mHealth in the Prevention and Control of Non-Communicable Diseases in India: Current Possibilities and the Way Forward.
Mobile health technology has been used effectively for healthcare delivery in many developing countries. India is currently facing an epidemic of Non-Communicable Diseases (NCDs). With greater availability of cheaper phones in the market, the user base of mobile phones in India is increasing rapidly. The present review was thus conducted to explore the current possibilities and future scope of mobile health for NCD prevention and control in India. Literature search was conducted using MEDLINE, EMBASE, and Cochrane Library to collect information regarding mobile health interventions. Two authors extracted the data and included studies if at least the abstract was available. Information from key reports and government websites were also included. We examined information from domains such as need for mobile health in NCDs in India, and the advantages, scope and challenges of mobile health for healthcare delivery in India. Existing mobile health systems in India, current evidence of mobile health use in NCDs, and the recent mobile health related initiatives taken by Government of India were also assessed. Though we found some examples of current mobile phone usage in many health related programmes in India, data from mobile health research is scarce, particularly for NCDs. The current evidence base needs to be strengthened. There is also a need for identifying various opportunities in the recent initiatives taken by Government of India. It can be concluded that though mobile health has many advantages, there are numerous challenges which need to be addressed before scaling it up at the national level.


Adherence to Public Health Measures Mitigates the Risk of COVID-19 Infection in Older Adults: A Community-Based Study.
To assess the prevalence and characteristics of coronavirus disease 2019 (COVID-19) cases during the reopening period in older adults, given that little is known about the prevalence of COVID-19 after the stay-at-home order was lifted in the United States, nor the actual effects of adherence to recommended public health measures (RPHM) on the risk of COVID-19. This was a cross-sectional study nested in a parent prospective cohort study, which followed a population-based sample of 2325 adults 50 years and older residing in southeast Minnesota to assess the incidence of viral infections. Participants were instructed to self-collect both nasal and oropharyngeal swabs, which were tested by reverse transcription polymerase chain reaction-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assay between May 8, 2020, and June, 30, 2020. We assessed the prevalence of COVID-19 cases and characteristics of study subjects. A total of 1505 eligible subjects participated in the study whose mean age was 68 years, with 885 (59%) women, 32 (2%) racial/ethnic minorities, and 906 (60%) with high-risk conditions for influenza. The prevalence of other Coronaviridae (human coronavirus [HCoV]-229E, HCoV-NL63, and HCoV-OC43) during the 2019 to 2020 flu season was 109 (7%), and none tested positive for SARS-CoV-2. Almost all participants reported adhering to the RPHM (1,488 [99%] for social distancing, 1,438 [96%] for wearing mask in a public space, 1,476 [98%] for hand hygiene, and 1,441 (96%) for staying home mostly). Eighty-six percent of participants resided in a single-family home. We did not identify SARS-COV-2 infection in our study cohort. The combination of participants' behavior in following the RPHM and their living environment may considerably mitigate the risk of COVID-19.


The effect of solid pancreatic mass lesions on pancreatic duct diameter at endoscopic ultrasound.
To evaluate the effect of solid pancreatic masses on the pancreatic duct (PD) at the endoscopic ultrasound (EUS) and the relationship of the location/size of a mass and PD dilation. Patients who underwent EUS for pancreatic indications from 2011 to 2013 at a single center were retrospectively identified. Those with biopsies that revealed adenocarcinoma or neuroendocrine tumors in the pancreas were identified and PD size was ascertained from EUS, computed tomography, or magnetic resonance imaging. Of the 475 patients who had a pancreatic EUS, 239 had a dilated PD and 236 had a normal PD. Patients with a dilated PD had a significantly higher incidence of pancreatic malignancy than those with a normal PD diameter (106/239, 44.4% vs. 32/236, 13.6%, P< 0.001). Of the 138 patients with a pancreatic malignancy, 106 (76.8%) had a dilated PD at some location in the pancreas. Over 80% of patients with a mass within the head, neck, or body had a dilated PD. For a mass located at the uncinate process or the tail, PD dilation was 65% and 23%, respectively. Fifty-six (80.0%) of the masses in the head, 11 (78.6%) masses in the neck, and 16 (76.2%) masses in the body had a dilated PD upstream of the mass. In addition, a step-wise increase in the incidence of PD dilation was correlated with an increase in mass size. About 67.6% of patients with masses measuring in the 1st quartile had dilated a PD, while 77.8%, 91.0%, and 71.4% of those with masses measuring in the 2nd, 3rd, and 4th quartiles, respectively, had a dilated PD. PD dilation is a warning sign for pancreatic malignancies, however, small masses or masses at the uncinate process or the tail of the pancreas may not affect the size of the PD.


Evaluating New Ophthalmic Digital Devices for Safety and Effectiveness in the Context of Rapid Technological Development.
The US Food and Drug Administration's medical device regulatory pathway was initially conceived with hardware devices in mind. The emerging market for ophthalmic digital devices necessitates an evolution of this paradigm. To facilitate innovation in ophthalmic digital health with attention to safety and effectiveness. This article presents a summary of the presentations, discussions, and literature review that occurred during a joint Ophthalmic Digital Health workshop of the American Academy of Ophthalmology, the American Academy of Pediatrics, the American Association for Pediatric Ophthalmology and Strabismus, the American Society of Cataract and Refractive Surgery, the American Society of Retina Specialists, the Byers Eye Institute at Stanford and the US Food and Drug Administration. Criterion standards and expert graders are critically important in the evaluation of automated systems and telemedicine platforms. Training at all levels is important for the safe and effective operation of digital health devices. The risks associated with automation are substantially increased in rapidly progressive diseases. Cybersecurity and patient privacy warrant meticulous attention. With appropriate attention to safety and effectiveness, digital health technology could improve screening and treatment of ophthalmic diseases and improve access to care.


Comorbidities and Risk Factors for Severe Outcomes in COVID-19 Patients in Saudi Arabia: A Retrospective Cohort Study.
The first novel coronavirus disease-19 (COVID-19) case in the Kingdom of Saudi Arabia (KSA) was reported in Qatif in March 2020 with continual increase in infection and mortality rates since then. In this study, we aim to determine risk factors which effect severity and mortality rates in a cohort of hospitalized COVID-19 patients in KSA. We reviewed medical records of hospitalized patients with confirmed COVID-19 positive results via reverse-transcriptase-polymerase-chain-reaction (RT-PCR) tests at Prince Mohammed Bin Abdulaziz Hospital, Riyadh between May and August 2020. Data were obtained for patient's demography, body mass index (BMI), and comorbidities. Additional data on patients that required intensive care unit (ICU) admission and clinical outcomes were recorded and analyzed with Python Pandas. A total of 565 COVID-19 positive patients were inducted in the study out of which, 63 (11.1%) patients died while 101 (17.9%) patients required ICU admission. Disease incidences were significantly higher in males and non-Saudi nationals. Patients with cardiovascular, respiratory, and renal diseases displayed significantly higher association with ICU admissions (p<0.001) while mortality rates were significantly higher in COVID-19 patients with cardiovascular, respiratory, renal and neurological diseases. Univariate cox proportional hazards regression model showed that COVID-19 positive patients requiring ICU admission [Hazard's ratio, HR=4.2 95% confidence interval, CI 2.5-7.2); p<0.001] with preexisting cardiovascular [HR=4.1 (CI 2.5-6.7); p<0.001] or respiratory [HR=4.0 (CI 2.0-8.1); p=0.010] diseases were at significantly higher risk for mortality among the positive patients. There were no significant differences in mortality rates or ICU admissions among males and females, and across different age groups, BMIs and nationalities. Hospitalized patients with cardiovascular comorbidity had the highest risk of death (HR=2.9, CI 1.7-5.0; p=0.020). Independent risk factors for critical outcomes among COVID-19 in KSA include cardiovascular, respiratory and renal comorbidities.


Effectiveness of ShotBlocker for Immunization Pain in Full-Term Neonates: A Randomized Controlled Trial.
Nonpharmacologic strategies exist to manage procedural pain in healthy newborn infants. The aim of this prospective randomized controlled trial (RCT) was to examine the efficacy of ShotBlocker for managing injection pain associated with the first intramuscular hepatitis B vaccine given to healthy full-term neonates. This randomized controlled trial study was conducted in a private university hospital in Istanbul, Turkey, in which 100 healthy term neonates were randomly assigned to either a ShotBlocker (n = 50) or control group (n = 50). The Neonatal Infant Pain Scale scores of the neonates in the ShotBlocker and control groups were compared before, during, and after the injections, and the physiological parameters were compared before and after the procedure. The pain scores of the neonates during (ShotBlocker group: 1.64 ± 0.80; control group: 2.96 ± 0.73) and after (ShotBlocker group: 0.74 ± 0.66; control group: 1.42 ± 0.76) the injection procedure were lower in the ShotBlocker group than in the control group (P = .000). The postinjection heart rate in the infants in the ShotBlocker group (145.02 ± 13.50) was found to be lower than in those for whom ShotBlocker was not used (150.24 ± 13.36) (P = .05). The use of ShotBlocker during the hepatitis B vaccine in term neonates is effective in reducing the acute pain.


The effect of critical pH on virus fate and transport in saturated porous medium.
Several viral transport experiments were conducted in a model aquifer 1 m long, using bacteriophages MS2 and phiX174 at various pH (4.6 to 8.3) conditions, to increase our understanding of virus behavior in ground water. The results indicate the existence of a critical pH at which the virus behavior changes abruptly. This is supported by data from field and batch experiments. The critical pH is determined to be 0.5 unit below the highest isoelectric point of the virus and porous medium. When water pH is below the critical pH, the virus has an opposite charge to at least one component of the porous medium, and is almost completely and irreversibly removed from the water. This suggests that electrostatic attraction at a subcritical water pH condition is an important factor controlling virus attenuation in ground water. The concept of critical pH can assist in the design of geologic barriers for preventing viral contamination in ground water.


