Open Microfluidic Capillary Systems.
Open microfluidic capillary systems are a rapidly evolving branch of microfluidics where fluids are manipulated by capillary forces in channels lacking physical walls on all sides. Typical channel geometries include grooves, rails, or beams and complex systems with multiple air-liquid interfaces. Removing channel walls allows access for retrieval (fluid sampling) and addition (pipetting reagents or adding objects like tissue scaffolds) at any point in the channel; the entire channel becomes a "device-to-world" interface, whereas such interfaces are limited to device inlets and outlets in traditional closed-channel microfluidics. Open microfluidic capillary systems are simple to fabricate and reliable to operate. Prototyping methods (e.g., 3D printing) and manufacturing methods (e.g., injection molding) can be used seamlessly, accelerating development. This Perspective highlights fundamentals of open microfluidic capillary systems including unique advantages, design considerations, fabrication methods, and analytical considerations for flow; device features that can be combined to create a "toolbox" for fluid manipulation; and applications in biology, diagnostics, chemistry, sensing, and biphasic applications.


Effectiveness of interventions applicable to primary health care settings to promote Mediterranean diet or healthy eating adherence in adults: A systematic review.
To evaluate the effects on healthy eating or the Mediterranean diet adherence achieved by interventions suitable for implementation in primary care settings. Medline (PubMed) and The Cochrane Library bibliographic searches retrieved randomized controlled trials published in English or Spanish, January 1990-January 2013. The inclusion criteria were adult population, >3 months follow-up, and interventions suitable for primary care settings. Exclusion resulted if studies focused exclusively on weight loss or did not analyze food intake (fats, fruits and vegetables--F&V, fiber) or Mediterranean diet adherence. Validity (risk of bias) was independently evaluated by two researchers; discrepancies were reviewed until a consensus was reached. Of the 15 included articles (14 studies), only 3 studies surpassed 12-months follow-up. Ten interventions emphasized healthy nutrition (n = 9948); 4 added activity levels (n = 3816). Six trials included participants with cardiovascular risk; 7 were community-based; 1 focused on women with cancer. Eleven studies showed 9.7% to 59.3% increased F&V intake with counseling interventions, compared to baseline (-13.3% to 27.8% in controls). Seven studies reported significant differences between intervention and control groups. Nutritional counseling moderately improves nutrition, increases intake of fiber, F&V, reduces dietary saturated fats, and increases physical activity. Studies with longer follow-up are needed to determine long-term effects, cardiovascular morbidity, and mortality.


The development of young siblings of children with autism from 4 to 54 months.
Cognitive and language skills of 39 siblings of children with autism (SIBS-A) and 39 siblings of typically developing children (SIBS-TD) at ages 4, 14, 24, 36, and 54 months were compared. Twelve of the 39 SIBS-A revealed a delay in cognition and/or language (including one child diagnosed with autism) compared to only two SIBS-TD. Developmental trajectories revealed that the cognitive differences disappeared by age 54 months, but some differences in language ability remained. Thus, most SIBS-A were well-functioning, but some revealed cognitive and/or language difficulties during the preschool years. Even these siblings by and large caught up by the age of 54 months, with receptive and expressive language abilities remaining an area of difficulty for some earlier identified siblings.


Growth characteristics and the mass transfer mechanism of single bubble on a photoelectrode at different electrolyte concentrations.
In the photoelectrochemical water splitting reaction, the bubble attached to the working electrode is an essential factor affecting the reaction resistance, current density and gas-liquid mass transfer. An experimental measurement system based on an electrochemical workstation synchronously coupled with a high-speed microscopic camera was proposed and used to systematically study the growth kinetics and mass transfer mechanism of single oxygen bubbles at different electrolyte concentrations (Na2SO4, 0.1-2.0 M) on the TiO2 photoanode surface. Under constant voltage and constant current control conditions, when the electrolyte concentration increases, the bubble detachment diameter and the bubble detachment frequency gradually decrease. The bubble coverage equation expressed in terms of gas evolution efficiency is proposed and is associated with the photocurrent and bubble radius. The average bubble coverage and average gas evolution efficiency decrease when the electrolyte concentration is increased. According to the Sherwood dimensionless number, various mass transfer coefficients during bubble growth were calculated. The results show that the average total mass transfer coefficient is positively correlated with the change trend of the electrolyte concentration, and the mass transfer coefficient of single-phase natural convection is one order of magnitude larger than the mass transfer coefficient of bubble-induced convection. Finally, a conclusion on the transient mass transfer process in the bubble evolution process was obtained, that is, the mass transfer coefficient of single-phase natural convection and the total mass transfer coefficient remain high during the first growth stage, and gradually decrease during the second growth stage. Therefore, regulating the electrolyte concentration can effectively promote the gas-liquid mass transfer in the photoelectrochemical water splitting reaction.


Identification and characterization of 114/A10, an antigen highly expressed on the surface of murine myeloid and erythroid progenitor cells and IL-3-dependent cell lines.
Monoclonal antibody (mAb) 114/A10, raised against the murine bone marrow-derived multipotential hemopoietic progenitor cell line B6SUtA, identifies an antigen highly expressed by various interleukin-3 (IL-3)-dependent cell lines, the myelomonocytic cell line WEHI-3, and a large proportion of primary myeloid and erythroid colony-forming cells. Spleen- and bone marrow-derived 114/A10-positive cells were shown to selectively proliferate in vitro in response to pokeweed mitogen-stimulated spleen cell-conditioned medium or recombinant IL-3. Western blot analysis indicated that the antigen recognized by mAb 114/A10 has a mean relative molecular mass of approximately 150,000, although it is extremely heterogeneous in nature, and differs greatly in size range among different cell lines.


Intersectoral Cost of Treating Pulmonary Non-Tuberculosis Mycobacterial Disease (NTM-PD) in Germany-A Change of Perspective in Disease Management.
In line with its increasing prevalence, pulmonary Mycobacterium avium complex (MAC) disease (MAC-PD) gives rise to substantial healthcare costs. However, there is only limited information on the costs of intersectoral reimbursement. Inpatient and outpatient costs for diagnosing and treating pulmonary MAC-PD in Germany in accordance with standard international guidelines were calculated and their potential effects on MAC disease management in Germany were determined. Hospitalization costs were calculated by using the German diagnosis related group (G-DRG) browser, with and without inclusion of the diseases most often associated with M. avium. Separated by drug macrolide susceptibility and severity of MAC-PD, the direct medical costs of suitable therapies in the outpatient setting were determined by Monte-Carlo simulation, including all conceivable options. According to our simulation, the weighted mean cost of outpatient treatment over 14 or 18 months, in either case followed by a post-treatment monitoring over 12 months, amounts to €8675.22 (95% confidence interval [CI] €8616.17 to €8734.27). Of that amount, the revenue for outpatient doctors´ services, dependent on treatment duration, is low, ranging between €894.79 (10.3%) and €979.42 (11.3%), accordingly. Mean drug costs for MAC-PD patients amount to €6130.25 [95% CI €6073.52 to €6186.98], i.e., more than two third (70.7%) of the total outpatient costs. In contrast, the non-surgical reimbursement for a hospital stay of up to 14 days is €3321.64. Hospital reimbursement does not increase in cases of complications (a higher number and/or challenging type of associated diseases), but it is fully paid even in cases that require as few as 2 days of hospitalization. The imbalance between well-rewarded hospital care and the low reimbursement for long-term treatment of MAC-PD outpatients may induce inappropriate disease management. In order to arrive at properly integrated care of MAC-PD patients in Germany, measures such as better incentives for physicians in the outpatient setting and a targeted use of resources in hospitals are required. Reimbursed, periodic case conferences between outpatient physicians and experts in hospitals as well as preventive short-term checks of MAC-PD patients in specialty clinics may promote cross-sector cooperation and improve overall treatment quality. Nationwide pilot studies are required to gain evidence on the effectiveness of the new approach.


Spontaneous migration of an inferior vena cava filter resulting in cardiac tamponade and percutaneous filter retrieval.
Thromboembolic disease accounts for thousands of hospitalizations every year in the US. Its primary management consists of anticoagulation. However, in certain instances this may be contraindicated or not sufficient. Mechanic occlusion of the inferior vena cava (IVC) becomes then a viable alternative. In this case a 35-year-old man presented with a saddle pulmonary embolus but was unable to be anticoagulated due to intestinal bleed. A removable IVC filter was then placed. The filter spontaneously migrated into the right atrium causing severe tricuspid regurgitation, perforation of the atrial wall, and cardiac tamponade. The device was successfully retrieved percutaneously and the patient discharged from the hospital in stable condition. This case illustrates the potentially lethal complications associated with the use of IVC filters, as well as the possibility to percutaneously recover them from within the right atrium.


