Physiological, molecular, and cellular mechanisms of impaired seawater tolerance following exposure of Atlantic salmon, Salmo salar, smolts to acid and aluminum.
We examined the physiological, molecular, and cellular mechanisms of impaired ion regulation in Atlantic salmon, Salmo salar, smolts following acute acid and aluminum (Al) exposure. Smolts were exposed to: control (pH 6.5, 3.4 micrpg l(-1) Al), acid and low Al (LAl: pH 5.4, 11 microg l(-1) Al), acid and moderate Al (MAl: pH 5.3, 42 microg l(-1) Al), and acid and high Al (HAl: pH 5.4, 56 microg l(-1) Al) for two and six days. At each time-point, smolts were sampled directly from freshwater treatment tanks and after a 24h seawater challenge. Exposure to acid/MAl and acid/HAl led to accumulation of gill Al, substantial alterations in gill morphology, reduced gill Na(+)/K(+)-ATPase (NKA) activity, and impaired ion regulation in both freshwater and seawater. Exposure to acid/MAl for six days also led to a decrease in gill mRNA expression of the apical Cl(-) channel (cystic fibrosis transmembrane conductance regulator I), increased apoptosis upon seawater exposure, an increase in the surface expression of mitochondria-rich cells (MRCs) within the filament epithelium of the gill, but reduced abundance of gill NKA-positive MRCs. By contrast, smolts exposed to acid and the lowest Al concentration exhibited minor gill Al accumulation, slight morphological modifications in the gill, and impaired seawater tolerance in the absence of a detectable effect on freshwater ion regulation. These impacts were accompanied by decreased cell proliferation, a slight increase in the surface expression of MRCs within the filament epithelium, but no impact on gill apoptosis or total MRC abundance was observed. However, MRCs in the gills of smolts exposed to acid/LAl exhibited morphological alterations including decreased size, staining intensity, and shape factor. We demonstrate that the seawater tolerance of Atlantic salmon smolts is extremely sensitive to acute exposure to acid and low levels of Al, and that the mechanisms underlying this depend on the time-course and severity of Al exposure. We propose that when smolts are exposed to acid and moderate to high Al concentrations, impaired seawater tolerance results from extensive gill Al accumulation, damage to the epithelium, reduced MRC and transport protein abundance, and a synergistic stimulation of apoptosis in the gill upon seawater exposure. When smolts are exposed to acid and low levels of Al, loss of seawater tolerance appears to be independent of these mechanisms and may result instead from a shift in the phenotype of MRCs present in the gill epithelium.


Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis screening and treatment of pregnant women in Port-au-Prince, Haiti.
In Haiti, routine screening for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) among pregnant women is not conducted; yet these sexually transmitted infections (STIs) are associated with adverse birth and newborn health outcomes. We aimed to assess the acceptability and feasibility of screening and the prevalence of STIs among pregnant women in Port-au-Prince, Haiti. Pregnant women of at least 18 years of age who attend Haitian Study Group for Kaposi's sarcoma and Opportunistic Infections (GHESKIO) clinics in Port-au-Prince, Haiti provided self-collected vaginal swab specimens. Laboratory testing was done with Xpert® CT/NG and Xpert® TV. The results of this study showed that of the 322 pregnant women who visited GHESKIO for their regular scheduled appointments, 300 (93.2%) consented for CT, NG, and TV testing. Of those, 107 women (35.7%) tested positive for at least one STI. There were 42 (14.7%) cases of CT, 8 (2.8%) NG, and 83 (29.0%) TV infections. Most infections were treated - 122 of 133 (91.7%). In summary, we found that it was highly acceptable and feasible to implement CT, NG, and TV screening among pregnant women in Port-au-Prince, Haiti. We found high prevalence of STIs among pregnant women, which suggest that STI screening in this population may be warranted.


Bilateral internuclear ophthalmoplegia in progressive supranuclear palsy with an overriding oculocephalic maneuver.
We present a patient with progressive supranuclear palsy (PSP) who had a bilateral internuclear ophthalmoplegia (INO) that could be fully overcome by the oculocephalic maneuver. In addition to being an unusual finding in the clinical setting of PSP, this phenomenon has interesting implications for the functional control of conjugate horizontal gaze.


Cluster-randomised trial of risk communication to enhance informed uptake of cervical screening.
Women overestimate both population and individual risk of cervical cancer. This may contribute to the recognised excess screening frequency for low-risk women. To investigate whether an individualized risk communication package could affect stated preferences for screening interval and actual screening behaviour. Pragmatic, practice-based cluster randomised controlled trial. Twenty-nine practices (15 intervention, 14 control) in North Wales recruited 1890 women attending for cervical smears. A risk communication package containing visual material was compared with normal practice. Practice nurses received training in its delivery. The short-term primary outcome was stated preference for screening interval; the long-term primary outcome was actual screening behaviour. In the short term, intervention arm women were significantly less likely to prefer a shorter than recommended interval (odds ratio [OR] = 0.51, 95% confidence interval [CI] = 0.41 to 0.64; P < 0.0001). At the five-year follow-up, fewer women in the intervention arm had attended for screening sooner than their recommended recall. The magnitude of difference in excess screening interval preference and behaviour was similar, but behaviour had a wider confidence interval and a marginally non-significant P-value (OR = 0.61, 95% CI = 0.36 to 1.03; P = 0.063). Better knowledge and more accurate risk perceptions were demonstrated, with an improvement in measures of anxiety. The extra cost per woman receiving the intervention was 6 Pounds. Women's perception of risk contributes to determining screening intervals in addition to practice factors. Simple risk information delivered in primary care affected women's stated preferences for tests. The impact on actual screening behaviour was more equivocal. Overall, the intervention showed a substantial benefit and any disbenefit can be ruled out. This approach to providing risk information could, at low cost, benefit other screening programmes and may relieve anxiety.


Public-private mix for tuberculosis care and control: a systematic review.
Public-private mix (PPM), recommended by the World Health Organization (WHO), was introduced to cope with the tuberculosis (TB) epidemic worldwide. In many developing countries, PPM has played a powerful role in TB control, while in others it has failed to meet expectations. Thus we performed a systematic review to determine the mechanisms used by global PPM programs implemented in different countries and to evaluate their performance. A comprehensive search of the current literature for original studies published up to May 2014 was done using electronic databases and online resources; these publications were then screened using rigorous criteria. Descriptive information and evaluative outcomes data were extracted from eligible studies for synthesis and analysis. A total of 78 eligible studies were included in the final review. These assessed 48 PPM TB programs worldwide, subsequently categorized into three mechanisms based on collaborative characteristics: support, contract, and multi-partner group. Furthermore, we assessed the effectiveness of PPM programs against six health system themes, including utilization of the directly observed treatment strategy (DOTS), case detection, treatment outcomes, case management, costs, and access and equity, under the different collaborative mechanisms. Analysis of the comparative studies suggested that PPM could improve overall outcomes of a TB service, and multiple collaborative mechanisms may significantly promote case detection, treatment, referral, and service accessibility, especially in resource-limited areas. However, the less positive outcomes of several programs indicated limited funding and poor governance to be the predominant reasons. PPM is a promising strategy to strengthen global TB care and control, but is affected by contextual characteristics in different areas. The scaling-up of PPM should contain essential commonalities, particularly substantial financial support and continuous material input. Additionally, it is important to improve program governance and training for the health providers involved, through integrated collaborative mechanisms.


3D Printing in Liver Surgery: A Systematic Review.
Rapid growth of three-dimensional (3D) printing in recent years has led to new applications of this technology across all medical fields. This review article presents a broad range of examples on how 3D printing is facilitating liver surgery, including models for preoperative planning, education, and simulation. We have performed an extensive search of the medical databases Ovid/MEDLINE and PubMed/EMBASE and screened articles fitting the scope of review, following previously established exclusion criteria. Articles deemed suitable were analyzed and data on the 3D-printed models-including both technical properties and desirable application-and their impact on clinical proceedings were extracted. Fourteen articles, presenting unique utilizations of 3D models, were found suitable for data analysis. A great majority of articles (93%) discussed models used for preoperative planning and intraoperative guidance. PolyJet was the most common (43%) and, at the same time, most expensive 3D printing technology used in the development process. Many authors of reviewed articles reported that models were accurate (71%) and allowed them to understand patient's complex anatomy and its spatial relationships. Although the technology is still in its early stages, presented models are considered useful in preoperative planning and patient and student education. There are multiple factors limiting the use of 3D printing in everyday healthcare, the most important being high costs and the time-consuming process of development. Promising early results need to be verified in larger randomized trials, which will provide more statistically significant results.


Genomic sequencing and analysis of Chilli ringspot virus, a novel potyvirus.
Chilli ringspot virus (ChiRSV), a novel potyvirus, was recently found in Hainan, China with high prevalence. The genomic sequence of the ChiRSV-HN/14 isolate was determined by sequencing overlapping cDNA segments generated by reverse transcription polymerase chain reaction with degenerate and/or specific primers. ChiRSV genome (GenBank Acc. no. JN008909) comprised of 9,571 nucleotides (nt) excluding the 3'-terminal poly (A) tail and contained a large open reading frame of 9,240 nt encoding a large polyprotein of 3,079 amino acids with predicted Mr of 349.1 kDa. A small, overlapping PIPO coding region was also found to span from nt 2,913 to 3,095, with a capacity to encode a peptide of 60 amino acids. ChiRSV shares sequence identities of only 48.5-65.4 and 42.9-68.7% with closely related potyviruses at the nucleotide and the amino acid levels, respectively. Phylogenetic analysis of the genomic sequences provided further evidence that ChiRSV is a distinct species of the Potyvirus genus. ChiRSV-HN/14 is most closely related to Tobacco vein banding mosaic virus and two other pepper-infecting potyviruses.