Factors driving species assemblage in Mediterranean soil seed banks: from the large to the fine scale.
Many studies have analysed the mechanisms that determine plant coexistence in standing vegetation, but the determinants of soil seed bank species assemblies have rarely been studied. In gypsum soil communities, aerial vegetation and seed banks are tightly connected in space and time, but the mechanisms involved in their organization may differ. The aim of this study is to understand the relative importance of biotic and abiotic factors controlling soil seed bank composition and structure. Persistent and complete (i.e. persistent plus transient) soil seed banks were investigated at two spatial scales in a very species-rich semi-arid community dominated by annuals. A water addition treatment equivalent to 50 % annual increase in average precipitation (abiotic factor) was applied for two consecutive years, and the relationships of the soil seed bank to the biological soil crust (BSC), above-ground vegetation and the presence of Stipa tenacissima tussocks (biotic factors) were simultaneously evaluated. As expected, the standing vegetation was tightly related to seed abundance, species richness and composition in both seed banks. Remarkably, BSC cover was linked to a decrease in seed abundance and species richness in the persistent seed bank, and it even determined complete seed bank composition at the fine spatial scale. However, this effect disappeared at coarser scales, probably because of the high spatial heterogeneity induced by BSCs. In contrast to findings on standing vegetation, Stipa and the irrigation treatment for two consecutive years had no effect on soil seed banks. Soil seed bank assemblies in our semi-arid plant community were the result of above-ground vegetation dynamics and of the direct filtering processes on seed fate operated by the spatially heterogeneous BSCs. Cover of BSCs was negatively correlated with seed abundance and species richness, and affected seed species composition in the soil. Changes in species composition and enrichment when the BSC cover is low suggest that BSCs promote a fine scale niche differentiation in the soil seed bank and thereby potentially enhance species coexistence and high species diversity in these communities.


Modelling and simulation of photosynthetic activities in C3 plants as affected by CO2.
CO2 concentration ([CO2]) in a greenhouse may be a limiting factor for plant growth. Current greenhouse CO2 control strategy usually depends on expert experience, which may control [CO2] in a moderate range but cannot make it optimal due to lack of considering plant photochemistry reactions. A state-space kinetic model structure covering major photosynthetic reactions as affected by CO2 is useful for [CO2] control strategy development in a greenhouse because modern control theories are usually based on state-space models. In this work, a state-space kinetic model structure for photosynthesis was built, which describes the major reaction cascades of photophosphorylation, Calvin cycle, and biophysical processes such as CO2 transport through the stomata under moderate [CO2] range without considering photorespiration. Simulations were performed with a large range of model parameters to demonstrate the effect of [CO2] on stable sugar production and the flexibilities of the developed model structure. The results clearly show whether increasing of CO2 will lead to more production of sugar or not in different scenarios. The model structure may be extended to cover other photosynthetic influence factors such as temperature by using the well-known Arrhenius equation.


Medicare--where is its future?
Canadian health care policy is in a period of transition. Continuing reform is necessary to ensure quality; to evaluate health outcomes; and to promote efficiency, effectiveness and appropriateness of care.


Outcomes of persistent pulmonary hypertension following transcatheter aortic valve replacement.
To determine the prevalence and factors associated with persistent pulmonary hypertension (PH) following transcatheter aortic valve replacement (TAVR) and its relationship with long-term mortality. Consecutive patients who underwent TAVR from July 2011 through January 2016 were studied. The prevalence of baseline PH (mean pulmonary artery pressure ≥25 mm Hg on right heart catheterisation) and the prevalence and the predictors of persistent≥moderate PH (pulmonary artery systolic pressure (PASP)>45 mm Hg on 1 month post-TAVR transthoracic Doppler echocardiography) were collected. Cox models quantified the effect of persistent PH on subsequent mortality while adjusting for confounders. Of the 407 TAVR patients, 273 (67%) had PH at baseline. Of these, 102 (25%) had persistent≥moderate PH. Mortality at 2 years in patients with no baseline PH versus those with PH improvement (follow-up PASP≤45 mm Hg) versus those with persistent≥moderate PH was 15.4%, 16.6% and 31.3%, respectively (p=0.049). After adjusting for Society of Thoracic Surgeons Predicted Risk of Mortality and baseline right ventricular function (using tricuspid annular plane systolic excursion), persistent≥moderate PH remained associated with all-cause mortality (HR=1.82, 95% CI 1.06 to 3.12, p=0.03). Baseline characteristics associated with increased likelihood of persistent≥moderate PH were ≥moderate tricuspid regurgitation, ≥moderate mitral regurgitation, atrial fibrillation/flutter, early (E) to late (A) ventricular filling velocities (E/A ratio) and left atrial volume index. Persistency of even moderate or greater PH at 1 month post-TAVR is common and associated with higher all-cause mortality.


Salmonella administration induces a reduction of wheel-running activity via a TLR5-, but not a TLR4, dependent pathway in mice.
In general, systemic bacterial infections induce sickness behavior. In mice, lipopolysaccharide (LPS), a component of gram-negative bacteria, strongly reduces physical activity via toll-like receptor (TLR) 4. However, gram-negative bacteria, such as Salmonella, also express flagella containing flagellin (FG) which binds to TLR5 and induces pro-inflammatory cytokine production. It is unclear whether FG induces sickness behavior. To determine whether Salmonella administration regulates the reduction of voluntary physical activity in mice, male C3H/HeN (wild type) and C3H/HeJ (tlr4 gene mutated) mice were administered living Salmonella (live) and examined for wheel-running activity. The production of TNF-alpha in RAW 264 cells was measured by the ELISA assay under both live and heat-killed (HK) Salmonella conditions in vitro. Wheel-running activity in both C3H/HeJ and C3H/HeN mice after i.p. injection of live Salmonella (1 x 10(6) CFU/kg) was significantly lower than that in vehicle groups (p < 0.01, respectively), although wheel-running activity in C3H/HeJ mice was not reduced after i.p. injection of HK Salmonella (1 x 10(6) CFU/kg). Furthermore, TNF-alpha production from RAW 264 cells with HK Salmonella treatment at the early phase was higher than that with live Salmonella treatment. Interestingly, gentamicin-treated (GMT) Salmonella, (which have bacterial flagella removed), did not induce reduction of wheel-running activity, although injection of the flagella-rich supernatant of GMT Salmonella significantly reduced it (p < 0.01). Indeed, FG treatment also induced reduction of wheel-running activity in mice (p < 0.01). Our findings suggest that the Salmonella-induced reduction of voluntary physical activity might be regulated by FG via TLR5, but not LPS via TLR4 in mice.


Single active-site mutants are sufficient to enhance serine:pyruvate α-transaminase activity in an ω-transaminase.
We have analyzed the natural evolution of transaminase structure and sequence between an α-transaminase serine-pyruvate aminotransferase and an ω-transaminase from Chromobacterium violaceum with < 20% sequence identity, and identified the active-site regions that are least conserved structurally. We also show that these structural changes correlate strongly with transaminase substrate specificity during evolution and therefore might normally be presumed to be essential determinants of substrate specificity. However, key residues are often conserved spatially during evolution and yet originate from within a different region of the sequence via structural reorganizations. In the present study, we also show that α-transaminase-type serine-pyruvate aminotransferase activity can be engineered into the CV2025 ω-transaminase scaffold with any one of many possible single-point mutations at three key positions, without the requirement for significant backbone remodeling, or repositioning of the residue from a different region of sequence. This finding has significant implications for enzyme redesign in which solutions to substrate specificity changes may be found more efficiently than is achieved by engineering in all sequence and structure determinants identified by correlation to substrate specificity.


Genome Size in North American Fireflies: Substantial Variation Likely Driven by Neutral Processes.
Eukaryotic genomes show tremendous size variation across taxa. Proximate explanations for genome size variation include differences in ploidy and amounts of noncoding DNA, especially repetitive DNA. Ultimate explanations include selection on physiological correlates of genome size such as cell size, which in turn influence body size, resulting in the often-observed correlation between body size and genome size. In this study, we examined body size and repetitive DNA elements in relationship to the evolution of genome size in North American representatives of a single beetle family, the Lampyridae (fireflies). The 23 species considered represent an excellent study system because of the greater than 5-fold range of genome sizes, documented here using flow cytometry, and the 3-fold range in body size, measured using pronotum width. We also identified common genomic repetitive elements using low-coverage sequencing. We found a positive relationship between genome size and repetitive DNA, particularly retrotransposons. Both genome size and these elements were evolving as expected given phylogenetic relatedness. We also tested whether genome size varied with body size and found no relationship. Together, our results suggest that genome size is evolving neutrally in fireflies.


Sample size for FDR-control in microarray data analysis.
We consider identifying differentially expressing genes between two patient groups using microarray experiment. We propose a sample size calculation method for a specified number of true rejections while controlling the false discovery rate at a desired level. Input parameters for the sample size calculation include the allocation proportion in each group, the number of genes in each array, the number of differentially expressing genes and the effect sizes among the differentially expressing genes. We have a closed-form sample size formula if the projected effect sizes are equal among differentially expressing genes. Otherwise, our method requires a numerical method to solve an equation. Simulation studies are conducted to show that the calculated sample sizes are accurate in practical settings. The proposed method is demonstrated with a real study.


How to define e-cigarette prevalence? Finding clues in the use frequency distribution.
E-cigarette use has rapidly increased. Recent studies define prevalence using a variety of measures; competing definitions challenge cross-study comparison. We sought to understand patterns of use by investigating the number of days out of the past 30 days when adults had used e-cigarettes. We used the 2014 Minnesota Adult Tobacco Survey, a random digit dial population survey (n=9304 adults). Questions included ever using e-cigarettes, number of days used in the past 30 days and reasons for use. Smoking status was determined by combustible cigarette use. Histograms of e-cigarette use were visually inspected for current, former and never smokers with any 30-day e-cigarette use. Different definitions of current use were compared. Use ≤5 days in the past 30 days demarcated a cluster of infrequent users at the low end of the distribution. Among those with use in the past 30 days, infrequent users were the majorities of current (59%) and never smokers (89.5%), but fewer than half of former smokers (43.2%). Infrequent users were more likely to cite curiosity and less likely to cite quitting/cutting down other tobacco use as reasons for use. Defining adult prevalence as any use in the past 30 days may include experimenters unlikely to continue use, and is of questionable utility for population surveillance of public health trends over time. Defining prevalence as >5 days excludes those infrequent users.