SPECIES-WIDE POPULATION STRUCTURE IN A SOUTHEASTERN U.S. FRESHWATER FISH, HETERANDRIA FORMOSA: GENE FLOW AND BIOGEOGRAPHY.
The phylogeography of the freshwater fish fauna of the southeastern United States has almost achieved paradigm status in evolutionary biology (Avise 1992), and the major geographic features responsible for shaping species distributions are well-characterized. Nevertheless, variation among species in distributions of allele or haplotype frequencies suggests that species-specific processes (e.g., migration) may also play a role in establishing those distributions. There has also been relatively little investigation into how population structure may differ among subregions in the Southeast, for example, on the Florida peninsula versus the U.S. mainland to the northwest and/or northeast. The geology of the peninsula is such that both physical and biotic fluctuations may have been (and still be) particularly important in establishing the population structure of freshwater taxa. This possibility leads to two interesting questions in population genetics. (1) Does gene flow in freshwater species of the region better approximate a one- or two-dimensional pattern? (2) Are populations on the peninsula farther from migration-genetic drift equilibrium than their counterparts on the mainland? These questions were addressed by examining the population strucuture of a livebearing fish, Heterandria formosa; several features of the biology of the species make it particularly likely that recent gene flow has been important in its evolution. I surveyed electrophoretic variation in 34 populations distributed throughout the species range. The phylogeographic patterns observed are in general concordance with those found in other species, although with some differences. A two-dimensional hypothesis of gene flow on the Florida peninsula better explains the data than does a one-dimensional one. There is no evidence that populations on the peninsula are farther from migration-drift equilibrium than those to the northwest. Populations in the northeast have lower genetic diversity than those to the south and west and show no isolation by distance; those results are consistent with a recent range expansion into the northeast, although smaller historical effective population sizes could also explain the pattern.


Frequency shift in the moving periodic structure.
The interaction between the electromagnetic wave and the moving periodic structure is analyzed. The main physical effect revealed by theoretical analysis is that the frequency shift of the scattered or transmitted mode is proportional to the speed and the mode order m over the period a. The frequency shift is independent of the incidence direction and the carrier frequency. The physical effect is verified by an experiment. The analysis released here is fundamental in speed measurement and may have certain significance in interdisciplinary fields.


Immigration Enforcement Climate in Georgia and the Mental Health of Latinx Immigrants.
Immigrant-related social policies and immigration enforcement contribute to a sociopolitical environment that affects immigrants' health. This exploratory study in six metro-Atlanta counties examined associations among immigrants' perceived vulnerability to harmful immigrant-related social policies and county-level 287(g) agreements (which facilitate cooperation between local law enforcement and federal immigration authorities), county-level immigration enforcement levels (arrests, community arrests, detainers, and removals), and immigrants' mental health. Using data from a 2020 study among Latinx parents who were undocumented or members of mixed-status families (N = 140), we merged data on individuals' perceived policy vulnerability and depressive and anxiety symptoms with county 287(g) status and immigration enforcement levels. Perceived policy vulnerability was not associated with county-level 287(g) status or immigration enforcement levels. Greater policy vulnerability and Immigration and Customs Enforcement arrests were associated with higher depressive and anxiety symptoms, but 287(g) status was associated with lower depressive and anxiety symptoms. Perceived policy vulnerability, 287(g) status, and immigration enforcement levels do not always align and can have different associations with mental health.


Decreased left atrial myocardial strain in patients with suboptimal blood pressure control.
Suboptimal blood pressure (BP) control is commonly observed in patients receiving antihypertensive agents, but the relationship between uncontrolled BP and left atrial (LA) impairment remains unknown. This study enrolled 279 hypertensive patients who had been medicated, as well as 85 matched normal controls. The BP of systolic <140 mmHg and diastolic<90 mmHg was defined as optimal (HT1 group, n=146), otherwise as suboptimal BP control (HT2 group, n = 133). LA myocardial function was assessed by the systolic (SSa), early diastolic (SEa), and late diastolic (SAa) LA strains. Both the HT1 group and HT2 group had higher BP reading, thicker interventricular septum, larger LA volume index, and enhanced active atrial emptying fraction than the control group (all <0.05). When compared with normal subjects, hypertensive patients displayed obvious reduction in the SSa (50.0 ± 10.9 vs. 35.9 ± 8.0%), SEa (30.1 ± 7.7 vs. 18.5 ± 7.1%) and SAa (19.9 ± 6.4 vs. 17.8 ± 4.2%) (all p < 0.001). In addition to a further impaired SEa found in the HT2 group than in the HT1 group (17.2 ± 5.3 vs. 19.8 ± 8.3%, p = 0.002), the treated BP of >140/90 mmHg appeared an independent risk factor associated with the abnormal SEa (odds ratio, 2.957; interval of confidence, 1.614-5.415; p = 0.001). Suboptimal BP control status in hypertensive patients is related to a further reduction of LA myocardial function assessed by the novel 2DSTI free strain, and suboptimal BP might be regarded as a composite risk factor and therefore a simplified treatment target. However, the prognostic value of LA free strain in patients with inability to achieve the BP target needs to be evaluated in future prospective studies.


Free radical scavenging and antioxidant activity of ascorbigen versus ascorbic acid: studies in vitro and in cultured human keratinocytes.
Ascorbigen (ABG) is formed by indole-3-carbinole and ascorbic acid in brassica vegetables. In the present study, ABG has been systematically analyzed for its free radical scavenging and antioxidant capacity. To directly measure the free scavenging activity of ABG and ascorbic acid (used as a positive control), electron spin resonance and spin trapping experiments were performed. Ascorbic acid exhibited a potent free radical scavenging activity, whereas ABG did not scavenge superoxide anion free radicals and showed only little scavenging activity toward 2,2-diphenyl-1-picrylhydrazyl free radicals. Similar data were obtained for the ferric reducing ability of plasma and trolox equivalent antioxidant capacity assays. In cultured human keratinocytes, ABG counteracted tert-buthylhydroperoxide-induced cytotoxicity, whereas ascorbic acid did not exhibit any protective activity. Furthermore, in ABG-treated human keratinocytes, a decrease in tert-buthylhydroperoxide-induced lipid peroxidation was detected, whereas an ascorbic acid pretreatment did not result in the prevention of lipid peroxidation. These data indicate that ascorbic acid seems to be a more potent free radical scavenger than ABG in vitro, while ABG prevented tert-buthylhydroperoxide cytotoxicity more effectively as compared to ascorbic acid in cultured cells.


Fruit and Vegetable Consumption and Changes in Anthropometric Variables in Adult Populations: A Systematic Review and Meta-Analysis of Prospective Cohort Studies.
Randomized controlled trials provide conflicting results on the effects of increased fruit and vegetable consumption on changes in body weight. We aimed to perform a systematic review and meta-analysis of prospective cohort studies on fruit and vegetable consumption in relation to changes in anthropometric measures. PubMed and EMBASE were searched up to July 2015 for prospective studies reporting on habitual fruit and/or vegetable consumption in relation to changes in body weight or waist circumference or to risk of weight gain/overweight/obesity in adults. Random-effects meta-analysis was applied to pool results across studies. Seventeen cohort studies (from 20 reports) including 563,277 participants met our inclusion criteria. Higher intake of fruits was inversely associated with weight change (decrease) (beta-coefficient per 100-g increment, -13.68 g/year; 95% CI, -22.97 to -4.40). No significant changes could be observed for combined fruit and vegetable consumption or vegetable consumption. Increased intake of fruits was inversely associated with changes (decrease) in waist circumference (beta: -0.04 cm/year; 95% CI, -0.05 to -0.02). Comparing the highest combined fruit & vegetable, fruit, and vegetable intake categories were associated with a 9%, 17%, and 17% reduced risk of adiposity (odds ratio [OR]: 0.91, 95% CI, 0.84 to 0.99), (OR: 0.83, 95% CI, 0.71 to 0.99), and (OR: 0.83, 95% CI, 0.70 to 0.99), respectively. This meta-analysis showed several inverse associations between fruit and vegetable intake and prospective improvements in anthropometric parameters, and risk of adiposity. The present meta-analysis seems to be limited by low study quality. Nevertheless, when combined with evolutionary nutrition and epidemiological modeling studies, these findings have public health relevance and support all initiatives to increase fruit and vegetable intake.


Setting Priorities for Monitoring and Managing Non-native Plants: Toward a Practical Approach.
Land managers face the challenge to set priorities in monitoring and managing non-native plant species, as resources are limited and not all non-natives become invasive. Existing frameworks that have been proposed to rank non-native species require extensive information on their distribution, abundance, and impact. This information is difficult to obtain and often not available for many species and regions. National watch or priority lists are helpful, but it is questionable whether they provide sufficient information for environmental management on a regional scale. We therefore propose a decision tree that ranks species based on more simple albeit robust information, but still provides reliable management recommendations. To test the decision tree, we collected and evaluated distribution data from non-native plants in highland grasslands of Southern Brazil. We compared the results with a national list from the Brazilian Invasive Species Database for the state to discuss advantages and disadvantages of the different approaches on a regional scale. Out of 38 non-native species found, only four were also present on the national list. If management would solely rely on this list, many species that were identified as spreading based on the decision tree would go unnoticed. With the suggested scheme, it is possible to assign species to active management, to monitoring, or further evaluation. While national lists are certainly important, management on a regional scale should employ additional tools that adequately consider the actual risk of non-natives to become invasive.