Inhibition of mitochondrial fission prevents hypoxia-induced metabolic shift and cellular proliferation of pulmonary arterial smooth muscle cells.
Chronic hypoxia exacerbates proliferation of pulmonary arterial smooth muscle cells (PASMC), thereby reducing the lumen of pulmonary arteries. This leads to poor blood oxygenation and cardiac work overload, which are the basis of diseases such as pulmonary artery hypertension (PAH). Recent studies revealed an emerging role of mitochondria in PAH pathogenesis, as key regulators of cell survival and metabolism. In this work, we assessed whether hypoxia-induced mitochondrial fragmentation contributes to the alterations of both PASMC death and proliferation. In previous work in cardiac myocytes, we showed that trimetazidine (TMZ), a partial inhibitor of lipid oxidation, stimulates mitochondrial fusion and preserves mitochondrial function. Thus, here we evaluated whether TMZ-induced mitochondrial fusion can prevent human PASMC proliferation in an in vitro hypoxic model. Using confocal fluorescence microscopy, we showed that prolonged hypoxia (48h) induces mitochondrial fragmentation along with higher levels of the mitochondrial fission protein DRP1. Concomitantly, both mitochondrial potential and respiratory rates decreased, indicative of mitochondrial dysfunction. In accordance with a metabolic shift towards non-mitochondrial ATP generation, mRNA levels of glycolytic markers HK2, PFKFB2 and GLUT1 increased during hypoxia. Incubation of PASMC with TMZ, prior to hypoxia, prevented all these changes and precluded the increase in PASMC proliferation. These findings were also observed using Mdivi-1 (a pharmacological DRP1 inhibitor) or a dominant negative DRP1 K38A as pre-treatments. Altogether, our data indicate that TMZ exerts a protective role against hypoxia-induced PASMC proliferation, by preserving mitochondrial function, thus highlighting DRP1-dependent morphology as a novel therapeutic approach for diseases such as PAH.


Ginsenoside-Rb1 attenuates dilated cardiomyopathy in cTnT(R141W) transgenic mouse.
Familial dilated cardiomyopathy (FDCM) is caused by defective genes and specific medicines are not currently available to treat this. Ginsenoside-Rb1 provides cardioprotection in the experimental models of myocardial ischemia-reperfusion injury. Here we investigate Rb1's effect on DCM in cTnT(R141W) transgenic mouse. The transgene-positive mice aged 2 months were randomized into the model group and Rb1 [70 mg/(kg.day)] group; transgene-negative mice were used as a control. After 4-month treatment, cardiac function was assessed by echocardiography; cardiac tissues were prepared for histology and electron microscopy. Expression levels of molecular markers of cardiac hypertrophy, fibrosis, and intercalated disc proteins were detected by RT-PCR. Rb1 significantly decreased mortality, chamber dilation, and contractile dysfunction in cTnT(R141W) mice. Rb1 attenuated cardiac hypertrophy, interstitial fibrosis, ultrastructural degeneration, and intercalated disc remodeling in DCM hearts. Western blotting showed that Rb1 significantly decreased heparin-binding epidermal growth factor-like growth factor (HB-EGF) expression and signal transduction and activators of transcription 3 (STAT3) activation, which were gradually increased in DCM hearts. Our results showed that Rb1 clearly alleviated cardiac dysfunction and remodeling in the cTnT(R141W) transgenic mouse, indicating its potential utility in the treatment of FDCM.


Prescription of nonsteroidal anti-inflammatory drugs and muscle relaxants for back pain in the United States.
Secondary analysis of the 2000 Medical Expenditure Panel Survey (MEPS). OBJECTIVE.: To examine national prescription patterns of nonsteroidal anti-inflammatory drugs (NSAIDs) and muscle relaxants among individuals with back pain in the United States. There is a lack of information on national prescription patterns of NSAIDs and muscle relaxants among individuals with back pain in the United States. Traditional NSAIDs, cyclooxygenase-2-specific (COX-2) inhibitors, and muscle relaxants were investigated. Individuals with back pain were stratified by socio-demographic characteristics and geographic regions. For each medication category, overall prescribing frequency was compared across different strata and individual drug prescription was analyzed. Traditional NSAIDs, COX-2 inhibitors, and muscle relaxants, respectively, accounted for 16.3%, 10%, and 18.5% of total prescriptions for back pain in 2000. Among individual drugs, ibuprofen and naproxen accounted for most of the prescriptions for traditional NSAIDs (60%), whereas two thirds of the prescriptions for muscle relaxants were attributable to cyclobenzaprine, carisoprodol, and methocarbamol. Prescription of COX-2 inhibitors or muscle relaxants demonstrated wide variations across different regions. Several individual characteristics including age, race, and educational level were associated with the prescription of some of the medications. Neither traditional NSAIDs, nor COX-2 inhibitors, nor muscle relaxants dominated prescriptions for back pain. However, a small number of individual drugs were attributable to most of the prescriptions for traditional NSAIDs or muscle relaxants. The prescription of some of the medications demonstrated wide variations across different regions or different racial and educational groups. More studies are needed to understand the source of the variations and what constitutes optimal prescribing.


Integration of cardiovascular regulation by the blood/endothelium cell-free layer.
The cell-free layer (CFL) width separating red blood cells in flowing blood from the endothelial cell membrane is shown to be a regulator of the balance between nitric oxide (NO) production by the endothelium and NO scavenging by blood hemoglobin. The CFL width is determined by hematocrit (Hct) and the vessel wall flow velocity gradient. These factors and blood and plasma viscosity determine vessel wall shear stress which regulates the production of NO in the vascular wall. Mathematical modeling and experimental findings show that vessel wall NO concentration is a strong nonlinear function of Hct and that small Hct variations have comparatively large effects on blood pressure regulation. Furthermore, NO concentration is a regulator of inflammation and oxygen metabolism. Therefore, small, sustained perturbations of Hct may have long-term effects that can promote pro-hypertensive and pro-inflammatory conditions. In this context, Hct and its variability are directly related to vascular tone, peripheral vascular resistance, oxygen transport and delivery, and inflammation. These effects are relevant to the analysis and understanding of blood pressure regulation, as NO bioavailability regulates the contractile state of blood vessels. Furthermore, regulation of the CFL is a direct function of blood composition therefore understanding of its physiology relates to the design and management of fluid resuscitation fluids. From a medical perspective, these studies propose that it should be of clinical interest to note small variations in patient's Hct levels given their importance in modulating the CFL width and therefore NO bioavailability. WIREs Syst Biol Med 2011 3 458-470 DOI: 10.1002/wsbm.150


Time to epinephrine and survival after paediatric out-of-hospital cardiac arrest.
Delay in administration of epinephrine is associated with decreased survival among children with in-hospital cardiac arrest with an initial non-shockable rhythm. Whether this association is applicable to paediatric out-of-hospital cardiac arrest (OHCA) population remains unknown. We aimed to determine whether time to epinephrine administration is associated with outcomes in paediatric OHCA. This was a nation-wide population-based study of paediatric OHCA in Japan from 2005 to 2012 based on data from the All-Japan Utstein Registry. We included paediatric OHCA patients (aged between 1 and 17 years) who received at least one dose of epinephrine. The primary outcome was 30-day survival. A total of 225 patients were included in the final cohort. Among the 225 patients, 23 (10.2%) survived 30 days after OHCA. The median time from emergency call to first epinephrine administration was 26 min [interquartile range, 20-32; range, 9-128; mean (standard deviation), 28.7 (15.5) min]. Longer time to epinephrine administration was associated with decreased chance of survival: 50.0, 41.2, 13.0, 11.6, 3.9, and 3.1%, respectively, when time to epinephrine was treated as a categorical variable categorized into ≤10, 11-15, 16-20, 21-25, 26-30, or > 30 min (P for trend <0.0001), and adjusted odds ratio 0.90 (95% confidence interval 0.82-0.96, P = 0.0011) when time to epinephrine was treated as a linear and continuous variable in a multivariable logistic regression model. Similar trends were observed for prehospital return of spontaneous circulation (P = 0.0032) and neurologically favourable survival (P = 0.0014). Among paediatric OHCA patients, delayed administration of epinephrine was associated with a decreased chance of favourable outcomes.


Oral health and oral health behaviour among 11-13-year-olds in Bhopal, India.
To assess the prevalence of dental caries, to describe the periodontal conditions, and to assess the level of attitude, knowledge and practice in relation to oral health and oral health behaviour among 11-13 year-old children in Bhopal, India. The data would aim to provide a baseline for planning and evaluation of oral health education programmes for children in the region. BASIC RESEARCH DESIGN AND OUTCOME MEASURES: A cross sectional study of 599 children 11-13 years was conducted. Random sampling procedures were used to obtain representative samples of children in rural (n = 181) and urban areas (n = 277). In urban slum areas convenience sampling was applied (n = 141). The data were collected through clinical examinations by means of WHO standard method, and a sub-sample completed a self-administered questionnaire on oral health behaviour, knowledge, and attitude. The caries prevalence proportion in both dentitions was 57% with a mean DMFT+dmft of 1.6. The caries experience was 2.5 times higher among children in slum areas compared to children living in rural areas. Fifteen per cent of the children had healthy gingiva and 91% of rural children had maximum CPI score 2. Mean number of sextants with CPI score 0 was 3.5 among children in urban areas and 0.6 for children in slum areas. Seventy-five per cent of the children reported toothbrushing once a day, 31% used a plastic toothbrush and the general level of knowledge on oral health was low. Intake of sugary food and soft drinks were more frequent in the slum areas compared to rural areas. Implementation of community-oriented oral health promotion programmes is needed in order to increase the level of knowledge and to change attitudes and practices in relation to oral health among children. Essential care should be provided to control oral disease symptoms.


A comparison of the validity of two psychiatric screening questionnaires (GHQ-12 and SRQ-20) in Brazil, using Relative Operating Characteristic (ROC) analysis.
The General Health Questionnaire (GHQ-12) (Goldberg, 1972) and the Self Report Questionnaire (SRQ-20) (Harding et al. 1980) were simultaneously validated against the criterion of the Clinical Interview Schedule (CIS) (Goldberg et al. 1970) in three primary care clinics in the city of Sao Paulo, Brazil. A comparison between the two screening instruments was carried out. The product-moment correlation between the two sets of scores was +0.72, and the validation coefficients for the GHQ-12 and the SRQ-20 were respectively: sensitivity 85% and 83%; specificity 79% and 80%; overall misclassification rate 18% and 19%. The two screening instruments were further compared by the application of Relative Operating Characteristic (ROC) analysis and, again, were found to be very similar in performance. The area under the ROC curve was 0.87 for the GHQ and 0.90 for the SRQ-20 (Z = 0.92, NS). Both psychiatric screening instruments were therefore found to be acceptably valid when assessed against the CIS in three primary care settings in Brazil. The application of ROC analysis to studies of this kind was feasible and straightforward. It was found to be superior to the conventional method of presentation of validity data. It is recommended that the application of ROC analysis to psychiatric screening studies be further utilized and explored.