Effect of baclofen on liquid and solid gastric emptying in rats.
Gamma-aminobutyric acid (GABA) is a potent inhibitory neurotransmitter. There is evidence that GABA(B) receptors located in the dorsal complex and in afferent fibers of the vagus nerve participate in the control of gastrointestinal motility. To assess the intracerebroventricularly (ICV) and intravenously (IV) effect of baclofen, a GABA(B) receptor agonist, on liquid and solid gastric emptying in rats. Adult male Wistar rats weighing 250-300 g (n = 6-8 animals) were used. Gastric emptying of liquid test meals labeled with phenol red was evaluated by the determination of percent gastric retention (%GR) 10 and 15 min after orogastric administration of saline and 10% glucose meals, respectively. Baclofen was injected ICV (1 and 2 µg/animal) through a tube implanted into the lateral ventricle of the brain and was injected IV (1 and 2 mg/kg) into a tail vein. The gastric emptying of liquid was determined 10 or 30 min after ICV and IV baclofen administration, respectively. The gastric emptying of the solid meal was assessed by the determination of percent gastric retention 2 h after the beginning of the ingestion of the habitual ratio by the animal, consumed over a period of 30 min. Baclofen was administered ICV (1 and 2 µg/animal) or IV (1 and 2 mg/kg) immediately after the end of the ingestion of the solid meal. The control groups received vehicle (sterile saline solution) ICV or IV. The group of animals receiving baclofen ICV (2 mg/animal) presented a significantly lower (P<0.05, Tukey test) %GR (mean ± SEM) of the saline (18.1 ± 2.5%) compared to control (33.2 ± 2.2%). In the group receiving the drug IV, the gastric retention of the same test meal did not differ from control. ICV and IV administration of baclofen had no effect on the gastric emptying of the 10% glucose solution compared to control. ICV administration of 1 or 2 mg baclofen/animal significantly increased the gastric retention of the solid test meal (57.9 ± 6.5% and 66.6 ± 6.3%, respectively) compared to control (35.1 ± 4.4%). The same phenomenon was observed only with the IV dose of 2 mg/kg (71.9 ± 2.6%) compared to control (52.7 ± 2.8%). Baclofen administered: 1. ICV (2 µg/animal), but not IV, increased gastric emptying of a non-caloric isotonic liquid test meal (saline); 2. when administered ICV or IV, it had no effect of gastric emptying of a 10% glucose solution; 3) when administered ICV (1 and 2 mg/animal) and IV (2 mg/kg) it delayed the gastric emptying of the solid meal.


[Spermatogenesis at inguinal hernias].
Overall 87 patients aged 26-38 years with inguinal hernias were analyzed. Laboratory examinations of ejaculate, blood concentration of sex hormones and anti- spermatozoon autoantibodies were performed at all the patients. Examination of ejaculate demonstrated good fertility at 18 (20.7%) patients only. Other tests also demonstrated different pathology. These disorders were higher-grade at patients with two-sided hernias and long anamnesis. It is concluded that inguinal hernia leads to fertility disorders.


Robust, Reproducible, and Economical Phosphopeptide Enrichment Using Calcium Titanate.
Mass-spectrometry-based phosphoproteomics has revolutionized phosphoprotein analysis and enhanced our understanding of diverse and fundamental cellular processes important for human health and disease. Because of their relative scarcity, phosphopeptides must be enriched before analysis. Many different enrichment methods and materials have been described, and many reports have made claims about the advantages of particular materials and methodological variations. We demonstrate an effective and highly reproducible single-step enrichment method using an off-the-shelf preparation of calcium titanate. Using two different cell lines and replicate analysis, we show that our method achieves a purity and depth of analysis comparable or superior to a widely used TiO2-based method at a reduced cost and effort. This method provides a new and immediately available tool for expanding the reach of phosphoproteomic inquiry.


Removal of bacterial contaminants and antibiotic resistance genes by conventional wastewater treatment processes in Saudi Arabia: Is the treated wastewater safe to reuse for agricultural irrigation?
This study aims to assess the removal efficiency of microbial contaminants in a local wastewater treatment plant over the duration of one year, and to assess the microbial risk associated with reusing treated wastewater in agricultural irrigation. The treatment process achieved 3.5 logs removal of heterotrophic bacteria and up to 3.5 logs removal of fecal coliforms. The final chlorinated effluent had 1.8 × 10(2) MPN/100 mL of fecal coliforms and fulfils the required quality for restricted irrigation. 16S rRNA gene-based high-throughput sequencing showed that several genera associated with opportunistic pathogens (e.g. Acinetobacter, Aeromonas, Arcobacter, Legionella, Mycobacterium, Neisseria, Pseudomonas and Streptococcus) were detected at relative abundance ranging from 0.014 to 21 % of the total microbial community in the influent. Among them, Pseudomonas spp. had the highest approximated cell number in the influent but decreased to less than 30 cells/100 mL in both types of effluent. A culture-based approach further revealed that Pseudomonas aeruginosa was mainly found in the influent and non-chlorinated effluent but was replaced by other Pseudomonas spp. in the chlorinated effluent. Aeromonas hydrophila could still be recovered in the chlorinated effluent. Quantitative microbial risk assessment (QMRA) determined that only chlorinated effluent should be permitted for use in agricultural irrigation as it achieved an acceptable annual microbial risk lower than 10(-4) arising from both P. aeruginosa and A. hydrophila. However, the proportion of bacterial isolates resistant to 6 types of antibiotics increased from 3.8% in the influent to 6.9% in the chlorinated effluent. Examples of these antibiotic-resistant isolates in the chlorinated effluent include Enterococcus and Enterobacter spp. Besides the presence of antibiotic-resistant bacterial isolates, tetracycline resistance genes tetO, tetQ, tetW, tetH, tetZ were also present at an average 2.5 × 10(2), 1.6 × 10(2), 4.4 × 10(2), 1.6 × 10(1) and 5.5 × 10(3) copies per mL of chlorinated effluent. Our study highlighted that potential risks associated with the reuse of treated wastewater arise not only from conventional fecal indicators or known pathogens, but also from antibiotic-resistant bacteria and genes.


Inferring RNA sequence preferences for poorly studied RNA-binding proteins based on co-evolution.
Characterizing the binding preference of RNA-binding proteins (RBP) is essential for us to understand the interaction between an RBP and its RNA targets, and to decipher the mechanism of post-transcriptional regulation. Experimental methods have been used to generate protein-RNA binding data for a number of RBPs in vivo and in vitro. Utilizing the binding data, a couple of computational methods have been developed to detect the RNA sequence or structure preferences of the RBPs. However, the majority of RBPs have not yet been experimentally characterized and lack RNA binding data. For these poorly studied RBPs, the identification of their binding preferences cannot be performed by most existing computational methods because the experimental binding data are prerequisite to these methods. Here we propose a new method based on co-evolution to predict the sequence preferences for the poorly studied RBPs, waiving the requirement of their binding data. First, we demonstrate the co-evolutionary relationship between RBPs and their RNA partners. We then present a K-nearest neighbors (KNN) based algorithm to infer the sequence preference of an RBP using only the preference information from its homologous RBPs. By benchmarking against several in vitro and in vivo datasets, our proposed method outperforms the existing alternative which uses the closest neighbor's preference on all the datasets. Moreover, it shows comparable performance with two state-of-the-art methods that require the presence of the experimental binding data. Finally, we demonstrate the usage of this method to infer sequence preferences for novel proteins which have no binding preference information available. For a poorly studied RBP, the current methods used to determine its binding preference need experimental data, which is expensive and time consuming. Therefore, determining RBP's preference is not practical in many situations. This study provides an economic solution to infer the sequence preference of such protein based on the co-evolution. The source codes and related datasets are available at https://github.com/syang11/KNN .


Comparative study of histopathological and immunohistochemical findings in skin biopsies from patients with psoriasis before and after treatment with acitretin.
Acitretin has been shown to be effective for psoriasis treatment. Its mechanism of action is not completely understood, and there are few studies focusing on histological and immunohistochemical differences before and after treatment of psoriasis with acitretin. This is a prospective study of 17 patients with plaque psoriasis treated with acitretin for 4 months with biopsies taken before and after therapy. Histological features and immunohistochemical reactions to cytokeratin (CK) 10, CK16, CK19, Ki67 and CD1a were evaluated and compared. There were nine men and eight women with median age of 47 years. Epidermal thickness, CK16 positivity, Ki67 and CD1a-positive cell index reduced after treatment (p < 0.01). Suprapapillary plate thickness stayed the same (p > 0.05) although the epidermal/suprapapillary thickness ratio was significantly higher before treatment (p < 0.01). CK10 positivity was lower and a thicker basal cell layer was seen in the epidermis before treatment (p < 0.01). CK19 was negative in all cases. Acitretin therapy improved histological and immunohistochemical features typical of psoriasis. In psoriasis, suprapapillary plates are not thin, but the epidermal/suprapapillary thickness ratio is increased. Basal cell layer is expanded in psoriasis. Langerhans' cells were less frequent after treatment, and that finding has to be investigated further to determine its role in acitretin mechanism of action.


Sp3 and Sp4 can repress transcription by competing with Sp1 for the core cis-elements on the human ADH5/FDH minimal promoter.
The human alcohol dehydrogenase 5 gene (also known as the formaldehyde dehydrogenase gene, ADH5/FDH) has a GC-rich promoter with many sites at which transcription factors bind. A minimal promoter extending from -34 base pairs (bp) to +61 bp directs high levels of transcription in several different cells, consistent with the ubiquitous expression of the gene. Nearly the entire minimal promoter can be bound by Sp1. We analyzed the transcriptional regulation of ADH5/FDH by members of the Sp1 multigene family. Two core cis-elements (-22 bp to +22 bp) had the highest affinity for Sp1. Mutagenesis revealed that these cis-elements are critical for transcriptional activation. The zinc-finger domains of Sp3 and Sp4 also bind selectively to the core cis-elements. In Drosophila SL2 cells, which lack endogenous Sp1, the minimal promoter cannot drive transcription. Introduction of Sp1 activated transcription over 50-fold, suggesting that Sp1 is critical in the initiation of transcription. Neither Sp3 nor Sp4 was able to activate transcription in those cells, and transcriptional activation by Sp1 was repressed by Sp3 or Sp4. These data suggest that Sp3 and Sp4 can repress transcription by competing with Sp1 for binding to the core cis-elements. The content of Sp1, Sp3, and Sp4 in different cells may be critical factors regulating transcription of the ADH5/FDH gene.


Assessing neural tuning for object perception in schizophrenia and bipolar disorder with multivariate pattern analysis of fMRI data.
Deficits in visual perception are well-established in schizophrenia and are linked to abnormal activity in the lateral occipital complex (LOC). Related deficits may exist in bipolar disorder. LOC contains neurons tuned to object features. It is unknown whether neural tuning in LOC or other visual areas is abnormal in patients, contributing to abnormal perception during visual tasks. This study used multivariate pattern analysis (MVPA) to investigate perceptual tuning for objects in schizophrenia and bipolar disorder. Fifty schizophrenia participants, 51 bipolar disorder participants, and 47 matched healthy controls completed five functional magnetic resonance imaging (fMRI) runs of a perceptual task in which they viewed pictures of four different objects and an outdoor scene. We performed classification analyses designed to assess the distinctiveness of activity corresponding to perception of each stimulus in LOC (a functionally localized region of interest). We also performed similar classification analyses throughout the brain using a searchlight technique. We compared classification accuracy and patterns of classification errors across groups. Stimulus classification accuracy was significantly above chance in all groups in LOC and throughout visual cortex. Classification errors were mostly within-category confusions (e.g., misclassifying one chair as another chair). There were no group differences in classification accuracy or patterns of confusion. The results show for the first time MVPA can be used successfully to classify individual perceptual stimuli in schizophrenia and bipolar disorder. However, the results do not provide evidence of abnormal neural tuning in schizophrenia and bipolar disorder.