Dangerous Headache: A Case of Dural Venous Sinus Thrombosis with Protein S Deficiency.
Dural Venous Sinus Thrombosis (DVST) is a sporadic cause of headache. DVST is a recherché complication of maxillary sinus infection. Maxillary sinusitis infection may spread directly to orbit via lamina papyracea and it is expedited by the presence veins of breschet. The authors present a clinical case of dural sinus thrombosis with protein S deficiency and also describe an effective management approach for DVST.


Is hysteroscopy of value in the investigation of female infertility?
A prospective multicentre study was designed to ascertain the value of hysteroscopy in the evaluation of female infertility. The study comprises 619 CO2 hysteroscopies in women complaining of infertility. Four hundred and ninety nine examinations (80%) were performed without anaesthesia or cervical dilatation. Twenty eight cases of malformation were diagnosed. Adhesions were found in 68 patients (11%), polypi in 56 (9.1%) and submucous fibroids in 51 (8.2%). Endometrial hyperplasia was diagnosed by hysteroscopy in 67 patients, but there was only 42% histological correlation. Examination of the tubal ostia by hysteroscopy revealed 26 patients (4%) with unilateral tubocornual polyps and one with bilateral polyps. The correlation with hysterosalpingography (HSG) in 185 patients was poor. In 20% where the HSG was reported as normal there were hysteroscopically demonstrable lesions whereas there were false positive findings at HSG in 35% of cases. Hysteroscopy is the only technique which provides an accurate clinical evaluation of the uterine cavity although it does not provide significant information about the cervical canal or fallopian tubes.


[Intravital bone imaging ~Osteocyte.]
Osteocytes are the most abundant cellular component of bone and have been considered dormant until recent evidence has demonstrated their critical roles in bone homeostasis and endocrine regulation. Until now the location of osteocytes within mineralized bone has restricted experimental access, especially in vivo. Here, intravital bone imaging by two-photon excitation microscopy allowed us to directly visualize the osteocytic lacuno-canalicular system. We demonstrated that sciatic neurectomy causes significant acidification around osteocytic lacunae and enlargement of lacuno-canalicular areas. These results show that two-photon intravital microscopy is useful for analysis of osteocytes in vivo.


Timely Pulmonary Valve Replacement May Allow Preservation of Left Ventricular Circumferential Strain in Patients with Tetralogy of Fallot.
Patients with Tetralogy of Fallot (TOF) and pulmonary insufficiency and a dilated right ventricle (RV) may suffer from a reduction in left ventricular (LV) performance. It is not clear whether timely pulmonary valve replacement (PVR) preserves LV mechanics. Ten TOF patients who underwent PVR were identified from hospital records, and pre- and postoperative cardiac magnetic resonance images were post-processed with a semi-automatic tissue tracking software. LV circumferential strain, time to peak strain, and torsion were compared before and after PVR. A control group of 10 age-matched normal volunteers was assessed as a comparison. LV circumferential strain did not change before vs. after PVR (basal -18.3 ± 3.7 vs. -20.5 ± 3%, p = 0.082; mid-ventricular -18.4 ± 3.6 vs. -19.1 ± 2%, p = 0.571; apical -22.7 ± 5.2 vs. -22.1 ± 4%; p = 0.703). There was also no difference seen between the baseline strain and normal controls (control basal -18.2 ± 3.3%, p = 0.937; mid -18 ± 3.2%, p = 0.798; apex -24.1 ± 5%, p = 0.552). LV torsion remained unchanged from baseline to post PVR [systolic 2.75 (1.23-9.51) °/cm vs. 2.3 ± 1.2°/cm, p = 0.285; maximum 5.5 ± 3.5°/cm vs. 2.34 (1.37-8.07) °/cm, p = 0.083]. There was no difference in time to measured peak LV circumferential strain before vs. after PVR (basal 0.44 ± 0.1 vs. 0.43 ± 0.05, p = 0.912; mid-ventricular 0.42 ± 0.08 vs. 0.38 ± 0.06, p = 0.186; apical 0.40 ± 0.08 vs. 0.40 ± 0.06, p = 0.995). At the same time, pulmonary regurgitation and RV end-diastolic and end-systolic volume indices decreased and LV end-diastolic volume increased after PVR. RV and LV ejection fractions remained constant. PVR allows for favorable remodeling of both ventricular volumes for TOF patients with significant pulmonary regurgitation. In this cohort, LV myocardial functional parameters such as circumferential strain, time to peak strain, and LV torsion were normal at baseline and remain unchanged after PVR.


Nutrient Intakes in Early Life and Risk of Obesity.
There is increasing evidence that environmental factors in early life predict later health. The early adiposity rebound recorded in most obese subjects suggests that factors promoting body fat development have operated in the first years of life. Birth weight, growth velocity and body mass index (BMI) trajectories seem to be highly sensitive to the environmental conditions present during pregnancy and in early life ("The first 1000 days"). Particularly, nutritional exposure can have a long-term effect on health in adulthood. The high protein-low fat diet often recorded in young children may have contributed to the rapid rise of childhood obesity prevalence during the last decades. Metabolic programming by early nutrition could explain the development of later obesity and adult diseases.


Boosting the Energy Density of Carbon-Based Aqueous Supercapacitors by Optimizing the Surface Charge.
The voltage of carbon-based aqueous supercapacitors is limited by the water splitting reaction occurring in one electrode, generally resulting in the promising but unused potential range of the other electrode. Exploiting this unused potential range provides the possibility for further boosting their energy density. An efficient surface charge control strategy was developed to remarkably enhance the energy density of multiscale porous carbon (MSPC) based aqueous symmetric supercapacitors (SSCs) by controllably tuning the operating potential range of MSPC electrodes. The operating voltage of the SSCs with neutral electrolyte was significantly expanded from 1.4 V to 1.8 V after simple adjustment, enabling the energy density of the optimized SSCs reached twice as much as the original. Such a facile strategy was also demonstrated for the aqueous SSCs with acidic and alkaline electrolytes, and is believed to bring insight in the design of aqueous supercapacitors.


Efficacy of cryotherapy for plantar warts: A systematic review and meta-analysis.
Recent systematic reviews of plantar warts continue to consider cryotherapy as one of the treatments of choice, but this method appears to have lower cure rates than alternative treatments. A systematic review using meta-analyses of the efficacy of cryotherapy in plantar warts treatment was performed. Systematic electronic searches were conducted. The primary endpoint was complete clearance of plantar warts. Risk-of-bias assessment was based on Cochrane Handbook recommendations. Meta-analyses used Review Manager v5.4.1 software. Cryotherapy appears to have lower cure rates than other treatments (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.12-0.78) with substantial heterogeneity (I2 = 80%). A second subgroup analysis had low heterogeneity (I2 = 28.2%). Subgroup analysis showed that plantar wart cure rates were significantly lower with cryotherapy compared to the physical treatment group (OR 0.05, 95% CI 0.01-0.49) with substantial heterogeneity (I2 = 79%), and antiviral, chemotherapy, and retinoid group (OR 0.30, 95% CI 0.14-0.66) without heterogeneity (I2 = 0%). Intralesional versus spray-on cryotherapy appears to be more effective (OR 0.21, 95% CI 0.09-0.48). No difference in efficacy between two rounds of 10-s and four rounds of 5-s freeze-thaw cycles in cryotherapy was found. Evidence of the superiority of antivirals and chemotherapy over cryotherapy in the treatment of plantar warts was found. However, no evidence supports the superiority or inferiority of cryotherapy compared to other treatments.


Carbonaceous aerosols in PM10 and pollution gases in winter in Beijing.
An intensive observation of organic carbon (OC) and elemental carbon (EC) in PM10 and gaseous materials (SO2, CO, and O3) was conducted continuously to assess the characteristics of wintertime carbonaceous aerosols in an urban area of Beijing, China. Results showed that the averaged total carbon (TC) and PM10 concentrations in observation period are 30.2 +/- 120.4 and 172.6 +/- 198.3 microg/m3, respectively. Average OC concentration in nighttime (24.9 +/- 19.6 microg/m3) was 40% higher than that in daytime (17.7 +/- 10.9 microg/m3). Average EC concentrations in daytime (8.8 +/- 15.2 microg/m3) was close to that in nighttime (8.9 +/- 15.1 microg/m3). The OC/EC ratios in nighttime ranging from 2.4 to 2.7 are higher than that in daytime ranging from 1.9 to 2.0. The concentrations of OC, EC, PM10 were low with strong winds and high with weak winds. The OC and EC were well correlated with PM10, CO and SO2, which implies they have similar sources. OC and EC were not well correlated with 03. By considering variation of OC/EC ratios in daytime and night time, correlations between OC and O3, and meteorological condition, we speculated that OC and EC in Beijing PM10 were emitted as the primary particulate form. Emission of motor vehicle with low OC/EC ratio and coal combustion sources with high OC/EC ratio are probably the dominant sources for carbonaceous aerosols in Beijing in winter. A simple ratio method was used to estimate the relative contribution of sources to carbonaceous aerosols in Beijing PM10. Motor vehicle source accounts for 80% and 68%, while coal combustion accounts for 20% and 32% in daytime and nighttime, respectively in Beijing. Averagely, the motor vehicle and coal combustion accounted for 74% and 26%, respectively, for carbonaceous aerosols during the observation period. It points to the motor vehicle is dominant emission for carbonaceous aerosols in Beijing PM10 in winter period, which should be paid attention to control high level of PM10 in Beijing effectively.