[Scapholunate instability of the wrist following distal radius fracture].
Scapholunate (SL) ligament disruption frequently occurs together with distal radius fractures. If it is not diagnosed and treated, instability develops and will eventually be manifested as arthritic lesions known as scapholunate advanced collapse (SLAC) of the wrist. The aim of this study was to record the occurrence of SL ligament disruption in the patients treated conservatively for displaced fractures of the distal radius and to find out which fracture types are most often associated with injury to the SL ligament. A total of 75 patients treated conservatively for distal radius fractures in 1997-98 were included in the study. The group comprised 41 women and 34 men, with fractures of the right upper limb in 44 and fractures of the left upper limb in 31 patients. They all were at active age, i. e., between 18 and 60 years, and came for a check-up 3 years after injury. They were examined for radiographic findings of SL instability and signs of SLAC development. Radiographs obtained after injury and images taken after reduction and then after bone union were retrospectively evaluated to look for signs of SL instability. The initial fractures were categorized on the AO classification and, for each fracture type, the percent of patients with co-existent SL instability was assessed. In the group of 75 patients examined at 3 years after injury, 16 (27 %) wrists showed radiographic signs of instability, with SLAC development in 13 patients and no arthritic lesions in three. All patients with SL instability reported pain, restricted range of motion in the wrist or reduced grip strength. The distribution of instability in relation to AO fracture type, expressed as percent, was as follows: SL instability associated with type A2 fracture was found in 38 %, with type A3 fracture in 17 %, and with type B in 25 % of the patients. SL instability was associated with type C1, type C2 and type C3 in 21 %, 27 % and 8 % of the patients, respectively. In radiographs taken after reduction, signs of damage to the SL ligament were apparent in 56 % of these patients. Radiographic findings at 6 weeks after injury showed signs of SL instability in as many as 81 % of the patients. Our results show that SL instability is found in association with type A2 and type A3 fractures, in which trauma force is "used" to break the distal radius and subsequently, due to carpal supination, to disrupt the SL ligament. In type B1 fractures, SL disruption results from an avulsion fracture of the radial styloid process due to ulnar deviation of the wrist. The retrospective evaluation of radiographs revealed that, immediately after reduction, signs of SL instability were obvious in 56 % of the cases. At that stage the condition could have been treated by K-wire transfixation and reattachment of the SL ligament. At 6 weeks, radiographic evidence of SL ligament disruption was found in 81 % of the patients. Even at that stage repair would have been possible by either reattachment or reconstruction of the ligament. It is apparent from these results that the evaluation of radiographic findings after reduction and during follow-up should also focus on other changes in the wrist in addition to signs of bone union. Fractures of the distal radius are no longer frequent only in elderly women, as has recently been common, but they are found more and more often in active young persons. Because their bones are healthier, soft tissues are affected more frequently. Injury to the SL joint results in the development of arthritic lesions which may rapidly progress in active patients. SLAC development can be prevented by early diagnosis of soft tissue lesions on X-ray images, because these are usually apparent after reduction or at follow-up. If doubts arise, arthroscopy or another examination should be done, even though these may not be sufficiently reliable.


Regulation of MHC class I assembly and peptide binding.
Peptide binding to MHC class I molecules is a component of a folding and assembly process that occurs in the endoplasmic reticulum (ER) and uses both cellular chaperones and dedicated factors. The involvement of glycoprotein quality-control chaperones and cellular oxidoreductases in peptide binding has led to models that are gradually being refined. Some aspects of the peptide loading process (e.g., the biosynthesis and degradation of MHC class I complexes) conform to models of glycoprotein quality control, but other aspects (e.g., the formation of a stable disulfide-linked dimer between tapasin and ERp57) deviate from models of chaperone and oxidoreductase function. Here we review what is known about the intersection of glycoprotein folding, oxidative reactions, and MHC class I peptide loading, emphasizing events that occur in the ER and within the MHC class I peptide loading complex.


Diagnostic reasoning: where we've been, where we're going.
Recently, clinical diagnostic reasoning has been characterized by "dual processing" models, which postulate a fast, unconscious (System 1) component and a slow, logical, analytical (System 2) component. However, there are a number of variants of this basic model, which may lead to conflicting claims. This paper critically reviews current theories and evidence about the nature of clinical diagnostic reasoning. We begin by briefly discussing the history of research in clinical reasoning. We then focus more specifically on the evidence to support dual-processing models. We conclude by identifying knowledge gaps about clinical reasoning and provide suggestions for future research. In contrast to work on analytical and nonanalytical knowledge as a basis for reasoning, these theories focus on the thinking process, not the nature of the knowledge retrieved. Ironically, this appears to be a revival of an outdated concept. Rather than defining diagnostic performance by problem-solving skills, it is now being defined by processing strategy. The version of dual processing that has received most attention in the literature in medical diagnosis might be labeled a "default/interventionist" model,(17) which suggests that a default system of cognitive processes (System 1) is responsible for cognitive biases that lead to diagnostic errors and that System 2 intervenes to correct these errors. Consequently, from this model, the best strategy for reducing errors is to make students aware of the biases and to encourage them to rely more on System 2. However, an accumulation of evidence suggests that (a) strategies directed at increasing analytical (System 2) processing, by slowing down, reducing distractions, paying conscious attention, and (b) strategies directed at making students aware of the effect of cognitive biases, have no impact on error rates. Conversely, strategies based on increasing application of relevant knowledge appear to have some success and are consistent with basic research on concept formation.


Benefits and Disadvantages of Electronic Patient-reported Outcome Measures: Systematic Review.
Patient-reported outcome measures (PROMs) are important in clinical practice and research. The growth of electronic health technologies provides unprecedented opportunities to systematically collect information via PROMs. The aim of this study was to provide an objective and comprehensive overview of the benefits, barriers, and disadvantages of the digital collection of qualitative electronic patient-reported outcome measures (ePROMs). We performed a systematic review of articles retrieved from PubMED and Web of Science. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed during all stages. The search strategy yielded a total of 2333 records, from which 32 met the predefined inclusion and exclusion criteria. The relevant ePROM-related information was extracted from each study. Results were clustered as benefits and disadvantages. Reported benefits of ePROMs were greater patient preference and acceptability, lower costs, similar or faster completion time, higher data quality and response rates, and facilitated symptom management and patient-clinician communication. Tablets were the most used ePROM modality (14/32, 44%), and, as a platform, Web-based systems were used the most (26/32, 81%). Potential disadvantages of ePROMs include privacy protection, a possible large initial financial investment, and exclusion of certain populations or the "digital divide." In conclusion, ePROMs offer many advantages over paper-based collection of patient-reported outcomes. Overall, ePROMs are preferred over paper-based methods, improve data quality, result in similar or faster completion time, decrease costs, and facilitate clinical decision making and symptom management. Disadvantages regarding ePROMs have been outlined, and suggestions are provided to overcome the barriers. We provide a path forward for researchers and clinicians interested in implementing ePROMs. PROSPERO CRD42018094795; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=94795.


Circularity and Independence in Phylogenetic Tests of Ecological Hypotheses.
It has been asserted that in order to avoid circularity in phylogenetic tests of ecological hypotheses, one must exclude from the cladistic analysis any characters that might be correlated with that hypothesis. The argument assumes that selective correlation leads to lack of independence among characters and may thus bias the analysis. This argument conflates the idea of independence between the ecological hypothesis and the phylogeny with independence among characters used to construct the tree. We argue that adaptation or selection does not necessarily result in the non-independence of characters, and that characters for a cladistic analysis should be evaluated as homology statements rather than functional ones. As with any partitioning of data, character exclusion may lead to weaker phylogenetic hypotheses, and the practice of mapping characters onto a tree, rather than including them in the analysis, should be avoided. Examples from pollination biology are used to illustrate some of the theoretical and practical problems inherent in character exclusion.


Effect of an aminocardenolide and digoxin upon atrioventricular refractory period in the dog.
The ability of digoxin and a 4-aminocardenolide, ASI-222, to alter atrioventricular nodal refractory period (AVRP) was determined as a function of the maximum subarrhythmic dose (MSAD) in the dog anesthetized with morphine-pentobarbital. ASI-222, a highly polar and potent inhibitor of Na+, K+-adenosine triphosphatase produces a cardiotoxicity in dogs prominently involving atrioventricular nodal blockade rather than ventricular premature ectopic beats and tachycardia seen with digoxin. AVRP was assessed with trains of electrically isolated stimuli of decreasing pulse interval delivered to the right atria. Digoxin and ASI-222 were infused i.v. at rates which produced cardiac arrhythmias in about 100 min in dogs either: 1) with intact nerves, 2) pretreated with atropine, 3) without reflex receptors (without vagus and carotid sinus nerves, 4) without cardiac sympathetic nerves and adrenals or 5) pretreated with metoprolol. In dogs with intact nerves, ASI-222 produced greater increases in AVRP than digoxin at fractions of the MSAD; however, both glycoside produced a similar elevation at the MSAD (approximately equal to 30% increase). Atropine did not alter the AVRP response to ASI-222 but prevented the lengthening due to digoxin except for that which occurred near the MSAD. Removal of reflex receptor afferents (and vagi) had an effect similar to atropine on the AVRP response to digoxin, but completely prevented any response to ASI-222. Prior sympathectomy or beta adrenergic blockade abolished the AVRP response to ASI-222 but did not alter the responses to digoxin.(ABSTRACT TRUNCATED AT 250 WORDS)


Integrated multimodal imaging of dynamic bone-tumor alterations associated with metastatic prostate cancer.
Bone metastasis occurs for men with advanced prostate cancer which promotes osseous growth and destruction driven by alterations in osteoblast and osteoclast homeostasis. Patients can experience pain, spontaneous fractures and morbidity eroding overall quality of life. The complex and dynamic cellular interactions within the bone microenvironment limit current treatment options thus prostate to bone metastases remains incurable. This study uses voxel-based analysis of diffusion-weighted MRI and CT scans to simultaneously evaluate temporal changes in normal bone homeostasis along with prostate bone metatastsis to deliver an improved understanding of the spatiotemporal local microenvironment. Dynamic tumor-stromal interactions were assessed during treatment in mouse models along with a pilot prospective clinical trial with metastatic hormone sensitive and castration resistant prostate cancer patients with bone metastases. Longitudinal changes in tumor and bone imaging metrics during delivery of therapy were quantified. Studies revealed that voxel-based parametric response maps (PRM) of DW-MRI and CT scans could be used to quantify and spatially visualize dynamic changes during prostate tumor growth and in response to treatment thereby distinguishing patients with stable disease from those with progressive disease (p<0.05). These studies suggest that PRM imaging biomarkers are useful for detection of the impact of prostate tumor-stromal responses to therapies thus demonstrating the potential of multi-modal PRM image-based biomarkers as a novel means for assessing dynamic alterations associated with metastatic prostate cancer. These results establish an integrated and clinically translatable approach which can be readily implemented for improving the clinical management of patients with metastatic bone disease.