In detail.
Two families with twins - one in which adult DZ twins continue to face the risk of frontotemporal dementia, and the other in which a mother copes with brittle bones in a newborn infant MZ pair - are featured. The nature and progress of the disorders are reviewed and personal perspectives from the twins and other family members are variously provided. Next, four current twin studies are briefly summarized. Topics include sex differences in social support systems, new reproductive technologies, comparative twin-singleton frequencies of placenta previa, and the nature and complications of heterotopic pregnancies. This article concludes with a brief sampling of human interest stories involving twins: a different looking DZ pair, newborn sextuplets, conjoined twins and opposite-sex twin athletes.


NF-κB and chromatin: ten years on the path from basic mechanisms to candidate drugs.
Release of nuclear factor κΒ (NF-κB) dimers from the inhibitors of NF-κΒ (IκBs) and their subsequent nuclear translocation are only the initial events leading to the induction of NF-κB-regulated genes. Once in the nucleus, NF-κB dimers must gain access to their cognate sites in target genes. While some sites are found in a constitutively accessible state, many others are associated with nucleosomal histones in a manner that prevents NF-κB binding. Binding to such sites requires specific chromatin remodeling events driven by functionally cooperating transcription factors. Ten years of research on the complex interplay between chromatin and NF-κB led to some major successes, most notably the identification of the specific sequence features or trans-acting factors controlling the state of accessibility of κB sites, as well as the dissection of the mechanisms and players involved in the opening of occluded sites. Moreover, attempts at identifying mechanism-based compounds that inhibit the activation of selected subsets of NF-κB-dependent genes acting on chromatin-regulated transitions are starting to give initial promising results in preclinical tests.


[Zosteriform eruption in a girl during resolution of varicella].
We show the case of a six-years-old little girl with a herpes zoster which appeared while a varicella was resolving. We are discussing the diagnosis difficulties of this process.


Supramolecular self-assembly of fluorescent peptide amphiphiles for accurate and reversible pH measurement.
We report the synthesis and self-assembly of fluorescent peptide amphiphiles (NBD-PA) composed of a fluorescent NBD probe and a peptide derivative VVAADD with a C12-alkyl-chain as the linker (NBD-C12-VVAADD). The self-assembly of NBD-PA formed beta-sheet structures at neutral pH in aqueous solution, contributed to an ∼10-fold increase in the fluorescence and quantum yield of NBD molecules, and conferred a supramolecular hydrogel with excellent viscoelastic properties, while gel-to-sol transition of NBD-PA occurred rapidly when the pH value was adjusted to strongly alkaline (e.g. pH 11). Through the pH-responsive self-assembly behavior, we further explored the relationship between fluorescence of NBD-PA and pH values. Interestingly, the fluorescence of the NBD-PA system exhibited an excellent sigmoidal function relationship (R2 = 0.9999) with the alkaline pH values, which enabled accurate pH measurement regardless of salt types and ionic strength of solvents. Furthermore, the fluorescence of NBD-PA was fully reversible upon cycles of pH shifts, with the chemical structure of NBD-PA well-maintained throughout the process. These features of NBD-PA would facilitate the design of in situ pH detection systems as well as pH-responsive actuators for various applications in future.


Toxicological evaluation of myristicin.
Myristicin, or methoxysafrole, is the principal aromatic constituent of the volatile oil of nutmeg, the dried ripe seed of Myristica fragrans. Myristicin is also found in several members of the carrot family (Umbelliferae). Several intoxications have been reported after an ingestion of approximately 5 g of nutmeg, corresponding to 1-2 mg myristicin/kg body weight (b.w.). Although these intoxications may be ascribed to the actions of myristicin, it is likely that other components of nutmeg may also be involved. The metabolism of myristicin resembles that of safrole. No information is available, however, concerning the quantitative importance of the different metabolic pathways. The acute toxicity of myristicin appears to be low. No toxic effects were observed in rats administered myristicin perorally at a dose of 10 mg/kg b.w., while 6-7 mg/kg b.w. may be enough to cause psychopharmacological effects in man. A weak DNA-binding capacity has been demonstrated, but there are no indications that myristicin exerts carcinogenic activity in short-term assays using mice. Intake estimations indicate that nonalcoholic drinks may be the most important single source of myristicin intake. Based on available data, it seems unlikely that the intake of myristicin from essential oils and spices in food, estimated to a few mg per person and day in this report, would cause adverse effects in humans. It is, however, at present not possible to make a complete risk assessment, as studies regarding genotoxicity and chronic toxicity, including reproductive toxicity and carcinogenicity, are still lacking.


MONITORING FIDELITY IN THE ADOLESCENT COMMUNITY REINFORCEMENT APPROACH (A-CRA): THE TRAINING PROCESS FOR A-CRA RATERS.
Ensuring evidence-based treatments are delivered with a high degree of fidelity is an important aspect of transporting these practices to community-based treatment providers. Just as training is critical for clinicians who plan to deliver the Adolescent Community Reinforcement Approach (A-CRA), a process of training and vetting individuals who assess sessions for fidelity also is critical. This article describes the training process for session raters who assess fidelity of A-CRA during the clinician training and certification process. A-CRA is currently being implemented in 32 independent community-based agencies as part of a large initiative funded by the Center for Substance Abuse Treatment.


Understanding psychiatric illness through natural language processing (UNDERPIN): Rationale, design, and methodology.
Psychiatric disorders are diagnosed through observations of psychiatrists according to diagnostic criteria such as the DSM-5. Such observations, however, are mainly based on each psychiatrist's level of experience and often lack objectivity, potentially leading to disagreements among psychiatrists. In contrast, specific linguistic features can be observed in some psychiatric disorders, such as a loosening of associations in schizophrenia. Some studies explored biomarkers, but biomarkers have yet to be used in clinical practice. The purposes of this study are to create a large dataset of Japanese speech data labeled with detailed information on psychiatric disorders and neurocognitive disorders to quantify the linguistic features of those disorders using natural language processing and, finally, to develop objective and easy-to-use biomarkers for diagnosing and assessing the severity of them. This study will have a multi-center prospective design. The DSM-5 or ICD-11 criteria for major depressive disorder, bipolar disorder, schizophrenia, and anxiety disorder and for major and minor neurocognitive disorders will be regarded as the inclusion criteria for the psychiatric disorder samples. For the healthy subjects, the absence of a history of psychiatric disorders will be confirmed using the Mini-International Neuropsychiatric Interview (M.I.N.I.). The absence of current cognitive decline will be confirmed using the Mini-Mental State Examination (MMSE). A psychiatrist or psychologist will conduct 30-to-60-min interviews with each participant; these interviews will include free conversation, picture-description task, and story-telling task, all of which will be recorded using a microphone headset. In addition, the severity of disorders will be assessed using clinical rating scales. Data will be collected from each participant at least twice during the study period and up to a maximum of five times at an interval of at least one month. This study is unique in its large sample size and the novelty of its method, and has potential for applications in many fields. We have some challenges regarding inter-rater reliability and the linguistic peculiarities of Japanese. As of September 2022, we have collected a total of >1000 records from >400 participants. To the best of our knowledge, this data sample is one of the largest in this field. Identifier: UMIN000032141.


3D printing of bioreactors in tissue engineering: A generalised approach.
3D printing is a rapidly evolving field for biological (bioprinting) and non-biological applications. Due to a high degree of freedom for geometrical parameters in 3D printing, prototype printing of bioreactors is a promising approach in the field of Tissue Engineering. The variety of printers, materials, printing parameters and device settings is difficult to overview both for beginners as well as for most professionals. In order to address this problem, we designed a guidance including test bodies to elucidate the real printing performance for a given printer system. Therefore, performance parameters such as accuracy or mechanical stability of the test bodies are systematically analysed. Moreover, post processing steps such as sterilisation or cleaning are considered in the test procedure. The guidance presented here is also applicable to optimise the printer settings for a given printer device. As proof of concept, we compared fused filament fabrication, stereolithography and selective laser sintering as the three most used printing methods. We determined fused filament fabrication printing as the most economical solution, while stereolithography is most accurate and features the highest surface quality. Finally, we tested the applicability of our guidance by identifying a printer solution to manufacture a complex bioreactor for a perfused tissue construct. Due to its design, the manufacture via subtractive mechanical methods would be 21-fold more expensive than additive manufacturing and therefore, would result in three times the number of parts to be assembled subsequently. Using this bioreactor we showed a successful 14-day-culture of a biofabricated collagen-based tissue construct containing human dermal fibroblasts as the stromal part and a perfusable central channel with human microvascular endothelial cells. Our study indicates how the full potential of biofabrication can be exploited, as most printed tissues exhibit individual shapes and require storage under physiological conditions, after the bioprinting process.


Application value of EV/EV71/CA16-SAT detection in children with hand-foot-mouth disease.
The objective of this work was to explore the application value of a new type of fluorescent nucleic acid isothermal amplification (SAT) to detect EV/EV71/CA16-SAT in children with hand-foot-mouth disease (HFMD). For this purpose, from March 2017 to September 2019, Chengdu Children's Specialized Hospital collected throat swabs from children with clinical manifestations of hand, foot and mouth disease, and used SAT technology to screen and detect universal enterovirus (EV) nucleic acid (There were 1860 children with EV-RNA) positive. Patients who are EV-RNA positive at any time: first use the same throat swab specimen to detect EV71/CA16-RNA; secondly, collect venous blood and use the colloidal gold method to detect IgM antibodies in EV71/CA16 serum. The patients with positive EV71/CA16-RNA or EV71/CA16-IgM (or both) were repeated the above two methods 2 weeks and 4 weeks after standard treatment for review and comprehensive analysis. Results showed that 763 cases were enrolled for the first time: 59.76% were male and 40.24% were female; the age ranged from 1 month to 13 years, of which 69.06% were from 1 to 4 years old; CA16-RNA positive 56.23%, EV71-RNA positive 21.89%, CA16/EV71 -RNA were all positive in 1.57%; CA16-IgM was positive in 64.48%, EV71-IgM was positive in 54.26%, and CA16/EV71-IgM were both positive in 18.74%. After 2 weeks, 722 cases were reexamined: 26.73% were positive for CA16-RNA, 7.89% were positive for EV71-RNA, 0.28% were both positive for CA16/EV71-RNA; 66.21% were positive for CA16-IgM, 51.52% were positive for EV71-IgM, and IgM were all positive in 17.73%. Four weeks later, 489 cases were reexamined: among them, CA16-RNA positive 5.73% of which were positive for EV71 color RNA (0.005%), and 12.68% of them were all positive for EV71lym. The strategy of combining SAT technology and colloidal gold method to detect EV/EV71/CA16 nucleic acid (RNA) and serum IgM antibody in children HFMD can improve the early detection rate and accuracy of HFMD; According to the comprehensive analysis of the detection results of children with HFMD at the early stage, 2 weeks and 4 weeks of the present study, it is suggested that EV/EV71/CA16-SAT nucleic acid detection can be used to judge the prognosis, follow-up treatment, set isolation time, return students to school, and community management in children with HFMD. and prevention and control have more clinical application value.