Chronic minocycline treatment improves hippocampal neuronal structure, NMDA receptor function, and memory processing in Fmr1 knockout mice.
Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability, and is the leading known single-gene cause of autism spectrum disorder. FXS patients display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently there is no cure for this condition, however minocycline is becoming commonly prescribed as a treatment for FXS patients. Minocycline has been reported to alleviate social behavioural deficits, and improve verbal functioning in patients with FXS; however, its mode of action is not well understood. Previously we have shown that FXS results in learning impairments that involve deficits in N-methyl-d-aspartate (NMDA) receptor-dependent synaptic plasticity in the hippocampal dentate gyrus (DG). Here we tested whether chronic treatment with minocycline can improve these deficits by enhancing NMDA receptor-dependent functional and structural plasticity in the DG. Minocycline treatment resulted in a significant enhancement in NMDA receptor function in the dentate granule cells. This was accompanied by an increase in PSD-95 and GluN2A and GluN2B subunits in hippocampal synaptoneurosome fractions. Minocycline treatment also enhanced dentate granule cell dendritic length and branching. In addition, our results show that chronic minocycline treatment can rescue performance in novel object recognition in FXS mice. These findings indicate that minocycline treatment has both structural and functional benefits for hippocampal cells, which may partly contribute to the pro-cognitive effects minocycline appears to have for treating FXS.


A revised description of Gyrodactylus cichlidarum Paperna, 1968 (Gyrodactylidae) from the Nile tilapia, Oreochromis niloticus niloticus (Cichlidae), and its synonymy with G. niloticus Cone, Arthur et Bondad-Reantaso, 1995.
A recent infestation of Gyrodactylus cichlidarum Paperna, 1968 on yolk sac fry of Nile tilapia, Oreochromis niloticus niloticus (L.), in an isolated aquarium system in the U.K. resulted in high mortalities and provided an opportunity to study this species in greater detail. A tentative identification was made using the measurements and drawings of the ventral bar and hamuli provided in the original description; however, details on the morphology of the marginal hooks were lacking. A comparison of the gyrodactylid material collected from O. n. niloticus with the holotype of G. cichlidarum, the only known available specimen, from Mango tilapia, Sarotherodon galilaeus galilaeus (L.), confirmed its identity. Proteolytic digestion and image analysis of the opisthaptoral hard parts were used to obtain tissue-free, accurate measurements as part of a complete revised description of G. cichlidarumn. Further, a comparison of G. cichlidarum from both hosts with the holotype and several paratypes of Gyrodactylus niloticus Cone, Arthur et Bondad-Reantaso, 1995 cited as parasitizing captive stocks of Nile tilapia in the Philippines revealed the two species to be synonymous. An 803 bp fragment of the ribosomal internal transcribed spacers 1 and 2 and the 5.8S was obtained and is provided with the revised description. This is the first DNA sequence from a Gyrodactylus species originating from the African continent. The sequence is very divergent from other species in the genus and only the 5.8S sequence places it unambiguously in the genus Gyrodactylus. In addition to G. cichlidarum, two specimens of another morphological similar species of Gyrodactylus were also found on the UK held stock of O. n. niloticus. These latter specimens, Gyrodacrylus sp., differed from G. cichlidarum in having a longer hamulus point with a smaller hamulus aperture and possessing marginal hook sickles that had a shorter shaft with a longer point giving the sickles a more rounded, closed appearance.


Trends in the supply and use of lipid-lowering drugs in Spain, 1983 through 1991.
Trends in the supply and use of lipid-lowering drugs in Spain were studied throughout the period of 1983-1991. Although the supply of such drugs remains excessive, a trend towards more rational standards has been apparent: 20 specialties out of 53 existing in 1983 have been withdrawn (10 fixed-dose combinations and 10 obsolete drugs). The overall use of lipid-lowering drugs rose from 2.51 DDD/1000 inhab/day in 1983 to 8.47 DDD/1000 inhab/day in 1991. The increase was mostly attributable to the subgroup of fibric acid derivatives (1.23 DDD/1000 inhab/day in 1983 and 6.14 in 1991). The bile acid sequestrants accounted for a small fraction of the overall use (0.23 DDD/inhab/day in 1991), in spite of its increasing consumption. The use of the two subgroups, nicotinic acid derivatives and fixed-dose combinations, has declined. The introduction into the market of HMG-CoA reductase inhibitors in 1991 contributed to the increase of the overall use in 1.28 DDD/1000 inhab/day but it seems not to have any negative influence on the use of other subgroups. Although the prevalence rates of hypercholesterolemia are similar, the use of lipid-lowering drugs in 1991 in Spain was 3 to 8 times higher than that of the Nordic countries. In conclusion, our data suggest that lipid-lowering drugs are highly used in Spain, at least in comparison with other western countries, and that the pattern of drug use is not in accordance with international recommendations.


Replisome-mediated translesion synthesis and leading strand template lesion skipping are competing bypass mechanisms.
A number of different enzymatic pathways have evolved to ensure that DNA replication can proceed past template base damage. These pathways include lesion skipping by the replisome, replication fork regression followed by either correction of the damage and origin-independent replication restart or homologous recombination-mediated restart of replication downstream of the lesion, and bypass of the damage by a translesion synthesis DNA polymerase. We report here that of two translesion synthesis polymerases tested, only DNA polymerase IV, not DNA polymerase II, could engage productively with the Escherichia coli replisome to bypass leading strand template damage, despite the fact that both enzymes are shown to be interacting with the replicase. Inactivation of the 3' → 5' proofreading exonuclease of DNA polymerase II did not enable bypass. Bypass by DNA polymerase IV required its ability to interact with the β clamp and act as a translesion polymerase but did not require its "little finger" domain, a secondary region of interaction with the β clamp. Bypass by DNA polymerase IV came at the expense of the inherent leading strand lesion skipping activity of the replisome, indicating that they are competing reactions.


A preclinical model for the analysis of genetically modified human skin in vivo.
Although skin is perhaps the most accessible of all somatic tissues for therapeutic gene transfer, it is a challenging site when attempting gene delivery. In addition to the transience of gene expression, important obstacles to cutaneous gene therapy have included the inability to sustain gene expression in a large proportion of keratinocytes within a given skin compartment. In this study, we have developed a novel experimental strategy that allows long-term regeneration of entirely genetically engineered human skin on the backs of NOD/SCID mice. Primary human keratinocytes were infected with a retroviral vector encoding the enhanced green fluorescent protein (EGFP) produced by transient transfection of 293T cells. EGFP expression allowed cell-sorting selection of a polyclonal population of productively transduced keratinocytes that were assembled in a live fibroblast-containing fibrin dermal matrix and orthotopically grafted onto mice. Epifluorescent illumination of the transplanted zone allowed in vivo monitoring of the genetically modified graft. EGFP-positive human skin was present on mice for 22 weeks after grafting. In addition, frozen sections prepared from the grafts displayed consistently strong EGFP-based fluorescence in all epidermal strata at every time point examined. Persistence of transgene expression was further confirmed through EGFP protein immunodetection. Purified EGFP-positive keratinocytes grafted as part of the fibrin-based artificial skin were capable of generating multilayer human epidermis on mice, with well-developed granulosum and corneum strata, and clearly defined rete ridges. Finally, the large proportion of transduced keratinocytes in our grafts allowed us to study, for the first time, the long-term in vivo clonal reconstitution pattern of the regenerated skin. Analysis of the provirus insertion sites indicates that a discrete number of epidermal stem cell clones was responsible for the maintenance of human skin regenerated in NOD/SCID recipients.


IL-6 produced by dendritic cells from lupus-prone mice inhibits CD4+CD25+ T cell regulatory functions.
The B6.Sle1.Sle2.Sle3 triple congenic mouse (B6.TC) is a model of lupus coexpressing the three major NZM2410-derived susceptibility loci on a C57BL/6 background. B6.TC mice produce high titers of antinuclear nephrogenic autoantibodies and a highly penetrant glomerulonephritis. Previous studies have shown the Sle1 locus is associated with a reduced number of regulatory T cells (Treg) and that Sle3 results in intrinsic defects of myeloid cells that hyperactivate T cells. In this report, we show that B6.TC dendritic cells (DCs) accumulate in lymphoid organs and present a defective maturation process, in which bone marrow-derived, plasmacytoid, and myeloid DCs express a significantly lower level of CD80, CD86, and MHC class II. B6.TC DCs also induce a higher level of proliferation in CD4(+) T cells than B6 DCs, and B6.TC DCs block the suppressive activity of Treg. B6.TC DCs overproduce IL-6, which is necessary for the blockade of Treg activity, as shown by the effect of anti-IL-6 neutralizing Ab in the suppression assays. The overproduction of IL-6 by DCs and the blockade of Treg activity maps to Sle1, which therefore not only confers a reduced number of Treg but also blocks their ability to regulate autoreactive T cells. Taken together, these results provide a genetic and mechanistic evidence for systemic autoimmunity resulting from an impaired regulatory T cell compartment in both number and function and for Sle1-expressing DCs playing a major role in the latter defect though their production of IL-6.