Prenatal diagnosis and postnatal course in four fetuses with very rare pulmonary artery anomalies.
Pulmonary artery (PA) anomalies are very rare congenital cardiac malformations, a significant number of which remain unrecognized or misdiagnosed during the prenatal period. We report the prenatal diagnosis and outcome of pregnancy with fetal PA anomalies and discuss the related management issues. We identified four cases of prenatally diagnosed rare PA anomalies that were seen and confirmed in the newborn period by echocardiography and computed tomographic angiography at our center from 2018 to 2020. The course of the pregnancy, perinatal outcome, and the postnatal course in each case were analyzed. Three fetuses were born by repeat cesarean section approximately at 39 weeks of gestation and the other woman delivered vaginally. Of the abnormal origin of the left PA (LPA) in two patients, the first had right PA abnormalities derivating from the ascending aorta, and in the second, the LPA originated from the right PA. Two patients had agenesis of ductus arteriosus (DA), the first was accompanied with tetralogy of Fallot (TOF) and right aortic arch with a normal pulmonary valve, the second patient presented with an Absent Pulmonary Valve syndrome with TOF. Prenatal ultrasonography can be used to correctly diagnose the abnormal origin of the PA branches. Branching of the PA, presence of DA, location of the aortic, and ductal arch by the trachea should be routinely screened in the prenatal anatomic examination and the three-vessel and trachea view can determine the primary clues of PA malformations.


The impact of rate heterogeneity on inference of phylogenetic models of trait evolution.
Rates of trait evolution are known to vary across phylogenies; however, standard evolutionary models assume a homogeneous process of trait change. These simple methods are widely applied in small-scale phylogenetic studies, whereas models of rate heterogeneity are not, so the prevalence and patterns of potential rate variation in groups up to hundreds of species remain unclear. The extent to which trait evolution is modelled accurately on a given phylogeny is also largely unknown because studies typically lack absolute model fit tests. We investigated these issues by applying both rate-static and variable-rates methods on (i) body mass data for 88 avian clades of 10-318 species, and (ii) data simulated under a range of rate-heterogeneity scenarios. Our results show that rate heterogeneity is present across small-scaled avian clades, and consequently applying only standard single-process models prompts inaccurate inferences about the generating evolutionary process. Specifically, these approaches underestimate rate variation, and systematically mislabel temporal trends in trait evolution. Conversely, variable-rates approaches have superior relative fit (they are the best model) and absolute fit (they describe the data well). We show that rate changes such as single internal branch variations, rate decreases and early bursts are hard to detect, even by variable-rates models. We also use recently developed absolute adequacy tests to highlight misleading conclusions based on relative fit alone (e.g. a consistent preference for constrained evolution when isolated terminal branch rate increases are present). This work highlights the potential for robust inferences about trait evolution when fitting flexible models in conjunction with tests for absolute model fit.


Giant hypothalamic hamartoma and dacrystic seizures.
Ictal crying is a rare type of epileptic seizure associated with hypothalamic hamartoma and with other lesions such as tumours, vascular malformations, hippocampal sclerosis, or cerebral infarction. We describe the case of an infant with gelastic, dacrystic and other types of seizures associated with a giant hypothalamic hamartoma, and present a video sequence of dacrystic seizures. Dacrystic episodes presented in clusters at sleep onset, initially in the form of moaning followed by face-flushing that rapidly evolved to crying, associated with a lateral and upper deviation of both eyeballs, along with clonic aspects of the eyelids. After a few seconds, the crying became less intense, she stared, and oro-alimentary automatisms became prominent along with some slow horizontal movements of the eyes and the head. Following surgery, at the age of nine months, the gelastic seizures stopped, but dacrystic seizures persisted. [Published with video sequences].


Cultural differences in the age-related positivity effect: Distinguishing between preference and effectiveness.
Prior studies have found mixed results regarding whether there are cultural differences in the age-related positivity effect, defined as older adults' showing a greater bias in cognitive processing for positively over negatively and neutrally valenced information relative to younger adults. This study attempted to address this controversy by examining visual attention toward culturally relevant versus irrelevant pictures that differed in valence among younger and older U.S. Americans and Hong Kong Chinese. Preferences (attentional biases toward particular valence) and effectiveness (whether the attentional biases are associated with better mood) were also distinguished. Findings revealed that regardless of cultural relevance of the pictures, older U.S. Americans showed more gaze preference for positive over negative pictures compared to their younger counterparts; this age difference was not found among Hong Kong Chinese. In contrast, older Hong Kong Chinese showed better mood as a function of more gaze preference for positive over negative pictures. Younger Hong Kong Chinese and younger and older U.S. Americans did not show this association. The results suggest that an age-related positivity effect exists at the preference level for U.S. Americans but at the effectiveness level for Chinese. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Microbial Shift in the Enteric Bacteriome of Coral Reef Fish Following Climate-Driven Regime Shifts.
Replacement of coral by macroalgae in post-disturbance reefs, also called a "coral-macroalgal regime shift", is increasing in response to climate-driven ocean warming. Such ecosystem change is known to impact planktonic and benthic reef microbial communities but few studies have examined the effect on animal microbiota. In order to understand the consequence of coral-macroalgal shifts on the coral reef fish enteric bacteriome, we used a metabarcoding approach to examine the gut bacteriomes of 99 individual fish representing 36 species collected on reefs of the Inner Seychelles islands that, following bleaching, had either recovered to coral domination, or shifted to macroalgae. While the coral-macroalgal shift did not influence the diversity, richness or variability of fish gut bacteriomes, we observed a significant effect on the composition (R2 = 0.02; p = 0.001), especially in herbivorous fishes (R2 = 0.07; p = 0.001). This change is accompanied by a significant increase in the proportion of fermentative bacteria (Rikenella, Akkermensia, Desulfovibrio, Brachyspira) and associated metabolisms (carbohydrates metabolism, DNA replication, and nitrogen metabolism) in relation to the strong turnover of Scarinae and Siganidae fishes. Predominance of fermentative metabolisms in fish found on macroalgal dominated reefs indicates that regime shifts not only affect the taxonomic composition of fish bacteriomes, but also have the potential to affect ecosystem functioning through microbial functions.


[AS-1L - a newly discovered strain of Cyanophage AS-1 in GDR].
In samples, taken from waters in the surroundings of Leipzig (GDR) in 1978, we found cyanophages in Central Europe for the first time. Among other cyanophages we isolated the new strain AS-1L. Out of 20 tested cultures of unicellular cyanobacteria seven strains belonging to the genus Synechococcus proved to be susceptible for this cyanophage. In morphology AS-1L corresponds to the cyanophage AS-1 found in the U.S.A., to which it is related serologically, too. AS-1L differs from the other strains of AS-1 by a shorter growth cycle, especially a shorter latent period, by the kinetics of inactivation by antiserum, and by a somewhat narrower pH scope of stability. Consequently the isolated cyanophage is to be looked at as a new strain of the cyanophage AS-1.


Blood-contacting magnetic levitation bearing design using computational fluid dynamics for haemocompatibility.
The Hemocompatibility Assessment Platform (HAP) is a testing rig that will allow for the evaluation of blood trauma caused by individual components of rotary blood pumps including the NeoVAD - a proposed paediatric Left Ventricular Assist Device (LVAD). It is important that the HAP itself is only minimally haemolytic such that the plasma free haemoglobin measured can be assumed to come from the test component. In this study, Computational Fluid Dynamics simulations have been carried out to inform the design of a magnetically levitated motor bearing gap. Simulations show that issues with the original design, namely stagnation regions and large recirculation zones can be mitigated with the introduction of a pipe that introduces blood-flow to the centre of the bearing and disrupts the secondary flow patterns that cause these issues.Clinical relevance- The consequent reduction in shear exposure time will reduce heamolsyis from the HAP. The redesign of the bearing will result in reduced baseline blood trauma from the HAP, thus allowing quantification of test component haemolysis and will therefore aid the design of future paediatric LVADs.


Dominant beta-thalassaemia trait in a Portuguese family is caused by a deletion of (G)TGGCTGGTGT(G) and an insertion of (G)GCAG(G) in codons 134, 135, 136 and 137 of the beta-globin gene.
We have studied a Portuguese family with a dominant beta-thalassaemia trait that was present in one member of each of three generations. It was characterized by a moderate anaemia, microcytosis and hypochromia, anisopoikilocytosis, Heinz body formation in peripheral red cells, splenomegaly, and a blood transfusion requirement during pregnancy. Sequence analyses of amplified DNA detected a deletion of (G) TG.GCT.GGT.GT(G) at codons 134-137 (Val.Ala.Gly.Val) and the insertion of (G)GC.AG(G) (Gly.Arg) at the same location. Thus, the resulting beta chain has an abnormal structure only at codons 134-137 and is two residues shorter than the normal 146 residues. This chain could not be detected in circulating red cells and must be degraded rapidly by proteolysis because the Heinz bodies consisted mainly of alpha chains.