A novel EB-1/AIDA-1 isoform, AIDA-1c, interacts with the Cajal body protein coilin.
Cajal bodies (CBs) are nuclear suborganelles that play a role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), which are crucial for pre-mRNA splicing. Upon nuclear reentry, Sm-class snRNPs localize first to the CB, where the snRNA moiety of the snRNP is modified. It is not clear how snRNPs target to the CB and are released from this structure after their modification. Coilin, the CB marker protein, may participate in snRNP biogenesis given that it can interact with snRNPs and SMN. SMN is crucial for snRNP assembly and is the protein mutated in the neurodegenerative disease Spinal Muscular Atrophy. Coilin knockout mice display significant viability problems and altered CB formation. Thus characterization of the CB and its associated proteins will give insight into snRNP biogenesis and clarify the dynamic organization of the nucleus. In this report, we identify a novel protein isoform of EB-1/AIDA-1, termed AIDA-1c, that interacts with the CB marker protein, coilin. Northern and nested PCR experiments reveal that the AIDA-1c isoform is expressed in brain and several cancer cell lines. Competition binding experiments demonstrate that AIDA-1c competes with SmB' for coilin binding sites, but does not bind SMN. When ectopically expressed, AIDA-1c is predominantly nuclear with no obvious accumulations in CBs. Interestingly, another EB-1/AIDA-1 nuclear isoform, AIDA-1a, does not bind coilin in vivo as efficiently as AIDA-1c. Knockdown of EB-1/AIDA-1 isoforms by siRNA altered Cajal body organization and reduced cell viability. These data suggest that specific EB-1/AIDA-1 isoforms, such as AIDA-1c, may participate in the regulation of nucleoplasmic coilin protein interactions in neuronal and transformed cells.


Role of immune interferon in the monocytic differentiation of human promyelocytic cell lines induced by leukocyte conditioned medium.
Conditioned medium (CM) from lectin-stimulated human leukocytes contains factors that induce human promyelocytic cell lines to differentiate along the monocytic pathway. In this report, we show that human promyelocytic cell lines are also induced to differentiate along this pathway by immune interferon (IFN gamma). Various preparations of IFN alpha tested did not induce this differentiation. In cultures containing IFN gamma, the cells are induced to coordinately express monocyte markers and functions such as monocyte-specific surface antigens, HLA-DR antigens, nonspecific esterase, receptors for the Fc fragment of IgG, and the ability to mediate antibody-dependent cell-mediated cytotoxicity. Our data indicate that differentiation induced by IFN gamma is not secondary to an arrest of growth of promyelocytic cell lines, but rather that a proportion of cells is induced along a programmed pathway of terminal differentiation similar to that of normal monocytes. CM contains IFN gamma, but its ability to induce differentiation is greater than expected on the basis of its content of IFN gamma. Treatments at 56 degrees C or at pH 2.0, which abolish IFN gamma activity, abrogate the differentiation ability of CM. The antiviral activity and the differentiation activity contained in the CM are coeluted from gel filtration and reverse-phase columns. Monoclonal antibodies anti-IFN gamma, which completely abrogate the differentiation ability of IFN gamma and the antiviral activity in the CM, completely suppress the induction of some monocyte markers by CM, but only reduce the expression of others. When IFN gamma is added to CM, promyelocytic cell lines are induced to differentiate to a much greater extent than that induced by either IFN gamma or IFN gamma-depleted CM alone. These results show that the differentiation activity of leukocyte CM is due to the synergistic effect of IFN gamma and other factors not yet identified.


Resveratrol in Patients with Minimal Hepatic Encephalopathy.
Minimal Hepatic Encephalopathy (MHE) is characterized by an impairment of social interaction, emotional behavior, sleep disorders, physical and mental symptoms, and diminished Quality of Life (QoL). The aim of our study is evaluating the potential liver health promoting a perspective of Resveratrol (RV) activities and evaluate whether RV treatment may improve health related quality of life (HRQL) and reduce depression and anxiety in patients with MHE. We evaluated depression using the Beck Depression Inventory test, anxiety with State-trait anxiety inventory test, quality of life through SF-36 test, and ammonia serum levels in 70 MHE patients that were randomized into two groups. In the comparison between RV group and placebo group we observed a decrease in Back Depression Inventory (BDI) (p < 0.001), in State-trait anxiety inventory (STAI) (p < 0.001), and improve in physical function (p < 0.001), in role physical (p < 0.05), in body pain (p < 0.05), in general health (p < 0.001), in vitality (p < 0.05), and in social function (p < 0.001). Resveratrol showed efficacy in the treatment of depression, anxiety, and ammonia serum levels, and improved the quality of life Of MHE patients.


Subjective Happiness Among Polish and Hadza People.
Life satisfaction and happiness were broadly studied in Western populations, whereas evidence from traditional societies remains surprisingly scarce. We collected data on the happiness from 145 Hadza, and compared it with data obtained from 156 Poles, representing Westernized society. Participants were asked to answer four simple questions from Subjective Happiness Scale (Lyubomirsky and Lepper, 1999). Results indicate that Hadza report a higher level of happiness with their lives than do Polish people. Our findings also show that sex was not related to happiness in both populations, while age was a negative predictor of happiness, but only among Poles. Therefore, we hypothesize that positive perception of aging in societies may increase their actual happiness.


Prehospital high-dose methylprednisolone in resuscitated out-of-hospital cardiac arrest patients (STEROHCA): a randomized clinical trial.
Patients who are successfully resuscitated following out-of-hospital cardiac arrest (OHCA) are still at a high risk of neurological damage and death. Inflammation and brain injury are components of the post-cardiac arrest syndrome, and can be assessed by systemic interleukin 6 (IL-6) and neuron-specific enolase (NSE). Anti-inflammatory treatment with methylprednisolone may dampen inflammation, thereby improving outcome. This study aimed to determine if prehospital high-dose methylprednisolone could reduce IL-6 and NSE in comatose OHCA patients. The STEROHCA trial was a randomized, blinded, placebo-controlled, phase II prehospital trial performed at two cardiac arrest centers in Denmark. Resuscitated comatose patients with suspected cardiac etiology were randomly assigned 1:1 to a single intravenous injection of 250 mg methylprednisolone or placebo. The co-primary outcome was reduction of IL-6 and NSE-blood levels measured daily for 72 h from admission. The main secondary outcome was survival at 180 days follow-up. We randomized 137 patients to methylprednisolone (n = 68) or placebo (n = 69). We found reduced IL-6 levels (p < 0.0001) in the intervention group, with median (interquartile range, IQR) levels at 24 h of 2.1 pg/ml (1.0; 7.1) and 30.7 pg/ml (14.2; 59) in the placebo group. We observed no difference between groups in NSE levels (p = 0.22), with levels at 48 h of 18.8 ug/L (14.4; 24.6) and 14.8 ug/L (11.2; 19.4) in the intervention and placebo group, respectively. In the intervention group, 51 (75%) patients survived and 44 (64%) in the placebo group. Prehospital treatment with high-dose methylprednisolone to resuscitated comatose OHCA patients, resulted in reduced IL-6 levels after 24 h, but did not reduce NSE levels.


Contact allergy to gold in patients with oral lichen lesions.
The aetiology of oral lichen lesions is obscure. In this study the frequency of contact allergy to gold in 83 patients with oral lichen lesions was compared with that in two control groups, comprising 319 age- and gender-matched patients with dermatitis selected from files and 83 clinically examined dermatitis patients. All patients were tested epicutaneously with gold sodium thiosulphate. The two control groups tested were under examination for a tentative diagnosis of allergic dermatitis not related to oral problems. The frequency of contact allergy to gold was 28.9% in the patients with oral lichen lesions, 18.2% in patients selected from files, and 22.9% in the clinically examined control patients. The difference in frequency between patients with oral lichen lesions and those taken from files was statistically significant.


Within-host selection is limited by an effective population of Streptococcus pneumoniae during nasopharyngeal colonization.
Streptococcus pneumoniae (pneumococcus) is a significant pathogen that frequently colonizes the human nasopharynx. Environmental factors, including antimicrobial use and host immunity, exert selection on members of the nasopharyngeal population, and the dynamics of selection are influenced by the effective population size of the selected population, about which little is known. We measured here the variance effective population size (N(e)) of pneumococcus in a mouse colonization model by monitoring the frequency change of two cocolonizing, competitively neutral pneumococcal strains over time. The point estimate of N(e) during nasal carriage in 16 BALB/c mice was 133 (95% confidence interval [CI] = 11 to 203). In contrast, the lower-bound census population exhibited a mean of 5768 (95% CI = 2,515 to 9,021). Therefore, pneumococcal N(e) during nasal carriage is substantially smaller than the census population. The N(e) during day 1 to day 4 of colonization was comparable to the Ne during day 4 to day 8. Similarly, a low Ne was also evident for the colonization of pneumococcus in BALB/c mice exposed to cholera toxin 4 weeks prior to challenge and in another mouse strain (DO11.10 RAG(-/-)). We developed a mathematical model of pneumococcal colonization composed of two subpopulations with differential contribution to future generations. By stochastic simulation, this model can reproduce the pattern of observed pneumococcal N(e) and predicts that the selection coefficients may be difficult to measure in vivo. We hypothesized that such a small N(e) may reduce the effectiveness of within host selection for pneumococcus.