Non-adrenergic, non-cholinergic parasympathetic secretion in the rat submaxillary and sublingual glands.
Atropine resistant secretion from the submaxillary and sublingual glands was demonstrated upon electrical stimulation of the chorda-lingual nerve at high frequencies. The flow rate of the protein-rich saliva was low, and it declined rapidly and markedly upon prolonged stimulation. The results show that one or more substances other than acetylcholine are released by parasympathetic stimulation and that they may be of importance for the regulation of the exocrine functions of the glands. When the continuous mode of electrical stimulation at a low frequency of the nerve was changed to an intermittent mode of stimulation at a high frequency (in the absence of atropine), the secretion of fluid and protein decreased.


A Small Regulatory RNA Contributes to the Preferential Colonization of Escherichia coli O157:H7 in the Large Intestine in Response to a Low DNA Concentration.
Enterohemorrhagic Escherichia coli (EHEC) serotype O157:H7 (O157) is one of the most notorious human pathogens, causing severe disease in humans worldwide. O157 specifically colonizes the large intestine of mammals after passing through the small intestine, and this process is influenced by differential signals between the two regions. Small regulatory RNAs (sRNAs) are able to sense and respond to environmental changes and regulate diverse physiological processes in pathogenic bacteria. Although some sRNAs of O157 have been extensively investigated, whether these molecules can sense differences between the small and large intestine and influence the preferential colonization in the large intestine by O157 remains unknown. In this study, we identified a new sRNA, Esr055, in O157 which senses the low DNA concentration in the large intestine and contributes to the preferential colonization of the bacteria in this region. The number of O157 wild-type that adhered to the colon is 30.18 times higher than the number that adhered to the ileum of mice, while the number of the ΔEsr055 mutant that adhered to the colon decreased to 13.27 times higher than the number adhered to the ileum. Furthermore, we found that the expression of Esr055 is directly activated by the regulator, DeoR, and its expression is positively affected by DNA, which is significantly more abundant in the ileum than in the colon of mice. Additionally, combining the results of informatics predictions and transcriptomic analysis, we found that several virulence genes are up-regulated in the ΔEsr055 mutant and five candidate genes (z0568, z0974, z1356, z1926, and z5187) may be its direct targets.


A Pilot Study of RNA Sequencing to Improve the Diagnostic Yield of Bronchoalveolar Lavage Specimens in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients.
Pulmonary complications often cause morbidity and mortality in pediatric allogeneic hematopoietic stem cell transplant (HSCT) recipients. While detection of infection and initiation of appropriate antimicrobial therapy improves survival, present techniques oftentimes do not detect infections in bronchoalveolar lavage (BAL) samples because of pretreatment with antimicrobial therapies and the need for a priori knowledge of likely viral pathogens, decreasing the yield of BAL. We evaluated whether RNA-based massively parallel sequencing (MPS) would improve detection of infections in BAL fluid in pediatric allogeneic HSCT recipients. Nine patients underwent 10 BAL (1 patient underwent 2 BAL) and had sufficient BAL fluid for inclusion in this study. Clinical microbiological testing identified infections in 7 patients, and MPS identified infections in 5 patients, although some of these detected organisms were not detected by clinical testing. Results were fully concordant in 5 patients, fully discordant in 3 patients, and partially discordant in 2 patients. Bacterial, viral, and fungal infections were detected via both techniques. This suggests that MPS in conjunction with routine clinical testing increases the yield of detection of infectious organisms in the BAL fluid.


Fracture Strength After Fatigue Loading of Lithium Disilicate Pressed Zirconia Crowns.
The aim of this study was to evaluate the fracture resistance of fatigued lithium disilicate pressed zirconia crowns versus other ceramic crowns. Lithium disilicate pressed zirconia, fluorapatite pressed zirconia, monolithic lithium disilicate, and monolithic zirconia crowns were fabricated. Cyclic and static loadings were applied to the mesiobuccal cusp tip after thermocycling and fracture strengths were recorded. Fatigued lithium disilicate pressed zirconia crowns were found to have a fracture resistance of 9,117.81 ± 727.04 N, compared with 9,240.61 ± 887.21 N for monolithic zirconia crowns, 3,030.18 ± 1,505.83 N for fluorapatite pressed zirconia crowns, and 4,173.94 ± 877.46 N for monolithic lithium disilicate crowns (P = .001). This in vitro study shows that fatigued lithium disilicate pressed zirconia and monolithic zirconia crowns have better fracture resistance than fluorapatite pressed zirconia and monolithic lithium disilicate crowns.


Orthopaedic Trauma Theatre Efficiency in the COVID-19 Pandemic: Are We Returning to Normality?
Background Recent studies have shown a decline in theatre efficiency and productivity coinciding with the coronavirus disease 2019 (COVID-19) pandemic. In this study, we evaluate trauma theatre task efficiency in three different time periods (April 2019, April 2020, and November 2020), and analyse if productivity has altered since the start of the pandemic. Methods The records of a total of 320 patients who underwent orthopaedic trauma surgery at a large district general hospital in April 2019, April 2020 (during the first wave of the pandemic) and November 2020 (during the second wave of the pandemic) were analysed. Primary outcomes measured include time to get to the theatre, anaesthetic preparation time, the sum of time of anaesthesia and surgical preparation time, duration of surgery and time to transfer to recovery. Patient demographics as well as the type of surgery were also analysed. Results The time to get to the theatre and anaesthetic preparation time significantly increased in April 2020 (p<0.05) but fell in November 2020 with no significant difference in comparison to before the pandemic in April 2019 (p>0.05). The duration of surgery and time to transfer to recovery significantly increased in April 2020 (p<0.05) and though reduced in November 2020, was still significantly greater in comparison to April 2019 (p<0.05). In April 2020, the proportion of patients aged 18-65 was just 26% as compared to 35% in April 2019. This figure rose again to 45% in November 2020. The number of hip fracture procedures remained similar during the three time periods, with 32, 32 and 36 hip fracture operations in April 2019, April 2020 and November 2020, respectively. Conclusion While operating theatres' efficiency decreased during the first wave of the COVID-19 pandemic, it increased again in the second wave, coming close to the 'normal' levels before the pandemic struck.


Psychometric properties of the Beliefs about Medicine Questionnaire-adjuvant endocrine therapy (BMQ-AET) for women taking AETs following early-stage breast cancer.
This study evaluated the Beliefs about Medicine Questionnaire to explore adherence to adjuvant endocrine therapy after treatment for breast cancer (BMQ-AET). Factor structure of the BMQ-AET was explored alongside internal consistency, convergent validity and acceptability. The BMQ-AET Specific Scale fitted the original 10 item model. Internal consistency of the BMQ-AET was much improved compared to the original BMQ and convergent validity showed predicted direction of correlation, although correlation with BMQ-AET concerns scale was low. Acceptability was good. The evaluation of the BMQ-AET is encouraging, and could facilitate future research around adherence to AET.


[A useful method for the diagnosis of Raynaud's phenomenon: cold suppression of reactive post-ischemic hyperemia in the fingers].
A method is described which is of assistance in diagnosing Raynaud's phenomenon by making it possible to estimate the degree of cold sensitivity. 5-minute ischemia provoked by tourniquet round the wrist results in reactive finger hyperemia when the tourniquet is released. In 25 of 28 patients with Raynaud's phenomenon, postischemia reactive hyperemia was suppressed by cooling the hand to between 10 and 20 degrees, but remained unchanged in normal subjects. The critical temperature at which Raynaud's phenomenon occurs can be determined in a given patient, and the natural history of the disease and the effect of treatment can be observed. Cold induced reactive hyperemia suppression is probably caused by Burton's critical closing phenomenon.


Comparison of Illumina 450K and EPIC arrays in placental DNA methylation.
Illumina HumanMethylation450 BeadChip (450K) has been commonly used to investigate DNA methylation in human tissues. Recently, it has been replaced by Illumina HumanMethylationEPIC BeadChip (EPIC) covering over 850,000 CpGs distributed genome-wide. Many consortia have now datasets coming from both arrays and aspire to analyze the two together. The placenta shows a high number of intermediate methylation levels and is often investigated for obstetric/birth outcomes, and potentially for long-term programming in offspring. We performed a systematic comparison between the two arrays using 108 duplicate placental samples from Gen3G birth cohort. We find that placenta shows a high per-sample correlation between the arrays, and higher median correlations at individual CpGs than those reported for blood. We identify 26,340 probes with absolute difference in per cent methylation >10%. We conclude that EPIC and 450K placental data can be combined, and we provide two lists of CpGs that should be excluded to avoid misleading results.