An In Vivo 11C-(R)-PK11195 PET and In Vitro Pathology Study of Microglia Activation in Creutzfeldt-Jakob Disease.
Microgliosis is part of the immunobiology of Creutzfeldt-Jakob disease (CJD). This is the first report using 11C-(R)-PK11195 PET imaging in vivo to measure 18 kDa translocator protein (TSPO) expression, indexing microglia activation, in symptomatic CJD patients, followed by a postmortem neuropathology comparison. One genetic CJD (gCJD) patient, two sporadic CJD (sCJD) patients, one variant CJD (vCJD) patient (mean ± SD age, 47.50 ± 15.95 years), and nine healthy controls (mean ± SD age, 44.00 ± 11.10 years) were included in the study. TSPO binding potentials were estimated using clustering and parametric analyses of reference regions. Statistical comparisons were run at the regional and at the voxel-wise levels. Postmortem evaluation measured scrapie prion protein (PrPSc) immunoreactivity, neuronal loss, spongiosis, astrogliosis, and microgliosis. 11C-(R)-PK11195-PET showed a significant TSPO overexpression at the cortical level in the two sCJD patients, as well as thalamic and cerebellar involvement; very limited parieto-occipital activation in the gCJD case; and significant increases at the subcortical level in the thalamus, basal ganglia, and midbrain and in the cerebellum in the vCJD brain. Along with misfolded prion deposits, neuropathology in all patients revealed neuronal loss, spongiosis and astrogliosis, and a diffuse cerebral and cerebellar microgliosis which was particularly dense in thalamic and basal ganglia structures in the vCJD brain. These findings confirm significant microgliosis in CJD, which was variably modulated in vivo and more diffuse at postmortem evaluation. Thus, TSPO overexpression in microglia activation, topography, and extent can vary in CJD subtypes, as shown in vivo, possibly related to the response to fast apoptotic processes, but reaches a large amount at the final disease course.


Quantitative analysis of potential transfer of continuous glass filament from eclipse prototype 9-014 cigarettes.
This study was designed to determine if the Eclipse prototype 9-014 cigarettes, which use a special form of continuous glass filament (CGF) as an insulator around the carbon heat source, yield CGFs via mainstream smoke. A previously developed method (Higuchi et al., 2000) that employed electrostatic precipitation-with a greater than 99% collection efficiency of mass-was used to capture CGFs transferred to mainstream smoke. The cigarettes were smoked using an exaggerated puffing condition more than twice the Federal Trade Commission (FTC) standard. Prior to smoking, cigarettes were subjected to handling procedures that simulated commercial shipping conditions. Using a modified standard addition method, and utilizing a mixture of water and glycerol as a mock condensate, CGFs were intentionally added to a series of (mock condensate) samples to develop knowledge of CGF recovery efficiency. The linear regression model of the recovered CGFs demonstrated a recovery efficiency of 86%. This efficiency rate was applied to the number of CGFs recovered from samples of smoke condensate and associated background samples. The number of CGFs in smoke condensate collected from the Eclipse 9-014 prototype was approximately 0.32 +/- 0.17 CGFs per cigarette (+/- standard deviation), including the background counts of CGFs, and 0.16 CGFs per cigarette when corrected for background contributions. The number of CGFs found in the smoke condensates for this prototype was statistically (p =.00031) distinguishable from zero and background in these experiments. The low number of CGFs seen in the transfer data from this prototype studied, the unique physical characteristics of the filaments (e.g., controlled physical dimensions), and the absence of biological activity of similar glass filaments/fibers indicate that biologically significant exposure to the Eclipse smoker does not occur.


Soluble alpha2-macroglobulin receptor is increased in endotracheal aspirates from infants and children after cardiopulmonary bypass.
Cytokine dysregulation contributes to the systemic inflammatory response after cardiopulmonary bypass. Clearance of cytokine binding proteins may be important in the resolution of inflammation. Our aim was to determine whether the cytokine binding protein alpha 2 -macroglobulin and its soluble receptor were upregulated in endotracheal aspirates from infants and children undergoing cardiopulmonary bypass. Seventy tracheal aspirates were collected before and after cardiopulmonary bypass from 35 infants and children undergoing surgical correction of congenital heart defects. alpha 2 -Macroglobulin and the soluble alpha 2 -macroglobulin receptor were identified by Western blot. With the use of multi-analyte cytokine profiling, pro-inflammatory and anti-inflammatory cytokines were quantified, normalized to total protein, and expressed as ratios. Paired t tests and Wilcoxon signed-rank tests were performed between prebypass and postbypass samples. Correlations were examined among alpha 2 -macroglobulin, soluble alpha 2 -macroglobulin receptor, cytokine ratios, and the clinical variables of cardiopulmonary bypass, aortic crossclamp, and circulatory arrest times. alpha 2 -Macroglobulin increased by 50% (mean densitometry increase 82,683 +/- 184,594, P = .012), and soluble alpha 2 -macroglobulin receptor increased by 17% (mean densitometry increase 506,148 +/- 687,037, P = .0001) after cardiopulmonary bypass. The ratio of interleukin-8/interleukin-4 increased by 136% ( P = .0001), and interleukin-8/interleukin-10 increased by 102% ( P = .001). The increase in soluble alpha 2 -macroglobulin receptor was positively correlated with the ratios of interleukin-8/interleukin-4 and interleukin-8/interleukin-10. There were no statistically significant positive correlations between the increase in alpha 2 -macroglobulin or soluble alpha 2 -macroglobulin receptor and measured clinical variables. We report for the first time the upregulation of alpha 2 -macroglobulin and soluble alpha 2 -macroglobulin receptor in tracheal aspirates after cardiopulmonary bypass in infants and children. Soluble alpha 2 -macroglobulin receptor correlates with increased alpha 2 -macroglobulin and a disproportionate increase in pro-inflammatory to anti-inflammatory cytokine ratios.


The next generation of users: prevalence and longitudinal patterns of tobacco use among US young adults.
We monitored the prevalence and patterns of use of the array of tobacco products available to young adults, who are at risk for initiation and progression to established tobacco use. We used data from waves 1 to 3 of GfK's KnowledgePanel (2011-2012), a nationally representative cohort of young adults aged 18 to 34 years (n = 2144). We examined prevalence and patterns of tobacco product use over time, associated demographics, and state-level tobacco policy. We used multivariable logistic regression to determine predictors of initiation of cigarettes as well as noncombustible and other combustible products. The prevalence of ever tobacco use rose from 57.28% at wave 1 to 67.43% at wave 3. Use of multiple products was the most common pattern (66.39% of tobacco users by wave 3). Predictors of initiation differed by product type and included age, race/ethnicity, policy, and use of other tobacco products. Tobacco use is high among young adults and many are using multiple products. Efforts to implement policy and educate young adults about the risks associated with new and emerging products are critical to prevent increased initiation of tobacco use.


Does sex-ratio selection influence nest-site choice in a reptile with temperature-dependent sex determination?
Evolutionary theory predicts that dioecious species should produce a balanced primary sex ratio maintained by frequency-dependent selection. Organisms with environmental sex determination, however, are vulnerable to maladaptive sex ratios, because environmental conditions vary spatio-temporally. For reptiles with temperature-dependent sex determination, nest-site choice is a behavioural maternal effect that could respond to sex-ratio selection, as mothers could adjust offspring sex ratios by choosing nest sites that will have particular thermal properties. This theoretical prediction has generated decades of empirical research, yet convincing evidence that sex-ratio selection is influencing nesting behaviours remains absent. Here, we provide the first experimental evidence from nature that sex-ratio selection, rather than only viability selection, is probably an important component of nest-site choice in a reptile with temperature-dependent sex determination. We compare painted turtle (Chrysemys picta) neonates from maternally selected nest sites with those from randomly selected nest sites, observing no substantive difference in hatching success or survival, but finding a profound difference in offspring sex ratio in the direction expected based on historical records. Additionally, we leverage long-term data to reconstruct our sex ratio results had the experiment been repeated in multiple years. As predicted by theory, our results suggest that sex-ratio selection has shaped nesting behaviour in ways likely to enhance maternal fitness.


Effects of Social Media and Smartphone Use on Body Esteem in Female Adolescents: Testing a Cognitive and Affective Model.
We examined the predictive relations of social media and smartphone use to body esteem in female adolescents and the mechanism that underlies these relations. As a result of frequent social media and smartphone use, adolescents are continually exposed to appearance-related media content. This likely reinforces a thin ideal and fosters appearance-based comparison and increases fear of external evaluation. Hence, we investigated a cognitive-affective framework in which the associations of social media and smartphone use with body esteem are serially mediated by cognitive internalization of an ideal body image, appearance comparisons, and social appearance anxiety. By testing female adolescents (N = 100) aged 13 to 18, we found that excessive social media use leads to unhealthy body esteem via intensified cognitive internalization, which aggravates appearance comparisons and anxiety regarding negative appearance evaluation. Further, we found that screen time for specific smartphone activities also harmed body esteem, independent of social media use. However, overall smartphone screen time did not affect body esteem when social media use was taken into consideration. Our findings underscore the multifactor mechanism that elucidates the negative impacts of social media and smartphone activities on body esteem in female adolescents, who are developmentally susceptible to poor body esteem.


Type classification of fingerprints: a syntactic approach.
A fingerprint classification procedure using a computer is described. It classifies the prints into one of ten defined types. The procedure is implemented using PICAP (picture array processor). The picture processing system includes a TV camera input and a special picture processor. The first part of the procedure is a transformation of the original print to a sampling matrix, where the dominant direction of the ridges for each subpicture is indicated. After smoothing, the lines in this pattern are traced out and converted to strings of symbols. Finally, a syntactic approach is adopted to make the type classification based on this string of symbols.


Impact of calcium and magnesium substituted strontium nano-hexaferrite on mineral uptake, magnetic character, and physiology of barley (Hordeum vulgare L.).
In this study, calcium and magnesium substituted strontium nano-hexaferrites (Sr0.96Mg0.02Ca0.02Fe12O19, SrMgCa nano-HF) were synthesized by the sol-gel auto-combustion method and their impact on the nutrient uptake, magnetic character and physiology of barley (Hordeum vulgare L.), a crop plant, was investigated. Structural, microstructural, and magnetic properties of nano-HF were evaluated by using vibrating sample magnetometry (VSM), X-ray diffraction (XRD), scanning electron microscopy (SEM) along with energy-dispersive X-ray (EDX) and elemental mapping techniques. Plants were hydroponically exposed to nano-HF (ranging from 125 to 1000 mg/L) for three weeks. Results showed that the SrMgCa nano-HF application enhanced germination rate (about 20%), tissue growth (about 38%), biomass (about 20%), soluble protein content (about 41%), and chlorophyll pigments (about 33-42%) when compared to the untreated control. In general, the plants showed the highest growth achievement at 125 or 250 mg/L of nano-HF treatment. However, higher doses diminished the growth parameters. Element concentrations and magnetic behavior analyses of plant parts proved that SrMgCa nano-HF with a size of 42.4 nm are up-taken by the plant roots and lead to increase in iron, calcium, magnesium, and strontium contents of leaves, which were about 20, 18, 3, and 60 times higher in 500 mg/L nano-HF-treated leaves than those of control, respectively. Overall, this study shows for the first time that the four elements have been internalized into the plant body through the application of substituted nano-HF. These findings suggest that mineral-substituted nanoparticles can be incorporated into plant breeding programs for the i) enhancement of seed germination and ii) treatment of plants by fighting with mineral deficiencies.