[Ureteral stenosis. Endo-urologic treatment (dilatation). Experience with 43 cases].
Stricture of the ureter has been traditionally treated by open surgical techniques that occasionally had to be performed not without risk to the patient owing to the presence of septic and associated uremic conditions that invariably had a negative influence on the outcome. With the advent of endourological techniques in the last decade, much has been published on endoscopic treatment of the different areas of the urinary tract. One of the fields where important developments have taken place is that relative to endourological treatment of ureteric strictures. Since we started our therapeutic protocol for our patients in 1983 to date, we have treated 43 patients by dilatation. Patient follow up ranging from 6 months to 6 1/2 years (mean follow up greater than 30 months) revealed good results were achieved in 76.74%. The complications have been scant, mortality nil, and patients have been able to resume social and occupational activities early. All the foregoing prompt us to consider this therapeutic modality as the treatment of choice.


Multimodal pain management after total hip and knee arthroplasty at the Ranawat Orthopaedic Center.
Improvements in pain management techniques in the last decade have had a major impact on the practice of total hip and knee arthroplasty (THA and TKA). Although there are a number of treatment options for postoperative pain, a gold standard has not been established. However, there appears to be a shift towards multimodal approaches using regional anesthesia to minimize narcotic consumption and to avoid narcotic-related side effects. Over the last 10 years, we have used intravenous patient-controlled analgesia (PCA), femoral nerve block (FNB), and continuous epidural infusions for 24 and 48 hours with and without FNB. Unfortunately, all of these techniques had shortcomings, not the least of which was suboptimal pain control and unwanted side effects. Our practice has currently evolved to using a multimodal protocol that emphasizes local periarticular injections while minimizing the use of parenteral narcotics. Multimodal protocols after THA and TKA have been a substantial advance; they provide better pain control and patient satisfaction, lower overall narcotic consumption, reduce hospital stay, and improve function while minimizing complications. Although no pain protocol is ideal, it is clear that patients should have optimum pain control after TKA and THA for enhanced satisfaction and function. Level V, expert opinion. See the Guidelines for Authors for a complete description of levels of evidence.


LC3-associated phagocytosis protects against inflammation and liver fibrosis via immunoreceptor inhibitory signaling.
Sustained hepatic and systemic inflammation, particularly originating from monocytes/macrophages, is a driving force for fibrosis progression to end-stage cirrhosis and underlies the development of multiorgan failure. Reprogramming monocyte/macrophage phenotype has emerged as a strategy to limit inflammation during chronic liver injury. Here, we report that LC3-associated phagocytosis (LAP), a noncanonical form of autophagy, protects against hepatic and systemic inflammation during chronic liver injury in rodents, with beneficial antifibrogenic effects. LAP is enhanced in blood and liver monocytes from patients with fibrosis and cirrhosis. Pharmacological inhibition of LAP components in human monocytes from patients with cirrhosis or genetic disruption of LAP in mice with chronic liver injury exacerbates both the inflammatory signature in isolated human monocytes and the hepatic inflammatory profile in mice, resulting in enhanced liver fibrosis. Mechanistically, patients with cirrhosis showed increased monocyte expression of Fc fragment of IgG receptor IIA (FcγRIIA) and enhanced engulfment of immunoglobulin G in LC3+ phagosomes that triggers an FcγRIIA/Src homology region 2 domain-containing phosphatase-1 (SHP-1) inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) anti-inflammatory pathway. Mice overexpressing human FcγRIIA in myeloid cells show enhanced LAP in response to chronic liver injury and resistance to inflammation and liver fibrosis. Activation of LAP is lost in monocytes from patients with multiorgan failure and restored by specifically targeting ITAMi signaling with anti-FcγRIIA F(ab')2 fragments, or with intravenous immunoglobulin (IVIg). These data suggest the existence of an ITAMi-mediated mechanism by which LAP might protect against inflammation. Sustaining LAP may open therapeutic perspectives for patients with chronic liver disease.


[Clinico-morphological tests to assess the function of neutrophilic granulocytes].
Clinico-morphological tests for the estimation of neutrophil granulocyte function were compared by their reproducibility, reliability and availability for standard clinical laboratories, and the results were analysed. Lysosomal-cationic test was offered for clinical practice, as it gives qualitative and quantitative assessment of the phagocytosis process, allows prediction of complications before their clinical onset, performance of rapid evaluation of the therapy used, reveals shifts in the level of non-specific resistance of the body. Methods of application of lysosomal-cationic test in the pathoanatomic practice have been developed for the study of intravital biopsy samples and surgical material.


Enhanced Biocatalytic Activity of Recombinant Lipase Immobilized on Gold Nanoparticles.
Bacterial lipases especially Pseudomonas lipases are extensively used for different biotechnological applications. With the better understanding and progressive needs for improving its activity in accordance with the growing market demand, we aimed in this study to improve the recombinant production and biocatalytic activity of lipases via surface conjugation on gold nanoparticles. The full length coding sequences of lipase gene (lipA), lipase specific foldase gene (lipf) and dual cassette (lipAf) gene were amplified from the genomic DNA of Pseudomonas aeruginosa PA14 and cloned into the bacterial expression vector pRSET-B. Recombinant lipases were expressed in E. coli BL-21 (DE3) pLysS then purified using nickel affinity chromatography and the protein identity was confirmed using SDS-PAGE and Western blot analysis. The purified recombinant lipases were immobilized through surface conjugation with gold nanoparticles and enzymatic activity was colorimetrically quantified. Here, two single expression plasmid systems pRSET-B-lipA and pRSET-B-lipf and one dual cassette expression plasmid system pRSET-B-lipAf were successfully constructed. The lipolytic activities of recombinant lipases LipA, Lipf and LipAf were 4870, 426 and 6740 IUmg-1, respectively. However, upon immobilization of these recombinant lipases on prepared gold nanoparticles (GNPs), the activities were 7417, 822 and 13035 IUmg-1, for LipA-GNPs, Lipf-GNPs and LipAf-GNPs, respectively. The activities after immobilization have been increased 1.52 and 1.93 -fold for LipA and LipAf, respectively. The lipolytic activity of recombinant lipases in the bioconjugate was significantly increased relative to the free recombinant enzyme where immobilization had made the enzyme attain its optimum performance.


Durvalumab induced sarcoid-like pulmonary lymphadenopathy.
Immune checkpoint inhibitors (ICIs) have become pivotal in the treatment of lung cancer. An increasing number of immune-related adverse events (irAEs) have been recognized with their use. To our knowledge, this is the first published case of sarcoid-like pulmonary lymphadenopathy associated with durvalumab, a monoclonal antibody against programmed death ligand-1 (PD-L1). A 76-year-old woman received adjuvant durvalumab for Stage IIA pT2aN1M0 (American Joint Committee on Cancer, Seventh edition) poorly differentiated lung adenocarcinoma. After three cycles, a sarcoid-like granulomatous reaction was identified in mediastinal and hilar lymph nodes. Although the lymphadenopathy remained stable in size with the ongoing treatment, progressive intracranial metastases were identified after a further three cycles of durvalumab. Sarcoid-like inflammation with the formation of non-caseating granulomas in the absence of systemic sarcoidosis is an irAE which may mimic disease progression. Although a subset of patients who experience this reaction may have a favourable response to checkpoint inhibition, progression of disease may occur contemporaneously.


Phosphorylation of human erythrocyte pyruvate kinase by soluble cyclic-AMP-dependent protein kinases. Comparison with human liver L-type enzyme.
Human red cell contain soluble adenosine-3',5'-phosphate-dependent protein kinases, which are able to phosphorylate the L' subunits of erythrocyte pyruvate kinase. Efficiency and maximum level of phosphorylation are very comparable in human liver and red cells. Phosphorylation of red cell pyruvate kinase results in the same kinetic modifications as for liver enzyme, namely a shift towards a 'T' allosteric state characterized by a decreased affinity for phosphoenolpyruvate and increased inhibition by the allosteric inhibitors ATP and alanine. In the course of red cell aging a small amount of partially proteolysed pyruvate kinase, devoid of the phosphorylatable site, appears; it resembles the subtilisin-treated L'4 enzyme and accounts for less than 20% of total pyruvate kinase subunits. Endogenous phosphorylation of pyruvate kinase from erythrocytes incubated in the presence of cyclic nucleotides produces the same kinetic modifications as phosphorylation in partially purified extract; this, however, does not change glucose consumption, lactate production and glycolytic intermediate concentrations of the incubated cells.


[The possibilities for the primary recovery of intestinal continuity in complicated cancer of the left half of the colon].
In 80 patients with complicated clinical course of carcinoma of the left half of the colon the primary restoration of the intestinal continuity was fulfilled (in 47 patients left-side hemicolectomy, in 15 patients subtotal colectomy, in 15 patients-Hartman operations). Postoperative complications were observed in 18 patients (22.5%), 7 patients died (8.8%). Functional long-term results were favorable in most patients. The clinical experience obtained suggests that primary restoration of the intestinal continuity deserves special attention in a number of cases.


Germline and reproductive tract effects intensify in male mice with successive generations of estrogenic exposure.
The hypothesis that developmental estrogenic exposure induces a constellation of male reproductive tract abnormalities is supported by experimental and human evidence. Experimental data also suggest that some induced effects persist in descendants of exposed males. These multi- and transgenerational effects are assumed to result from epigenetic changes to the germline, but few studies have directly analyzed germ cells. Typically, studies of transgenerational effects have involved exposing one generation and monitoring effects in subsequent unexposed generations. This approach, however, has limited human relevance, since both the number and volume of estrogenic contaminants has increased steadily over time, intensifying rather than reducing or eliminating exposure. Using an outbred CD-1 mouse model, and a sensitive and quantitative marker of germline development, meiotic recombination, we tested the effect of successive generations of exposure on the testis. We targeted the germline during a narrow, perinatal window using oral exposure to the synthetic estrogen, ethinyl estradiol. A complex three generation exposure protocol allowed us to compare the effects of individual, paternal, and grandpaternal (ancestral) exposure. Our data indicate that multiple generations of exposure not only exacerbate germ cell exposure effects, but also increase the incidence and severity of reproductive tract abnormalities. Taken together, our data suggest that male sensitivity to environmental estrogens is increased by successive generations of exposure.