Complications of obesity-hypoventilation syndrome in childhood.
The obesity-hypoventilation syndrome is rare in children, but it leads to serious complications and is associated with a high mortality. We report a child with this syndrome whose condition improved after intestinal bypass surgery. Review of the literature indicates that vigorous treatment of this disorder is necessary to prevent fatalities.


Concomitant monoclonal immunoglobulin deposition disease and crystalglobulin-induced nephropathy with a membranoproliferative pattern of glomerular injury .
Monoclonal immunoglobulin paraproteins can deposit in the kidney in variable forms and eliciting differing patterns of injury. Crystalglobulin-induced nephropathy is a rare form of monoclonal immunoglobulin deposition in the kidney, characterized by glomerular capillary endoluminal crystalline material evident by light and electron microscopy that exhibits immunoglobulin restriction via immunofluorescence studies. We present a case of a patient with acute kidney injury, and a subsequent kidney biopsy notably revealed concurrent monoclonal immunoglobulin deposition disease (MIDD) and crystalglobulin-induced nephropathy secondary to an IgM/κ monoclonal protein that resulted in a membranoproliferative pattern of glomerular injury. The two process were distinctly evident by ultrastructural crystalline and non-crystalline (as seen with cases of more conventional MIDD) deposits in the glomeruli. The paraprotein constituency is novel (IgM/κ) for crystalglobulin-induced nephropathy (prior cases exhibited IgG/κ restriction) as was the finding of the two monoclonal immunoglobulin deposition processes contributing to development of an active glomerulitis characterized by a membranoproliferative pattern of glomerular injury (crystalglobulin-induced nephropathy has not been associated with an active glomerulitis before).


Underlying host risk factors for nontuberculous mycobacterial lung disease.
Nontuberculous mycobacteria (NTM) are environmental microbes that cause a variety of human diseases, particularly chronic lung infections. Despite the fact that NTM are widespread in the environment, relatively few people develop NTM lung disease, suggesting intrinsic vulnerability in some individuals. This paper reviews the evidence that underlying disorders predispose to NTM lung disease, in particular primary conditions that result in bronchiectasis, chronic obstructive pulmonary disease, α-1-antitrypsin anomalies, pneumoconiosis, pulmonary alveolar proteinosis, and frank immunosuppressive states such as that associated with the use of anti-tumor necrosis factor-α biologics, posttransplantation immunosuppression, and HIV infection. Over the past several decades, NTM lung disease has been increasingly identified in postmenopausal women with slender body habitus. Thus we will also review the clinical and experimental evidence which supports the observation that such individuals are predisposed to NTM lung disease.


[Determination of oxygenates in methanol-to-olefin gasoline byproducts and methanol-to-gasoline product with solid phase extraction-gas chromatography].
Silica solid phase extraction (SPE) column was used for sample pretreatment to enrich the target analytes and simplify background. Due to its high efficiency, reliability and simplicity, the technique has been widely used in many fields. The byproduct gasoline of methanol-to-olefin (MTO) and the product of methanol-to-gasoline (MTG) mainly consist of hydrocarbons along with small amounts of oxygenates. Trace amounts of oxygenates are hard to identify because of their complex hydrocarbon components. With the SPE technique, the samples were separated into two major classes, oxygenates and hydrocarbons. Oxygenates were then determined with gas chromatography-mass spectrometry (GC-MS). The elution conditions of the silica solid phase extraction column were optimized with the standard sample. Under the optimized elution conditions, the hydrocarbons were first eluted from the SPE column with 5 mL dichloromethane, the oxygenates were then eluted with 3 mL acetonitrile. The recoveries of standard samples were tested before and after pretreatment. The standard recoveries were 87.7%-95.3%. The oxygenates except methanol and ethanol were then quantified by gas chromatography-flame ionization detection (GC-FID) and internal standard method. Methanol and ethanol were then quantified by extracting characteristic ion chromatograms and external standard method. The results show that the oxygenates of MTO byproduct gasoline and MTG product mainly consist of ketones and aldehydes. The method improves the sensitivities of the target compounds and reduces the interference of the background.


Phytochemical investigation and evaluation of anti-inflammatory and anti-arthritic activities of essential oil of Strobilanthus ixiocephala Benth.
Column chromatographic fractionation of essential oil obtained by hydrodistillation from the flowering tops of S. ixiocephala resulted in the isolation of beta-caryophyllene, fenchyl acetate, T-cadinol and a new sesquiterpene alcohol for which a name ixiocephol has been proposed. The beta-caryophyllene and fenchyl acetate were identified by Co-TLC with authentic samples whereas T-cadinol and ixiocephol were structurally elucidated by UV, IR, 1H NMR, 13C NMR and Mass spectral data. The GC-MS analysis of the essential oil has also revealed the presence of various monoterpenoids and sesquiterpenoids. The essential oil of S. ixiocephala demonstrated a dose dependant anti-inflammatory activity in carrageenan-induced rat paw oedema. It has also revealed good activity in cotton pellet granuloma and adjuvant induced arthritis model in rats.


Centenary of tele-electrocardiography and telephonocardiography.
In the history of electrocardiography the names of two physiologists stand out: Augustus Waller (1865-1922) and Willem Einthoven (1860-1927). Waller was the first to show that the beating heart produces a weak electric potential, which can be registered by a measuring device connected to electrodes attached to the skin. Einthoven developed a 'string' galvanometer, which was much faster and more sensitive than the system used by Waller. Einthoven's electrocardiograph was ready for use in 1903. To facilitate investigations of patients Einthoven connected his instrument to the Academic Hospital in Leyden, by a telephone line, as suggested by his engineering colleague Johannes Bosscha in Delft. The first successful tele-electrocardiogram was transmitted on Sunday 22 March 1905. The heart tones were registered by wiring a specially developed microphone placed on the subject's chest to another string galvanometer. The event was therefore a first both for tele-electrocardiography and for telephonocardiography. We are still awaiting the full-scale implementation of these achievements, 100 years later.


Microbial contamination in next generation sequencing: implications for sequence-based analysis of clinical samples.
The high level of accuracy and sensitivity of next generation sequencing for quantifying genetic material across organismal boundaries gives it tremendous potential for pathogen discovery and diagnosis in human disease. Despite this promise, substantial bacterial contamination is routinely found in existing human-derived RNA-seq datasets that likely arises from environmental sources. This raises the need for stringent sequencing and analysis protocols for studies investigating sequence-based microbial signatures in clinical samples.


A VEGF-A/SOX2/SRSF2 network controls VEGFR1 pre-mRNA alternative splicing in lung carcinoma cells.
The splice variant sVEGFR1-i13 is a truncated version of the cell membrane-spanning VEGFR1 receptor that is devoid of its transmembrane and tyrosine kinase domains. We recently showed the contribution of sVEGFR1-i13 to the progression and the response of squamous lung carcinoma to anti-angiogenic therapies. In this study, we identify VEGF165, a splice variant of VEGF-A, as a regulator of sVEGFR1-i13 expression in these tumors, and further show that VEGF165 cooperates with the transcription factor SOX2 and the splicing factor SRSF2 to control sVEGFR1-i13 expression. We also demonstrate that anti-angiogenic therapies up-regulate sVEGFR1-i13 protein level in squamous lung carcinoma cells by a mechanism involving the VEGF165/SOX2/SRSF2 network. Collectively, our results identify for the first time a signaling network that controls VEGFR1 pre-mRNA alternative splicing in cancer cells.


Quality of Mobile Apps for Care Partners of People With Alzheimer Disease and Related Dementias: Mobile App Rating Scale Evaluation.
Over 11 million care partners in the United States who provide care to people living with Alzheimer disease and related dementias (ADRD) cite persistent and pervasive unmet needs related to their caregiving role. The proliferation of mobile apps for care partners has the potential to meet care partners' needs, but the quality of apps is unknown. This study aims to evaluate the quality of publicly available apps for care partners of people living with ADRD and identify design features of low- and high-quality apps to guide future research and user-centered app development. We searched the US Apple App and Google Play stores with the criteria that included apps needed to be available in the US Google Play or Apple App stores, accessible to users out of the box, and primarily intended for use by an informal (family or friend) care partner of a person living with ADRD. We classified and tabulated app functionalities. The included apps were then evaluated using the Mobile App Rating Scale (MARS) using 23 items across 5 dimensions: engagement, functionality, aesthetics, information, and subjective quality. We computed descriptive statistics for each rating. To identify recommendations for future research and app development, we categorized rater comments on score-driving factors for each MARS rating item and what the app could have done to improve the item score. We evaluated 17 apps. We found that, on average, apps are of minimally acceptable quality. Functionalities supported by apps included education (12/17, 71%), interactive training (3/17, 18%), documentation (3/17, 18%), tracking symptoms (2/17, 12%), care partner community (3/17, 18%), interaction with clinical experts (1/17, 6%), care coordination (2/17, 12%), and activities for the person living with ADRD (2/17, 12%). Of the 17 apps, 8 (47%) had only 1 feature, 6 (35%) had 2 features, and 3 (18%) had 3 features. The MARS quality mean score across apps was 3.08 (SD 0.83) on the 5-point rating scale (1=inadequate to 5=excellent), with apps scoring highest on average on functionality (mean 3.37, SD 0.99) and aesthetics (mean 3.24, SD 0.92) and lowest on average on information (mean 2.95, SD 0.95) and engagement (mean 2.76, SD 0.89). The MARS subjective quality mean score across apps was 2.26 (SD 1.02). We identified apps whose mean scores were more than 1 point below minimally acceptable quality, whereas some were more than 1 point above. Many apps had broken features and were rated as below acceptable for engagement and information. Minimally acceptable quality is likely to be insufficient to meet care partner needs. Future research should establish minimum quality standards across dimensions for care partner mobile apps. Design features of high-quality apps identified in this study can provide the foundation for benchmarking these standards.


