa and the rest of the world.


New insights into mycelial pellets for aerobic sludge granulation in membrane bioreactor: Bio-functional interactions among metazoans, microbial communities and protein expression.
Direct cultivation of aerobic granular sludge (AGS) in membrane bioreactor (MBR) has gained increasing attention. Mycelial pellets (MPs) has been shown capable of promoting rapid granulation of aerobic sludge in MBR, yet mechanisms remain unclear and in-depth insight into cross-scale interactions between MPs and indigenous microbiota as well as the corresponding protein expression functions is necessary. Herein, we found that the addition of MPs in MBR resulted in massive growth of metazoans with 40-400 /mL for rotifers, 20-140 /mL for nematodes and 2-420 /mL for oligochaetes in the initial phase of granulation. This facilitated the MPs to rapidly aggregate with bacteria to form defensive granules for physical protection from predation by metazoans, which inhibited the overgrowth of filamentous bacteria Thiothrix and promoted the reproduction of functional bacteria related to nitrogen removal (Nitrospira, Trichococcus and Acinetobacter). Proteomic analysis demonstrated that the upregulation of functional proteins was mainly ascribed to the decrease of Thiothrix and the increase of Nitrospira, resulting in the enhancement of metabolic pathways involved in glycolysis/gluconeogenesis, citrate (TCA) cycle, oxidative phosphorylation, pyruvate metabolism, nitrogen metabolism and biosynthesis of amino acids, which was responsible for MPs-induced AGS with denser structure, more abundant proteins and β-polysaccharides, higher species diversity, significant nitrogen removal (33.12-42.33%) and lower membrane fouling potential. This study provided a novel and comprehensive insight into the enhanced granulation of aerobic sludge by MPs and the functional superiority of MPs-induced AGS in MBR system.


Broad-spectrum pan-genus and pan-family virus vaccines.
Although the development and clinical application of SARS-CoV-2 vaccines during the COVID-19 pandemic demonstrated unprecedented vaccine success in a short time frame, it also revealed a limitation of current vaccines in their inability to provide broad-spectrum or universal protection against emerging variants. Broad-spectrum vaccines, therefore, remain a dream and challenge for vaccinology. This review will focus on current and future efforts in developing universal vaccines targeting different viruses at the genus and/or family levels, with a special focus on henipaviruses, influenza viruses, and coronaviruses. It is evident that strategies for developing broad-spectrum vaccines will be virus-genus or family specific, and it is almost impossible to adopt a universal approach for different viruses. On the other hand, efforts in developing broad-spectrum neutralizing monoclonal antibodies have been more successful and it is worth considering broad-spectrum antibody-mediated immunization, or "universal antibody vaccine," as an alternative approach for early intervention for future disease X outbreaks.