Mobile Phone Sensor Correlates of Depressive Symptom Severity in Daily-Life Behavior: An Exploratory Study.
Depression is a common, burdensome, often recurring mental health disorder that frequently goes undetected and untreated. Mobile phones are ubiquitous and have an increasingly large complement of sensors that can potentially be useful in monitoring behavioral patterns that might be indicative of depressive symptoms. The objective of this study was to explore the detection of daily-life behavioral markers using mobile phone global positioning systems (GPS) and usage sensors, and their use in identifying depressive symptom severity. A total of 40 adult participants were recruited from the general community to carry a mobile phone with a sensor data acquisition app (Purple Robot) for 2 weeks. Of these participants, 28 had sufficient sensor data received to conduct analysis. At the beginning of the 2-week period, participants completed a self-reported depression survey (PHQ-9). Behavioral features were developed and extracted from GPS location and phone usage data. A number of features from GPS data were related to depressive symptom severity, including circadian movement (regularity in 24-hour rhythm; r=-.63, P=.005), normalized entropy (mobility between favorite locations; r=-.58, P=.012), and location variance (GPS mobility independent of location; r=-.58, P=.012). Phone usage features, usage duration, and usage frequency were also correlated (r=.54, P=.011, and r=.52, P=.015, respectively). Using the normalized entropy feature and a classifier that distinguished participants with depressive symptoms (PHQ-9 score ≥5) from those without (PHQ-9 score <5), we achieved an accuracy of 86.5%. Furthermore, a regression model that used the same feature to estimate the participants' PHQ-9 scores obtained an average error of 23.5%. Features extracted from mobile phone sensor data, including GPS and phone usage, provided behavioral markers that were strongly related to depressive symptom severity. While these findings must be replicated in a larger study among participants with confirmed clinical symptoms, they suggest that phone sensors offer numerous clinical opportunities, including continuous monitoring of at-risk populations with little patient burden and interventions that can provide just-in-time outreach.


Early complications in endovascular treatment of abdominal aortic aneurysm.
The incidence of perioperative complications during endovascular repair of abdominal aortic aneurysm (EVAR) is reported in limited series. The aim of this study is to evaluate a multi-center survey of unexpected intraprocedural critical events of EVAR. A questionnaire relative to intraprocedural complications during EVAR was sent to major vascular surgery divisions in Italy. Eleven answered to the survey. The data obtained are relative to 1696 procedures. A wide range of incidence of critical events was observed, from a lower value of 2.7% to a higher value of 68.8% (mean 21.16%). The problems relative to the insertion phase of the delivery system were 7.7%. Endoleaks were reported in 5.5% of cases. Stent graft release was problematic in 0.4% of cases and in another 0.4% there was a problem in shaft retrieval. Unintentional coverage of renal or polar arteries occurred in 0.8% of the procedures ; hypogastric arteries were unwillingly excluded in 2.7% of cases. Aortic or iliac artery rupture had an incidence of 0.7% ; arterial dissection occurred in 0.9%, atheroembolism in 0.5%, lower limb ischemia due to graft limb kinks in 0.7% and to occlusion in 0.9%. Perioperative critical events represent a serious problem only in few cases of EVAR ; they are common but in many cases not predictable ; in most circumstances they can be easily corrected with adjunctive manoeuvres during the same procedure. There is a highly significant correlation between the total workload and the incidence of critical events ; these do not appear to be related to the learning curve.


[Case report of a silent injury of the superficial femoral artery with a late diagnosis].
The authors present a report on almost complete severing of the superficial femoral artery which took a clinically almost inapparent course and the diagnosis was established late. They draw attention to the necessity to consider this type of injury if a foreign body penetrates deeply into Hunter's canal and when the course of the condition is silent.


Mechanism of Cu deposition on the alpha-Al(2)O(3) (0001) surface.
The growth mechanism of the Cu/alpha-Al(2)O(3) (0001) interface is studied by first-principles molecular-dynamics simulations as a function of the transition-metal coverage (theta) and the temperature of the system. On the anhydrous surface growth of Cu(0) 3D clusters is predicted. On the partially hydroxylated surface, a Cu(I) monolayer, relatively stable upon the temperature rising, is first observed (theta<1/3 ML). Increasing Cu loading leads to Cu(I)/Cu(0) mixed phases that when heated aggregate into 3D particles increasing the number of Cu(0) atoms, in agreement with the Auger spectra of Kelber et al.


Physical Activity Trends of Finnish Adolescents With Long-Term Illnesses or Disabilities From 2002-2014.
Adolescents' physical activity level is a major source of concern. For adolescents with long-term illnesses or disabilities (LTID), being physically active can prevent secondary conditions. This is one of the first studies reporting trends in physical activity of adolescents with LTID in relation to gender, age, and sports club membership. Data were collected from the Health Behavior in School-aged Children study in Finland during 2002, 2006, 2010, and 2014. In 13- and 15-year-olds (N = 2206), 17.1% reported having LTID. Daily physical activity recall was the dependent variable. Binary logistic regression analysis was conducted separately for sports club members (n = 936) and nonmembers (n = 1270). The proportion of physically active adolescents with LTID in 2014 was higher than in 2002 for girls (15.6% vs 8.7%) and boys (26.6% vs 13.0%). Girl sports club members were 2 times more likely to be physically active in 2014 than in 2002. The largest trend between 2014 and 2002 was among boy nonmembers (odds ratio: 4.62, 95% confidence interval, 2.02-10.58). More adolescents with LTID took part in daily moderate-to-vigorous physical activity in 2014 than in 2002; however, physical activity levels still remain low. Sports club membership was similar to that of the general population.


Insights into a viral motor: the structure of the HK97 packaging termination assembly.
Double-stranded DNA viruses utilise machinery, made of terminase proteins, to package viral DNA into the capsid. For cos bacteriophage, a defined signal, recognised by small terminase, flanks each genome unit. Here we present the first structural data for a cos virus DNA packaging motor, assembled from the bacteriophage HK97 terminase proteins, procapsids encompassing the portal protein, and DNA containing a cos site. The cryo-EM structure is consistent with the packaging termination state adopted after DNA cleavage, with DNA density within the large terminase assembly ending abruptly at the portal protein entrance. Retention of the large terminase complex after cleavage of the short DNA substrate suggests that motor dissociation from the capsid requires headful pressure, in common with pac viruses. Interestingly, the clip domain of the 12-subunit portal protein does not adhere to C12 symmetry, indicating asymmetry induced by binding of the large terminase/DNA. The motor assembly is also highly asymmetric, showing a ring of 5 large terminase monomers, tilted against the portal. Variable degrees of extension between N- and C-terminal domains of individual subunits suggest a mechanism of DNA translocation driven by inter-domain contraction and relaxation.


Sibship size, birth order and psychotic experiences: Evidence from 43 low- and middle-income countries.
Sibship size and birth order may be contributing factors to the multifactorial etiology of psychosis. Specifically, several studies have shown that sibship size and birth order are associated with schizophrenia. However, there are no studies on their association with psychotic experiences (PE). Cross-sectional, community-based data from 43 low- and middle-income countries which participated in the World Health Survey were analyzed. The Composite International Diagnostic Interview was used to identify four types of past 12-month PE. The association of sibship size and birth order with PE was assessed with multivariable logistic regression. The final sample consisted of 212,920 adults [mean (SD) age 38.1 (16.0) years; 50.7% females]. In the multivariable analysis, compared to individuals with no siblings, the OR increased linearly from 1.26 (95%CI = 1.01-1.56) to 1.72 (95%CI = 1.41-2.09) among those with 1 and ≥ 9 siblings, respectively. Compared to the first-born, middle-born individuals were more likely to have PE when having a very high number of siblings (i.e. ≥9). Future studies should examine the environmental and biological factors underlying the association between sibship size/birth order and PE. Specifically, it may be important to examine the unmeasured factors, such as childhood infections and adversities that may be related to both family structure and PE.


Identification of presumed corneal neuromas and microneuromas using laser-scanning in vivo confocal microscopy: a systematic review.
This systematic review critically evaluated peer-reviewed publications describing morphological features consistent with, or using terms related to, a 'neuroma' or 'microneuroma' in the human cornea using laser-scanning in vivo confocal microscopy (IVCM). The review was prospectively registered on PROSPERO (CRD42020160038). Comprehensive literature searches were performed in Ovid MEDLINE, Ovid Embase and the Cochrane Library in November 2019. The review included primary research studies and reviews that described laser-scanning IVCM for examining human corneal nerves. Papers had to include at least one of a pre-specified set of keyword stems, broadly related to neuromas and microneuromas, to describe a corneal nerve feature. Twenty-five papers (20 original studies; 5 reviews) were eligible. Three original studies evaluated corneal nerve features in healthy eyes. Most papers assessed corneal nerves in ocular and systemic conditions; seven studies did not include a control/comparator group. There was overlap in terminology used to describe nerve features in healthy and diseased corneas (eg, bulb-like/bulbous, penetration, end/s/ing). Inspection of IVCM images within the papers revealed that features termed 'neuromas' and 'microneuromas' could potentially be physiological corneal stromal-epithelial nerve penetration sites. We identified inconsistent definitions for terms, and limitations in IVCM image acquisition, sampling and/or reporting that may introduce bias and lead to inaccurate representation of physiological nerve characteristics as pathological. These findings identify a need for consistent nomenclature and definitions, and rigorous IVCM scanning and analysis protocols to clarify the prevalence of physiological, as opposed to pathological, corneal nerve features.


Adjunctive vancomycin powder in pediatric spine surgery is safe.
Therapeutic level II cohort study. To evaluate the safety of adjunctive local application of vancomycin powder (VP) for infection prophylaxis in posterior instrumented thoracic and lumbar spine wounds in pediatric patients weighing more than 25 kg. Spine surgeons have largely turned to vancomycin prophylaxis in an attempt to decrease the incidence of late surgical site infection and acute surgical site infection from methicillin-resistant Staphylococcus aureus. In adult patients, the adjunctive local application of VP with an intravenous cephalosporin has been shown to decrease postsurgical wound infection rates significantly; however, the safety of VP as an adjunct in pediatric spine surgery has not been reported. We reviewed data collected under a systematic protocol specifically designed to monitor the safety profile of VP. We measured changes in creatinine and systemic vancomycin levels after intrawound application of 500 mg of unreconstituted VP during spine deformity correction surgery in patients weighing more than 25 kg (patients also received routine intravenous cephalosporin prophylaxis). Laboratory values were measured preoperatively and on postoperative days 1 and 4. Any adverse reactions and infections through available follow-up (2-8 mo) were recorded. Eighty-seven consecutive pediatric patients with spinal deformity weighing more than 25 kg who received intraoperative VP during a 9-month period were identified. Sixty-three percent of the patients in this series had adolescent idiopathic scoliosis, 15% congenital scoliosis, 15% neuromuscular scoliosis, and 5% spondylolisthesis. The average change in creatinine levels between the preoperative and postoperative day 1 draw was -0.03 and between the preoperative and postoperative day 4 draw was -0.075. The postoperative systemic vancomycin levels remained undetectable. None of the patients experienced nephrotoxicity or red man syndrome. Three of the 87 patients developed a surgical site infection. In this cohort there were no clinically significant changes in creatinine level or systemic vancomycin level caused by use of intraoperative VP. 2.