A method of bilateral cleft lip nose repair--a preliminary report.
By redefining the surgical anatomy of the nose, we were able to develop a new technique for the repair of the bilateral cleft lip nose. The lower one-third of the nose was divided into an outer layer, composed of skin, and an inner composed of fascia, muscle, cartilage and the skin of the vestible. From this viewpoint, the bilateral cleft lip nose deformity was reinterpreted as a combination of dislocation and deformity of the inner layer, and rotational displacement of the inner layer with respect to the outer layer. Using the double alar wing flap incision, we were afforded good visualization and anatomic reconstruction without tension by rotating the inner and outer layers in opposite directions. The length of the columella, the alar facial angle, the width of the nose and the size of alae have been satisfactory in 6 patients.


Suppression of FVIII-Specific Memory B Cells by Chimeric BAR Receptor-Engineered Natural Regulatory T Cells.
Anti-drug antibody formation poses tremendous obstacles for optimal treatment of hemophilia A (HA). In this study, we sought to utilize chimeric receptor-modified natural regulatory T cells (Tregs) to target FVIII-specific memory B cells, which are responsible for persistent anti-FVIII neutralizing antibodies (inhibitors) in HA patients. Thus, CD4+CD25 hi CD304+ natural Tregs were FACS sorted from naïve C57BL/6 mice and retrovirally transduced to express a chimeric B-cell antibody receptor (BAR) containing the immunodominant A2 domain of FVIII. Plasmablast-depleted (CD138 neg ) splenocytes from FVIII immunized FVIII-knockout HA mice served as the source for FVIII-specific memory B cells, which were specifically stimulated in vitro with FVIII and enumerated in a B-cell ELISPOT assays. Adding A2-BAR Tregs (1 per 150 splenocytes), but not conventional T cells, to the CD138- splenocytes significantly suppressed the formation of anti-FVIII antibody secreting cells (ASC), compared to the non-relevant OVA-BAR Tregs control group. The observation that A2-BAR Tregs can suppress the response to FVIII suggests that bystander suppression can occur in the local milieu in this system. Transwell experiments confirmed that the suppression was contact-dependent. Moreover, even in the presence of antibodies to FVIII (so-called inhibitors), similarly prepared CD4+CD25 hi CD127 low A2-BAR human natural Tregs completely suppressed polyclonal anti-FVIII ASC formation. In conclusion, we demonstrated in vitro that FVIII domain-expressing BAR Tregs could efficiently target and suppress FVIII-specific memory B cells.


The WOX11-LBD16 Pathway Promotes Pluripotency Acquisition in Callus Cells During De Novo Shoot Regeneration in Tissue Culture.
De novo shoot regeneration in tissue culture undergoes at least two phases. Explants are first cultured on auxin-rich callus-inducing medium (CIM) to produce a group of pluripotent cells termed callus; the callus is then transferred to cytokinin rich shoot-inducing medium (SIM) to promote the formation of shoot progenitor cells, from which adventitious shoots may differentiate. Here, we show that the Arabidopsis thaliana transcription factor gene LATERAL ORGAN BOUNDARIES DOMAIN16 (LBD16) is involved in pluripotency acquisition in callus cells. LBD16, which is activated by WUSCHEL RELATED HOMEOBOX11 (WOX11), is specifically expressed in the newly formed callus on CIM and its expression decreases quickly when callus is moved to SIM. Blocking the WOX11-LBD16 pathway results in the loss of pluripotency in callus cultured on CIM, leading to shooting defects on SIM. Further analysis showed that LBD16 may function in the establishment of the root primordium-like identity in the newly formed callus, indicating that the root primordium-like identity is the cellular nature of pluripotency in callus cells. Additionally, LBD16 promotes cell division during callus initiation. Our study clarified that the WOX11-LBD16 pathway promotes pluripotency acquisition in callus cells.


Evidence of the formation and conversion of unstable thionyl isocyanate: Gas-phase spectroscopic studies.
Thionyl diisocyanate which is unstable at ambient temperature is generated from a heterogeneous reaction of gaseous thionyl dichloride with silver cyanate and studied for the first time in the gas phase at 298 K. N-isocyanatoformyl sulfinylimide is also observed with photoelectron spectroscopy in the gas phase for the first time. The conversion of thionyl diisocyanate to N-isocyanatoformyl sulfinylimide via 1,3 shift at different temperatures is studied by using photoelectron spectroscopy and mass spectroscopy with the help of theoretical computations. On the basis of combined observations and quantum chemical calculations, possible 1,3-isocyanato shifts and dissociation processes for thionyl isocyanate and its cation have been discussed in detail.


Correlation between RBC changes and coagulation parameters in high altitude population.
To explore the correlations between RBCs indexes and the basic coagulation parameters, and provide data for further studies on high altitude-induced thrombotic disease. A total of eligible 433 volunteers were divided into different groups according to HGB concentration and HCT, respectively. PT, APTT, TT and Fbg were measured by clotting assays. HGB content, HCT and PLT count were assessed by automated hematology analyzer. APTT and PT were significantly higher in group 4 (high HGB or HCT groups) (p < 0.05 for all comparison) and PLT count was significantly lower in group 4 than in other groups (p < 0.01 for all comparison). APTT and PT showed negative correlations with HGB concentration (r = -0.168 and -0.165 resp.; both p < 0.01), whereas positive correlations were found between APTT and HCT, PT and HCT (r = 0.225 and 0.258, resp.; both p < 0.01). PLT, TT and Fbg showed no correlation with HGB and HCT. HGB and HCT may not correlate with basic coagulation parameters in high altitude population, their predictive value for high altitude-induced thrombotic disease may relatively independent and this remain to be determined in further studies.


Statistical characteristics of moxifloxacin-induced QTc effect.
Moxifloxacin has been the most commonly used positive control in "thorough" QTc (TQT) studies. In a TQT study, the assay sensitivity is often considered to be established if the baseline corrected mean difference in QTc between moxifloxacin and placebo is greater than 5 ms in common practice at one or more prespecified time points and the observed moxifloxacin induced QTc effect over time follows the proper pharmacokinetics profile. To better understand the statistical characteristics of moxifloxacin-induced QTc prolongation and to provide guidance for future studies, 20 TQT studies that involved moxifloxacin have been evaluated. We study the QTc profile of the baseline adjusted mean difference in QTc between moxifloxacin and placebo over time. Zhang (2008) proposed that the moxifloxacin induced QTc effect can be evaluated between 1 and 4 h after a single dose (400 mg) administration near the time (T(max)) of peak concentration instead of all time points (typically 9-12 time points) at which QT was measured for the study drug evaluation. After evaluating 20 TQT studies, we confirm that the maximum moxifloxacin effect occurs in the time window between 1 and 4 h post dose. We also investigate the variability of the data as well as correlations between time points and between regimens. These findings and results can be used as a reference for future studies.


The effect of heterogeneously-distributed RyR channels on calcium dynamics in cardiac myocytes.
Calcium plays an essential role in excitation-contraction coupling in muscle, and derangements in calcium handling can produce a variety of potentially harmful conditions, especially in cardiac muscle. In cardiac tissue specialized invaginations of the sarcolemma, called T-tubules, penetrate deep into each sarcomere, and depolarization of the SL leads to an influx of calcium through voltage-sensitive channels in the T-tubules that in turn triggers further calcium release from the sarcoplasmic reticulum via ryanodine-sensitive calcium channels. Under certain conditions, such as elevated external Ca2+, cardiac cells can release calcium from the sarcoplasmic reticulum spontaneously, producing a calcium 'spark' and propagating traveling waves of elevated Ca2+ concentration, without depolarization of the SL (Wier and Blatter, 1991a, Cell Calcium 12, 241-254; Williams, 1993, Cell Calcium 14, 724-735; Cheng et al., 1993a, Science 262, 740-744). However, under normal resting conditions these potentially harmful waves seldom occur. In this paper we investigate the role of the periodic distribution of ryanodine-sensitive channels in determining whether a spark can trigger a wave, using a modification of the kinetic model proposed by Tang and Othmer, 1994b, Biophys. J. 67, 2223-2235, for calcium-induced calcium release. We show that the spatial localization of these channels near the T-tubules has a significant effect on both wave propagation and the onset of oscillations in this system. Spatial localization provides a possible explanation for the differing effects of various experimental protocols on the system's ability to propagate a traveling wave.