Intranigral substance P modulation of striatal dopamine: interaction with N-terminal and C-terminal substance P fragments.
The effects of unilateral injections of two substance P fragments, the N-terminal substance P (1-7) (SP1-7) and the C-terminal substance P (6-11) (SP6-11) into the substantia nigra, pars reticulata on dopamine (DA) release in the ipsilateral striatum of halothane-anaesthetized rats were studied using microdialysis. SP1-7 and SP6-11 were also tested for their ability to modify the DA stimulation produced by intranigral injections of SP or neurokinin A (NKA). In addition, the SP antagonist Spantide I was tested for its ability to modify the DA stimulation produced by an intranigral injection of SP1-7. Intranigral injections of SP1-7 (0.001-5.0 nmol) inhibited DA release after low doses (0.001-0.01 nmol), but stimulated DA release after high doses (0.1-5.0 nmol). Striatal dihydroxyphenylacetic acid (DOPAC) levels increased moderately after high doses of SP1-7 (1.0-5.0 nmol). Intranigral injections of SP6-11 (0.01-5.0 nmol) inhibited DA release, but enhanced striatal DOPAC levels, dose-dependently. SP1-7 (0.01-0.1 nmol), but not SP6-11 (0.1 nmol), blocked the stimulation of striatal DA release produced by intranigral SP (0.07 nmol). Neither SP1-7 (0.1 nmol) nor SP6-11 (0.1 nmol) could modify the stimulation of striatal DA release produced by intranigral NKA (0.09 nmol). The increase in DA release after a high dose of SP1-7 (1.0 nmol) was not modified by co-administration with Spantide I (0.07 nmol).(ABSTRACT TRUNCATED AT 250 WORDS)


Leisure-time physical activity and lung cancer: a meta-analysis.
Several studies have evaluated the relationship between physical activity and lung cancer. To summarize and review these studies, we conducted a meta-analysis of all relevant reports published from 1966 through October 2003. Adjusted odds ratios (ORs) from the original studies were pooled by the inverse of their variance, and all pooled estimates were accompanied by an assessment of heterogeneity across investigations. Test for linear trend across activity categories (low, moderate, high) were applied. The combined ORs were 0.87 (95 confidence interval=0.79-0.95) for moderate leisure-time physical activity (LPA) and 0.70 (0.62-0.79) for high activity (p trend = 0.00). This inverse association occurred for both sexes, although it was somewhat stronger for women. No evidence of publication bias was found. Several studies were able to adjust for smoking, but none adjusted for possible confounding from previous malignant respiratory disease. Our simulations suggest that this condition is unlikely to entirely explain the inverse association. The findings of this meta-analysis indicate that higher levels of LPA protect against lung cancer. The inverse association is possible remains confounded by inadequately controlled smoking patterns. However on the whole, confounding seems an unlikely explanation for the findings of individual studies on non-smokers.


Genetics of colorectal cancer.
The multistep nature of cancer has been well-documented through molecular genetic studies of colorectal cancer. The information provided by basic, translational and clinical science highlighted several genes associated with different hereditary syndromes predisposing to colorectal cancer. Due to these and other findings, the molecular pathogenesis of this cancer has been clarified also with respect to genetic pathways which can lead to an otherwise undistinguishable disease. As a result of both the available and continuously added data, our knowledge and understanding of colorectal cancer is subject to constant changes. Ultimately, these are expected to result in multiple and strategical managements based on molecular genetics which will likely change our approach to this cancer in the incoming millennium.


Viral invasion fitness across a continuum from lysis to latency.
The prevailing paradigm in ecological studies of viruses and their microbial hosts is that the reproductive success of viruses depends on the proliferation of the 'predator', that is, the virus particle. Yet, viruses are obligate intracellular parasites, and the virus genome-the actual unit of selection-can persist and proliferate from one cell generation to the next without lysis or the production of new virus particles. Here, we propose a theoretical framework to quantify the invasion fitness of viruses using an epidemiological cell-centric metric that focuses on the proliferation of viral genomes inside cells instead of virus particles outside cells. This cell-centric metric enables direct comparison of viral strategies characterized by obligate killing of hosts (e.g. via lysis), persistence of viral genomes inside hosts (e.g. via lysogeny), and strategies along a continuum between these extremes (e.g. via chronic infections). As a result, we can identify environmental drivers, life history traits, and key feedbacks that govern variation in viral propagation in nonlinear population models. For example, we identify threshold conditions given relatively low densities of susceptible cells and relatively high growth rates of infected cells in which lysogenic and other chronic strategies have higher potential viral reproduction than lytic strategies. Altogether, the theoretical framework helps unify the ongoing study of eco-evolutionary drivers of viral strategies in natural environments.


Smart patient, smart community: improving client participation in family planning consultations through a community education and mass-media program in Indonesia.
In health care consultations, patients often receive insufficient information from providers and communicate little with providers about their needs or concerns. This study evaluated a combined community education and mass media intervention to improve clients' participation in family planning consultations. A household survey was conducted with 1,200 women in three sub-districts (two intervention and one control) of West Java province in Indonesia. A comparison of post-campaign findings among family planning clients suggests that the intervention as a whole had a positive effect on client participation, specifically the number of clients who prepared questions to ask the service provider prior to a family planning visit in the past year. Multivariate analyses showed that the "Smart Card" intervention and elements of the "Sahabat" (Friend) mass media campaign were positively associated with clients' preparation of questions and question asking behavior during family planning consultations, indicating that a combined community education and mass-media approach can improve client communication with providers and improve the quality of family planning counseling.


Alkyl Glucosides on Hydrophobic Surfaces Studied by Surface Force and Wetting Measurements
The wetting properties of hydrophobized surfaces in the presence of alkyl glucosides have been studied using a Wilhelmy balance technique, and the interparticle forces acting between such surfaces have been investigated using the interferometric surface force apparatus. The adsorption at concentrations well below the cmc is rather limited both for the anomerically pure octyl beta-glucoside and for the technical product based on the branched octyl glucoside, 2-ethylhexyl glucoside. However, the adsorption results in a decreasing surface hydrophobicity, and consequently the force needed to separate two such surfaces from each other is reduced. At the cmc for octyl beta-glucoside, a surfactant monolayer is adsorbed on each surface. The interaction between the glucose units gives rise to a short-range repulsive force. Beyond the range of this repulsive force a weak attraction is experienced. Addition of a small amount of octyl alpha-glucoside does not change the short-range interaction significantly. The technical 2-ethylhexyl glucoside surfactant behaves similarly to the anomerically pure surfactant at low concentrations. The solution with the technical glucoside phase-separates at high surfactant concentration. It is observed that under such conditions a thick layer is deposited on each surface.


Severe laryngeal injury caused by blunt trauma to the neck: a case report.
Acute blunt laryngeal trauma can be a life-threatening event and often poses a difficult airway management problem. Patients may be unable to supply important anemnestic facts because of aphonia or intubation as a result of their injury. Therefore the immediate recognition and appropriate initial assessment and treatment are vital for a successful outcome. The first step is assuring an appropriate airway, either by careful intubation or temporary tracheotomy. An assessment of potential vascular and oesophageal injuries must be undertaken. The use of computerized tomography (CT) with contrast material is especially useful in identifying and localizing the damage caused by blunt neck injuries. Laryngeal fractures, air in the soft tissues and the extravasation of contrast material in the neck are all helpful in assessing the injuries before surgical intervention. Immediate initial surgery is aimed at stabilizing the cartilaginous framework and repairing the mucosa. We present a case of severe laryngeal injury caused by blunt trauma to the neck; our evaluation, treatment and the outcome.


Sox17 modulates Wnt3A/beta-catenin-mediated transcriptional activation of the Lef-1 promoter.
Wnt/β-catenin-dependent activation of lymphoid enhancer factor 1 (Lef-1) plays an important role in numerous developmental processes. In this context, transcription of the Lef-1 gene is increased by Wnt-mediated TCF4/β-catenin activation on the Lef-1 promoter through mechanisms that remain poorly defined. In mouse airway submucosal gland progenitor cells, Wnt3A transiently induces Lef-1 gene expression, and this process is required for epithelial cell proliferation and glandular morphogenesis. In the present study, we sought to identify additional candidate transcriptional regulators of the Lef-1 gene during glandular morphogenesis. To this end, we found that Sox17 expression is dramatically downregulated in early glandular progenitor cells that induce Lef-1 expression. Wnt stimulation of undifferentiated primary airway epithelial cells induced similar changes in Sox17 and Lef-1 expression. Reporter assays revealed that ectopic expression of Sox17 suppresses Wnt3A/β-catenin activation of the Lef-1 promoter in cell lines. EMSA and ChIP analyses defined several Sox17- and TCF4-binding sites that collaborate in transcriptional control of the Lef-1 promoter. More specifically, Sox17 bound to four sites in the Lef-1 promoter, either directly or indirectly through TCF complexes. The DNA- or β-catenin-binding domains of Sox17 controlled context-specific binding of Sox17/TCF complexes on the Lef-1 promoter. Combinatorial site-directed mutagenesis of Sox17- or TCF-binding sites in the Lef-1 promoter demonstrated that these sites control Wnt/β-catenin-mediated induction and/or repression. These findings demonstrate for the first time that Sox17 can directly regulate Wnt/β-catenin-dependent transcription of the Lef-1 promoter and reveal new context-dependent binding sites in the Lef-1 promoter that facilitate protein-protein interactions between Sox17 and TCF4.