Electrospray ionization Fourier transform mass spectrometric analysis of intact bikunin glycosaminoglycan from normal human plasma.
A mixture of glycosaminoglycan (GAG) chains from a plasma proteoglycan bikunin was fractionated using native, continuous-elution polyacrylamide gel electrophoresis, and the resulting fractions were analyzed by electrospray ionization Fourier transform mass spectrometry (ESI FTMS). Molecular mass analysis of the intact GAG afforded information about the length and composition of GAG chains in the mixture. Ambiguity in the interpretation of the intact GAG mass spectra was eliminated by conducting an additional experiment in which the GAG chains of known molecular mass were treated with a GAG-degrading enzyme, chondroitinase ABC, and the digestion products were analyzed by ESI FTMS. The plasma bikunin GAG chains consisted predominantly of odd number of saccharides, although few chains consisting of even number of saccharides were also detected. Majority of the analyzed chains were tetrasulfated or pentasulfated and comprised by 29 to 41 monosaccharides.


Nanoparticle-mediated targeted drug delivery for breast cancer treatment.
Breast cancer (BC) is the most common malignancy in women worldwide, and one of the deadliest after lung cancer. Currently, standard methods for cancer therapy including BC are surgery followed by chemotherapy or radiotherapy. However, both chemotherapy and radiotherapy often fail to treat BC due to the side effects that these therapies incur in normal tissues and organs. In recent years, various nanoparticles (NPs) have been discovered and synthesized to be able to selectively target tumor cells without causing any harm to the healthy cells or organs. Therefore, NPs-mediated targeted drug delivery systems (DDS) have become a promising technique to treat BC. In addition to their selectivity to target tumor cells and reduce side effects, NPs have other unique properties which make them desirable for cancer treatment such as low toxicity, good compatibility, ease of preparation, high photoluminescence (PL) for bioimaging in vivo, and high loadability of drugs due to their tunable surface functionalities. In this study, we summarize with a critical analysis of the most recent therapeutic studies involving various NPs-mediated DDS as alternatives for the traditional treatment approaches for BC. It will shed light on the significance of NPs-mediated DDS and serve as a guide to seeking for the ideal methodology for future targeted drug delivery for an efficient BC treatment.


Stress in the Norwegian police service.
High levels of stress have been attributed to the conditions of police work, but there is little empirical evidence for this. To develop a new instrument to measure job stress in the police; to assess the most severe and frequent police stressors; to compare levels of stress according to the demographic and organizational factors; and to study stress in relation to personality traits, work locus of control and coping strategies. A comprehensive nationwide questionnaire survey of 3272 Norwegian police at all hierarchical levels, including the Norwegian Police Stress Survey (NPSS), the Job Stress Survey, the Basic Character Inventory, the Work Locus of Control Scale, and the Coping Strategies Scale. Work injuries were appraised as the most stressful but least frequent stressor and job pressure was reported the least severe but most frequent stressor. Females experienced job stressors less frequently, but appraised them as more severe than men did. Older police officers reported more job pressure severity and fewer work injuries. The police in districts where peer support was planned but not implemented, and who worked in districts with more than 50,000 inhabitants, perceived the lack of support more severely than others. The correlations between stress and personality traits, work locus of control, and coping were moderate. The NPSS captures police-specific stressors that are not adequately measured by global stress instruments. The study of stress in police work should preferably involve a nationwide use of police-specific stress instruments.


Sulfur dioxide: a novel gaseous signal in the regulation of cardiovascular functions.
The atmospheric pollutant sulfur dioxide (SO(2)) is endogenously generated from the normal metabolism of sulfur-containing amino acids through the aspartate aminotransferase pathway. SO(2) is produced in cardiovascular tissues, and the aspartate aminotransferase mRNA is localized in endothelia and in vascular smooth muscle cells near the endothelial layer. Recent studies explored the physiological and pathophysiological effects of endogenous SO(2) on the cardiovascular system, and various potential mechanisms were found. These discoveries suggest a novel role of endogenous SO(2) in the modulation of the cardiovascular system and provide a basis for new treatments for cardiovascular diseases.


Variability in energy cost of running at the end of a triathlon and a marathon.
The aim of this study was to investigate the increase in energy cost of running occurring at the end of a triathlon and a marathon event and to link them to the metabolic and hormonal changes, as well as to variations in stride length. Seven subjects took part in 3 experimental situations: a 2 h 15 min triathlon (30 min swimming, 60 min cycling and 45 min running), a 2 h 15 min marathon (MR) were the last 45 min were run at the same speed as the triathlon run (TR), and a 45 min isolated run (IR) done at triathlon speed. The results show that energy cost during MR was higher than during TR (p < 0.01) (+ 8.9%). Similar observations were made for pulmonary ventilation (+ 7.9%) and heart rate (+ 6.3%). Moreover, the values were significantly greater than the values obtained during the IR. TR and MR lead to greater weight loss (p < 0.01) (2.4 +/- 0.3 kg) than IR (1 +/- 0.2 kg). The triathlon and the marathon produced a large decrease in plasma volume (respectively 19.6 +/- 1.4% and 12.9 +/- 1.1%) compared to IR (2 +/- 0.4%). Plasma renin activity was higher for the triathlon and the marathon than for the IR (p < 0.01). MR produces a significantly greater increase in plasma free fatty acids (F.F.A.) than TR (p < 0.05) and IR (p < 0.01). In addition, the F.F.A. at the end of TR were significantly higher than IR (p < 0.05). At the end of the trial the mean stride lengths for TR and IR were greater (+ 15%) (p < 0.01) than for MR. This study, carried out with subjects running overground, confirms the decrease in running efficiency previously shown at the end of a laboratory triathlon, and demonstrates that this decrease is lower than that occurring during a marathon.


53BP1 and BRCA1 control pathway choice for stalled replication restart.
The cellular pathways that restart stalled replication forks are essential for genome stability and tumor prevention. However, how many of these pathways exist in cells and how these pathways are selectively activated remain unclear. Here, we describe two major fork restart pathways, and demonstrate that their selection is governed by 53BP1 and BRCA1, which are known to control the pathway choice to repair double-strand DNA breaks (DSBs). Specifically, 53BP1 promotes a fork cleavage-free pathway, whereas BRCA1 facilitates a break-induced replication (BIR) pathway coupled with SLX-MUS complex-mediated fork cleavage. The defect in the first pathway, but not DSB repair, in a 53BP1 mutant is largely corrected by disrupting BRCA1, and vice versa. Moreover, PLK1 temporally regulates the switch of these two pathways through enhancing the assembly of the SLX-MUS complex. Our results reveal two distinct fork restart pathways, which are antagonistically controlled by 53BP1 and BRCA1 in a DSB repair-independent manner.


Regional distribution of alpha 1-adrenoceptor subtypes in rat kidney.
alpha 1-Adrenoceptors are expressed in high density in the rat kidney. Recent studies have shown that alpha 1-adrenoceptors are heterogeneous and can be subtyped based on their affinity for the antagonists WB 4101 (alpha 1A greater than alpha 1B) and chloroethylclonidine (alpha 1B-selective). We therefore investigated the distribution of alpha 1-adrenoceptor subtypes using [3H]prazosin binding in membranes prepared from cortex, the outer stripe of the outer medulla (OSOM), the inner stripe of the outer medulla (ISOM) and inner medulla dissected from rat kidney. [3H]Prazosin binding was detectable in each region with the following maximum binding site values for [3H]prazosin (femtomoles per milligram of protein): cortex, 186 +/- 20; OSOM, 76 +/- 14; ISOM, 34 +/- 2; and inner medulla, 8 +/- 2. Pretreatment of membranes with chloroethylclonidine (10 microM for 10 min) reduced maximum binding sites to 41 +/- 4% (75 +/- 9 fmol/mg) of control in cortex, 41 +/- 9% of control in OSOM (29 +/- 8 fmol/mg) and 15 +/- 3% of control in ISOM (5 +/- 1 fmol/mg). In competition studies, WB 4101 labeled both high and low affinity sites in cortex (respective pKi values = 10.01 +/- 0.3 and 8.23 +/- 0.1) and OSOM (pKi values = 9.6 + 0.3 and 8.3 +/- 0.5), but only low affinity sites in ISOM (pKi = 8.41 +/- 0.1). The relative prevalence of high:low affinity sites revealed by WB 4101 was 53:47 for cortex, 52:48 for OSOM and virtually all low affinity for ISOM. Prior treatment with chloroethylclonidine greatly reduced the low affinity component of the WB 4101 competition curve in cortex and OSOM. We conclude that: 1) the density of alpha 1-adrenoceptors is highest in the cortex and decreases from cortex to papilla and 2) the alpha 1A and alpha 1B subtypes are approximately equally distributed in the cortex and OSOM, but the alpha 1B subtype predominates in ISOM.


The state of primary care in the United States of America and lessons for primary care groups in the United Kingdom.
The health care system of the United States of America (USA) is lavishly funded and those with adequate insurance usually receive excellent attention. However, the system is fragmented and inequitable. Health workers often find it difficult to separate vocational roles from business roles. Care tends to focus on the acute rather than the chronic, on 'episodes of illness' rather than 'person-centred' care, on short-term fixes rather than long-term approaches, on scientific/technical solutions rather than discourse or the 'art of healing', and on individual health rather than population health. The majority of US doctors are trained in the 'hightech' hospital paradigm and there is no equivalent of the United Kingdom (UK) general practitioner (GP), who lies at the hub of a primary health care team (PHCT) and who is charged with taking a long-term view, co-ordinating health care for individual patients, and acting as patient advocate without major conflicting financial incentives. However, primary care groups/trusts (PCGs) could learn from US management and training techniques, case management, NHS Direct equivalents, and the effects of poorly developed PHCTs. PCGs could develop the UK's own version of utilisation management. A cash-limited, unified budget within an underfunded National Health Service poses threats to general practice. In both the USA and the UK, primary care is a prominent tool in new attempts at cost control. PCGs offer the opportunity of better integration with public health and social services, but threaten GPs' role as independent advocates by giving them a rationing role. Managed care has forced a similar role onto our US counterparts with consequent public displeasure and professional disillusion. UK GPs will have to steer a careful course if they are to avoid a similar fate.