White and other fur colourations and hybridization in golden jackals (Canis aureus) in the Carpathian basin.
The golden jackal (Canis aureus) is a reoccurring species in the centre of the Carpathian basin, in Hungary. In total, 31 golden jackal tissue samples were collected, from 8 white-coated, 2 black-coated and one mottled animal across Hungary. Sequences and fragment length polymorphisms were studied for white colour (MC1R), and for black coat colouration (CBD103). In each white animal, the most widespread mutation causing white fur colour in dogs in homozygous form was detected. Three animals were found to carry the mutation in heterozygous form. The two black golden jackals were heterozygous for the 3 bp deletion in CBD103 that mutation for black coat colouration in dogs, and one of them also carried the mutation causing white fur. None of the white animals showed signs of hybridization, but both the black and the mottled coloured individuals were found to be hybrids based on genetic testing. Kinship was found three times, twice between white animals, and once between a white animal and an agouti animal carrying the mutation of white coat. Our results confirm the findings that golden jackal-dog hybrids may occur without human intervention, and the detected mutation causing white fur colour in golden jackals could possibly be due to an early hybridization event.


Plasmon enhancement of luminescence upconversion.
Frequency conversion has always been an important topic in optics. Nonlinear optics has traditionally focused on frequency conversion based on nonlinear susceptibility but with the recent development of upconversion nanomaterials, luminescence upconversion has begun to receive renewed attention. While upconversion nanomaterials open doors to a wide range of new opportunities, they remain too inefficient for most applications. Incorporating plasmonic nanostructures provides a promising pathway to highly efficient upconversion. Naturally, a plethora of theoretical and experimental studies have been published in recent years, reporting enhancements up to several hundred. It is however difficult to make meaningful comparisons since the plasmonic fields are highly sensitive to the local geometry and excitation condition. Also, many luminescence upconversion processes involve multiple steps via different physical mechanisms and the overall output is often determined by a delicate interplay among them. This review is aimed at offering a comprehensive framework for plasmon enhanced luminescence upconversion. We first present quantum electrodynamics descriptions for all the processes involved in luminescence upconversion, which include absorption, emission, energy transfer and nonradiative transitions. We then present a bird's eye view of published works on plasmon enhanced upconversion, followed by more detailed discussion on comparable classes of nanostructures, the effects of spacer layers and local heating, and the dynamics of the plasmon enhanced upconversion process. Plasmon enhanced upconversion is a challenging and exciting field from the fundamental scientific perspective and also from technological standpoints. It offers an excellent system to study how optical processes are affected by the local photonic environment. This type of research is particularly timely as the plasmonics is placing heavier emphasis on nonlinearity. At the same time, efficient upconversion could make a significant impact on many applications including solar energy conversion and biomedical imaging. The marriage of luminescent materials research with nanophotonics currently being initiated with plasmon enhanced upconversion research explores a new frontier in photonics that could potentially spawn many exciting new fields.


[Pluriglandular insufficiency due to transfusion haemosiderosis in Blackfan-Diamond anaemia (author's transl)].
The article reports on a boy aged 16 1/2 years suffering from transfusion haemosiderosis associated with corticoid-resistant blackfan diamond anaemia. Besides hepatosplenomegalia and cardiomegalia, the course of the disease was mainly determined by the deficient functioning of several endocrine glands. The diagnosis revealed primary hypothyroidism, hypoparathyroidism and partial insufficiency of the pituitary gland.


Strategy for mitigation of marine debris: analysis of sources and composition of marine debris in northern Taiwan.
Six sites (two sites for each of rocky shores, sandy beaches, and fishing ports) in northern Taiwan were selected to investigate the amount and density of marine debris in each of the four seasons and after spring and neap tides from 2012 to 2013. The results indicate that marine debris was higher on rocky shores than sandy beaches and fishing ports. There is no significant difference between season and tide. The dominant debris was plastic-type, followed by polystyrene. The majority of debris originated from recreational activities, followed from ocean/waterway activities. The results suggest that the following actions are needed: (1) continue and reinforce the plastic-limit policy; (2) increase the cleaning frequency at rocky shores; (3) promote marine environmental education, with a goal of debris-free coasts; (4) recycle fishing gear and to turn that gear into energy; and (5) coordinate between agencies to establish a mechanism to monitor debris.


Studies with a reconstituted muscle glycolytic system. The rate and extent of glycolysis in simulated post-mortem conditions.
The reconstituted glycolytic system described previously (Scopes, 1973) was used to simulate post-mortem glycolytic metabolism in muscle. The effects of the following factors have been investigated: ATPase (adenosine triphosphatase) amount, AMP deaminase amount, percentage of the phosphorylase in the a form and the effect of diluting the glycolytic enzyme complex as a whole. It was confirmed that the rate of metabolism was solely dependent on the amount of ATPase present and that various concentrations of the glycolytic enzymes had no effect over a wide range encompassing the variation found in anatomically different muscles. The extent of metabolism, represented by the value of the ;ultimate' pH, depended markedly on the amount of phosphorylase in the a form; as little as 1% of the a form resulted in a considerably lower pH than in its absence. To a lesser extent the amount of AMP deaminase also affected the ultimate pH, but this was probably only significant for comparisons of genetically distinct muscles with widely differing amounts of AMP deaminase. The reconstituted system behaved almost identically with regard to post-mortem glycolytic metabolism compared with intact muscle tissue. It is concluded that the controlling effectors found with the reconstituted system apply to intact muscle also.


Prolonged febrile seizures cause reversible reductions in white matter integrity.
Prolonged febrile seizures (PFS) are the commonest cause of childhood status epilepticus and are believed to carry a risk of neuronal damage, in particular to the mesial temporal lobe. This study was designed to determine: i) the effect of prolonged febrile seizures on white matter and ii) the temporal evolution of any changes seen. 33 children were recruited 1 month following PFS and underwent diffusion tensor imaging (DTI) with repeat imaging at 6 and 12 months after the original episode of PFS. 18 age-matched healthy control subjects underwent similar investigations at a single time point. Tract-based spatial statistics (TBSS) was used to compare fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) between patients and controls on a voxel-wise basis within the white matter skeleton. Widespread reductions in FA along multiple white matter tracts were found at 1 and 6 months post-PFS, but these had resolved at 12 months. At one month post-PFS the main changes seen were reductions in AD but at 6 months these had predominantly changed to increases in RD. These widespread white matter changes have not previously been noted following PFS. There are many possible explanations, but one plausible hypothesis is that this represents a temporary halting of normal white matter development caused by the seizure, that then resumes and normalises in the majority of children.


L-carnitine and creatine in Friedreich's ataxia. A randomized, placebo-controlled crossover trial.
Impaired oxidative phosphorylation is a crucial factor in the pathogenesis of Friedreich's ataxia (FA). L-carnitine and creatine are natural compounds that can enhance cellular energy transduction. We performed a placebo-controlled triple-phase crossover trial of L-carnitine (3 g/d) and creatine (6.75 g/d) in 16 patients with genetically confirmed FA. Primary outcome measures were mitochondrial ATP production measured as phosphocreatine recovery by 31Phosphorus magnetic resonance spectroscopy, neurological deficits assessed by the international co-operative ataxia rating scale and cardiac hypertrophy in echocardiography. After 4 months on L-carnitine phosphocreatine recovery was improved compared to baseline (p<0.03, t-test) but comparison to placebo and creatine effects did not reach significance (p=0.06, F-test). Ataxia rating scale and echocardiographic parameters remained unchanged. Creatine had no effect in FA patients. L-carnitine is a promising substance for the treatment of FA patients, and larger trials are warranted.


Gyrfalcons Falco rusticolus adjust CTNS expression to food abundance: a possible contribution to cysteine homeostasis.
Melanins form the basis of animal pigmentation. When the sulphurated form of melanin, termed pheomelanin, is synthesized, the sulfhydryl group of cysteine is incorporated to the pigment structure. This may constrain physiological performance because it consumes the most important intracellular antioxidant (i.e., glutathione, GSH), of which cysteine is a constitutive amino acid. However, this may also help avoid excess cysteine, which is toxic. Pheomelanin synthesis is regulated by several genes, some of them exerting this regulation by controlling the transport of cysteine in melanocytes. We investigated the possibility that these genes are epigenetically labile regarding protein intake and thus contribute to cysteine homeostasis. We found in the Icelandic population of gyrfalcon Falco rusticolus, a species that pigments its plumage with pheomelanin, that the expression of a gene regulating the export of cystine out of melanosomes (CTNS) in feather melanocytes of developing nestlings increases with food abundance in the breeding territories where they were reared. The expression of other genes regulating pheomelanin synthesis by different mechanisms of influence on cysteine availability (Slc7a11 and Slc45a2) or by other processes (MC1R and AGRP) was not affected by food abundance. As the gyrfalcon is a strict carnivore and variation in food abundance mainly reflects variation in protein intake, we suggest that epigenetic lability in CTNS has evolved in some species because of its potential benefits contributing to cysteine homeostasis. Potential applications of our results should now be investigated in the context of renal failure and other disorders associated with cystinosis caused by CTNS dysfunction.


Glial cell responses, complement and apolipoprotein J expression following axon injury in the neonatal rat.
Immature motoneurons are highly susceptible to degeneration following axon injury. The response of perineuronal glia to axon injury may significantly influence neuronal survival and axon regeneration. We have examined the central reactions to neonatal facial nerve transection with emphasis on the expression of complement component C3 (C3) and the multifunctional apolipoprotein J (ApoJ). Axotomy was performed on one-day-old rats. Animals were perfused from eight hours to two weeks after the lesion. The astroglial marker, glial fibrillary acidic protein (GFAP) was increased from one day and the microglial marker OX-42 from two days after injury. ApoJ immunoreactivity was increased in axotomized neuronal perikarya and astroglial cells from one day postaxotomy, but no C3 immunoreactive profiles were found at any postoperative survival time. Cell proliferation as judged by bromodeoxyuridine labeling and immunoreactivity for the cyclin Ki-67 antigen (antibody MIB5) occurred only at two days after injury. Double immunostaining revealed that the vast majority of proliferating cells were microglia, although occasional cells double labeled astrocytes were found as well. Our results indicate that the non-neuronal response in neonatal animals differ from that of adult ones as follows: 1) microglia transform rapidly into phagocytes in parallel with the degeneration of axotomized neurons, 2) despite the presence of neuronal degeneration, no expression of C3 was found, and the upregulation of the expression of the complement C3 receptor (CR3) is delayed, 3) ApoJ is strongly upregulated in perineuronal astrocytes as well as in the axotomized motoneurons. The marked upregulation of ApoJ in both instances suggests a general role of this protein in the neuronal response to axotomy.


Present status and future concerns of expanded newborn screening in malaysia: sustainability, challenges and perspectives.
Newborn screening (NBS) program is an important tool for the early diagnosis and preventive treatment of life-long impairments. NBS is one of the strategies recommended by the World Health Organization to promote the primary prevention of congenital anomalies and the health of children with these conditions. However, NBS initiation and implementation in developing countries, especially South-East Asian and North African regions, are slow and challenging. Expanded NBS is not mandatory and has not yet been incorporated into the public healthcare system in our country. Limited funding, manpower shortages, inadequate support services, low public awareness, and uncertain commitment from healthcare practitioners are the main challenges in establishing this program at the national level. Involvement and support from policy makers are very important to the success of the program and the benefit of the entire population.


The gut microbiome is associated with brain structure and function in schizophrenia.
The effect of the gut microbiome on the central nervous system and its possible role in mental disorders have received increasing attention. However, knowledge about the relationship between the gut microbiome and brain structure and function is still very limited. Here, we used 16S rRNA sequencing with structural magnetic resonance imaging (sMRI) and resting-state functional (rs-fMRI) to investigate differences in fecal microbiota between 38 patients with schizophrenia (SZ) and 38 demographically matched normal controls (NCs) and explored whether such differences were associated with brain structure and function. At the genus level, we found that the relative abundance of Ruminococcus and Roseburia was significantly lower, whereas the abundance of Veillonella was significantly higher in SZ patients than in NCs. Additionally, the analysis of MRI data revealed that several brain regions showed significantly lower gray matter volume (GMV) and regional homogeneity (ReHo) but significantly higher amplitude of low-frequency fluctuation in SZ patients than in NCs. Moreover, the alpha diversity of the gut microbiota showed a strong linear relationship with the values of both GMV and ReHo. In SZ patients, the ReHo indexes in the right STC (r = - 0.35, p = 0.031, FDR corrected p = 0.039), the left cuneus (r = - 0.33, p = 0.044, FDR corrected p = 0.053) and the right MTC (r = - 0.34, p = 0.03, FDR corrected p = 0.052) were negatively correlated with the abundance of the genus Roseburia. Our results suggest that the potential role of the gut microbiome in SZ is related to alterations in brain structure and function. This study provides insights into the underlying neuropathology of SZ.


Rapid transient and longer-lasting innate cytokine changes associated with adaptive immunity after repeated SARS-CoV-2 BNT162b2 mRNA vaccinations.
Cytokines and chemokines play an important role in shaping innate and adaptive immunity in response to infection and vaccination. Systems serology identified immunological parameters predictive of beneficial response to the BNT162b2 mRNA vaccine in COVID-19 infection-naïve volunteers, COVID-19 convalescent patients and transplant patients with hematological malignancies. Here, we examined the dynamics of the serum cytokine/chemokine responses after the 3rd BNT162b2 mRNA vaccination in a cohort of COVID-19 infection-naïve volunteers. We measured serum cytokine and chemokine responses after the 3rd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in COVID-19 infection-naïve individuals by a chemiluminescent assay and ELISA. Anti-Spike binding antibodies were measured by ELISA. Anti-Spike neutralizing antibodies were measured by a pseudotype assay. Comparison to responses found after the 1st and 2nd vaccinations showed persistence of the coordinated responses of several cytokine/chemokines including the previously identified rapid and transient IL-15, IFN-γ, CXCL10/IP-10, TNF-α, IL-6 signature. In contrast to the transient (24hrs) effect of the IL-15 signature, an inflammatory/anti-inflammatory cytokine signature (CCL2/MCP-1, CCL3/MIP-1α, CCL4/MIP-1β, CXCL8/IL-8, IL-1Ra) remained at higher levels up to one month after the 2nd and 3rd booster vaccinations, indicative of a state of longer-lasting innate immune change. We also identified a systemic transient increase of CXCL13 only after the 3rd vaccination, supporting stronger germinal center activity and the higher anti-Spike antibody responses. Changes of the IL-15 signature, and the inflammatory/anti-inflammatory cytokine profile correlated with neutralizing antibody levels also after the 3rd vaccination supporting their role as immune biomarkers for effective development of vaccine-induced humoral responses. These data revealed that repeated SARS-Cov-2 BNT162b2 mRNA vaccination induces both rapid transient as well as longer-lasting systemic serum cytokine changes associated with innate and adaptive immune responses. Clinicaltrials.gov, identifier NCT04743388.


Activin and Nodal Are Not Suitable Alternatives to TGFβ for Chondrogenic Differentiation of Mesenchymal Stem Cells.
Objective Previously, we demonstrated the importance of transforming growth factor-β (TGFβ)-activated SMAD2/3 signaling in chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). However, TGFβ also signals via the SMAD1/5/9 pathway, which is known to induce terminal differentiation of BMSCs. In this study, we investigated whether other SMAD2/3-activating ligands, Activin and Nodal, can induce chondrogenic differentiation of BMSCs without inducing terminal differentiation. Design Activation of SMAD2/3 signaling and chondrogenesis were evaluated in human BMSCs ( N = 3 donors) stimulated with TGFβ, Activin, or Nodal. SMAD2/3 activation was assessed by determining phosphorylated-SMAD2 (pSMAD2) protein levels and SMAD2/3-target gene expression of SERPINE1. Chondrogenesis was determined by ACAN and COL2A1 transcript analysis and histological examination of proteoglycans and collagen type II. Results Both Activin and TGFβ enhanced pSMAD2 and SERPINE1 expression compared to the control condition without growth factors, demonstrating activated SMAD2/3 signaling. pSMAD2 and SERPINE1 had a higher level of expression following stimulation with TGFβ than with Activin, while Nodal did not activate SMAD2/3 signaling. Of the 3 ligands tested, only TGFβ induced chondrogenic differentiation as shown by strongly increased transcript levels of ACAN and COL2A1 and positive histological staining of proteoglycans and collagen type II. Conclusions Even with concentrations up to 25 times higher than that of TGFβ, Activin and Nodal do not induce chondrogenic differentiation of BMSCs; thus, neither of the 2 ligands is an interesting alternative candidate for TGFβ to induce chondrogenesis without terminal differentiation. To obtain stable cartilage formation by BMSCs, future studies should decipher how TGFβ-induced terminal differentiation can be prevented.


The impact and management of sexual dysfunction secondary to pharmacological therapy of benign prostatic hyperplasia.
Benign prostatic hyperplasia (BPH) is one of the most common genitourinary complications in men over 50 years of age and typically presents with lower urinary tract symptoms (LUTS). Classes of medications include α1-adrenoceptor blockers, 5α-reductase inhibitors, and phosphodiesterase 5 inhibitors. Today, α1-adrenoceptor blockers and 5α-reductase inhibitors are often combined to give a synergistic effect. A review of the current literature identified several adverse sexual side effects, including erectile dysfunction (ED), decreased libido, orgasmic disorders, and ejaculatory disorders. We believe it is important to know the extent of these side effects, as the clinician and patient will need to decide the cost of improved voiding symptoms. The chief adverse effect is ejaculatory disorders, including the absence of ejaculation. Clinical consideration for BPH should include the elements of male sexual function, patients' age, and the characteristics and comprehensive effects of each group of drugs. Methodological bias in clinical studies, such as the subjective evaluation of the sexual side effect, makes it difficult to determine the ideal drug for treatment.


Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease.
Steatosis in patients with nonalcoholic fatty liver disease (NAFLD) is due to an imbalance between intrahepatic triglyceride (IHTG) production and export. The purpose of this study was to evaluate TG metabolism in adipose tissue and liver in NAFLD. Fatty acid, VLDL-TG, and VLDL-apolipoprotein B-100 (apoB100) kinetics were assessed by using stable isotope tracers in 14 nondiabetic obese subjects with NAFLD (IHTG, 22.7% +/- 2.0%) and 14 nondiabetic obese subjects with normal IHTG content (IHTG, 3.4% +/- 0.4%), matched on age, sex, body mass index, and percent body fat. Compared with the normal IHTG group, the NAFLD group had greater rates of palmitate release from adipose tissue into plasma (85.4 +/- 6.6 and 114.1 +/- 8.1 micromol/min, respectively; P = .01) and VLDL-TG secretion (11.4 +/- 1.1 and 24.3 +/- 3.1 micromol/min, respectively; P = .001); VLDL-apoB100 secretion rates were not different between groups. The increase in VLDL-TG secretion was primarily due to an increased contribution from "nonsystemic" fatty acids, presumably derived from lipolysis of intrahepatic and intra-abdominal fat and de novo lipogenesis. VLDL-TG secretion rate increased linearly with increasing IHTG content in subjects with normal IHTG but reached a plateau when IHTG content was >/=10% (r = 0.618, P < .001). Obese persons with NAFLD have marked alterations in both adipose tissue (increased lipolytic rates) and hepatic (increased VLDL-TG secretion) TG metabolism. Fatty acids derived from nonsystemic sources are responsible for the increase in VLDL-TG secretion. However, the increase in hepatic TG export is not adequate to normalize IHTG content.


Implication of Toll-like receptor and tumor necrosis factor alpha signaling in septic shock.
Septic shock is initiated by a systemic inflammatory response to microbial infection that frequently leads to impaired perfusion and multiple organ failure. Because of its high risk of death, septic shock is a major problem particularly for patients in the intensive care unit. In general, bacterial lipopolysaccharide (LPS) is a strong activator of various immune responses and stimulates monocytes/macrophages to release a variety of inflammatory cytokines. However, overproduction of inflammatory factors in response to bacterial infections is known to cause septic shock, similar to that induced by LPS. Studies of LPS-signaling pathways and downstream inflammatory cytokines may have critical implications in the treatment of sepsis. In recent years, there has been significant progress in understanding the signaling pathways activated by LPS and its receptor Toll-like receptor 4 (TLR4), as well as by tumor necrosis factor alpha (TNFalpha), a potent inflammatory cytokine induced by LPS stimulation. This review briefly summarizes our current knowledge of these signaling pathways and critical signal transducers. Characterization of key signal transducers may allow us to identify tractable, novel targets for the therapeutic interventions of sepsis.