Evolutionarily conserved requirement for core binding factor beta in the assembly of the human immunodeficiency virus/simian immunodeficiency virus Vif-cullin 5-RING E3 ubiquitin ligase.
The human immunodeficiency virus type 1 (HIV-1)-encoded virion infectivity factor (Vif) is required to inactivate the host restriction factor APOBEC3 by engaging Cullin 5 (Cul5)-RING ubiquitin ligase (CRL5). Core binding factor beta (CBF-β) is a novel regulator of Vif-CRL5 function; as yet, its mechanism of regulation remains unclear. In the present study, we demonstrate that CBF-β promotion of Vif-CRL5 assembly is independent of its influence on Vif stability and is also a conserved feature of primate lentiviral Vif proteins. Furthermore, CBF-β is critical for the formation of the Vif-ElonginB/ElonginC-Cul5 core E3 ubiquitin ligase complex in vitro. CBF-β from diverse vertebrate species supported HIV-1 Vif function, indicating the conserved nature of Vif-CBF-β interfaces. Considering the importance of the interaction between Vif and CBF-β in viral CRL5 function, disrupting this interaction represents an attractive pharmacological intervention against HIV-1. HIV-1 encodes virion infectivity factor (Vif) to inactivate its host's antiviral APOBEC3 proteins. Vif triggers APOBEC3 degradation by forming Vif-Cullin 5 (Cul5)-RING ubiquitin ligase (CRL5). Core binding factor beta (CBF-β) is a novel regulator of Vif-CRL5 function whose mechanism of regulation remains poorly defined. In the present study, we demonstrate that the promotion of Vif-CRL5 assembly by CBF-β can be separated from its influence on Vif stability. The promotion of Vif-CRL5 assembly, but not the influence on Vif stability, is conserved among primate lentiviral Vif proteins: we found that CBF-β from diverse vertebrate species supported HIV-1 Vif function. Considering the importance of the interaction between Vif and CBF-β in viral CRL5 function and HIV-1 replication, disrupting this interaction is an attractive strategy against HIV-1.


Kinship, maternal effects, and management: Juvenile mortality and survival in captive African painted dogs, Lycaon pictus.
In 77 African painted dog (Lycaon pictus) litters born in North American zoos since 1998, pup mortality at 30 days was 53% (n = 478). More alarmingly, 52% of those 77 litters had zero pups surviving at 30 days. Many variables may have the potential to affect pup mortality in captivity, including kinship, maternal age, prior maternal breeding experience, and numerous social and husbandry factors. Data on these variables were obtained from the North American Regional Studbook, with supplemental information compiled from a survey sent to painted dog breeding facilities in North America. Survival curve analysis revealed significant effects for maternal age and kinship, with kinship being most significant (χ2 , df = 19.71, 1; P < 0.0001). Pups born to unrelated parents had a median age at death two orders of magnitude higher than pups born to parents who were related to each other. Pup mortality was also lower for experienced mothers and for females under 2.5 years or between 4.5 and 6.5 years old. Follow-up analyses of these findings indicated that among first-time mothers, the youngest females achieved the lowest juvenile mortality, while juvenile mortality for experienced mothers was relatively low in all age classes until 6.5 years old. Regression analysis indicated that chances of survival are improved for pups born to younger mothers, unrelated parents, and in packs of >2 individuals. Enclosure size and area per animal may also be important factors. Our findings indicate that specific characteristics can be used to predict and potentially reduce pup mortality in captive African painted dogs. Zoo Biol. 35:367-377, 2016. © Wiley Periodicals, Inc.


Impact of valve calcification on systolic and diastolic valvular function--an in vitro model.
Despite continuous development of anticalcification treatment for bioprosthetic valves, calcification remains one major cause of structural failure. The aim of this study is to investigate changes in hemodynamic performance and leaflet kinematics in progressively calcified pericardial and porcine aortic valve prostheses. Five pericardial (Edwards Perimount Magna) and 5 porcine (Medtronic Mosaic Ultra) aortic valve prostheses (Ø23 mm) were exposed to a high concentration Calcium-phosphate fluid in an in vitro pulse duplicator (300 cycles/minute) for 6 weeks. The prostheses were removed weekly and tested in an artificial circulation system (70 beats/min, Cardiac Output 5 l/min). All prostheses underwent X-ray, computed tomography (CT)-Scan and photographic examination for evaluation of progressive calcification. Leaflet kinematics were visualized with a high-speed camera. Pericardial valves demonstrated faster degeneration with significantly larger radiographic areas of leaflet calcification (16.5+/-4.3% versus 5.6%+/-2.0%) and also significantly higher Ca-uptake (170+/-71 microg/mg versus 103+/-49 microg/mg) after 6 weeks. Despite degeneration systolic function remained superior for pericardial valves (mean effective orifice area [EOA] 1.52+/-0.05 versus 1.28+/-0.11 cm2, P<0.01), but leaflet kinematics showed longer closing times (135+/-11 msec versus 85+/-9 msec after 6 weeks) accompanied by higher regurgitant flow (7.8+/-1.12 mL versus 1.2+/-0.28 mL, P<0.001). In vitro pericardial valves calcified faster and more severe than porcine valves leading to impaired diastolic function with prolongation of closing times and higher closing volume. Systolic function remained almost undisturbed by the calcification process. As a consequence in clinical settings, follow-up examinations for structural valve deterioration in porcine valves should focus on systolic performance, in pericardial valves on diastolic function.


Intrinsic metallic and semiconducting cubic boron nitride nanofilms.
We show by density functional theory calculations with both hybrid and semilocal functionals that cubic boron nitride (111) nanofilms are intrinsically metallic and even turn into semiconductors once the thickness is less than 0.69 nm, which is in sharp contrast to the known insulating nature of boron nitride materials. The exceptional metallic or semiconducting band gap is due to a combined effect of thickness-dependent inbuilt electric polarization and labile near-gap states unique in the polar nanofilms. The band gap and dipole moment of the nanofilms can be further significantly tuned by applying an in-plane strain. These distinguished features of the boron nitride nanofilms are robust to surface passivation and can be enhanced by hybridizing with diamond films, thereby opening an exciting prospect of using the versatile cubic nanofilms in future electronic and piezoelectric devices.


Clinical Significance and Prognosis Value of Wnt Signaling Pathway in Cervical Cancer.
Cervical cancer is among the most commonly diagnosed cancer in women, supporting the need for identification of novel prognostic and predictive biomarkers to predict the risk of developing of this malignancy or predict the prognosis of patients. Against this background, the activation of the Wingless-type (Wnt)/β-catenin pathway has been suggested as the main dysregulated pathways, which is involved in the multistep process of cervical carcinogenesis, suggesting its value as a potential biomarker or therapeutic target. The aim of current review is to give an overview about the potential application of WNT pathway and its value which is differentially expressed in cervical cancer versus non-tumorigenic tissue as biomarker for risk stratification and predict the prognosis of patients with cervical cancer. J. Cell. Biochem. 118: 3028-3033, 2017. © 2017 Wiley Periodicals, Inc.


Solving the micronutrient problem in the Asia Pacific region.
Over two billion people, or more than one out of three individuals throughout the world, are at risk of iron, vitamin A and iodine deficiencies. Although countries of the Asia Pacific region have generally shown a remarkable decline in the proportion of malnourished children, micronutrient deficiencies remain significant public health problems. The World Summit for Children in 1990, and the FAO/WHO International Conference on Nutrition held in Rome in 1992, affirmed that the elimination of the various forms of micronutrient malnutrition would constitute a significant contribution to social, economic and public health development. Governments and non-governmental organisations from virtually all nations, together with the international development community, have made the elimination of iodine deficiency disorders and vitamin A deficiency important goals to be achieved by the end of the decade, along with a substantial reduction in the levels of iron deficiency anaemia. A further important factor in implementing multisectoral micronutrient interventions is the cost-effectiveness of such interventions. The three main complementary intervention strategies to controlling and preventing micronutrient deficiencies are: (i) food-based approaches such as fortification and dietary diversification; (ii) supplementation when appropriate; and (iii) public health measures to control infection, including incorporating micronutrients into other child survival activities such as immunisation. Much of the global experience in these strategies comes from countries of the Asia Pacific region, with some significant examples of success.


A heterochromatin inducing protein differentially recognizes self versus foreign genomes.
Krüppel-associated box-domain zinc finger protein (KRAB-ZFP) transcriptional repressors recruit TRIM28/KAP1 to heterochromatinize the mammalian genome while also guarding the host by silencing invading foreign genomes. However, how a KRAB-ZFP recognizes target sequences in the natural context of its own or foreign genomes is unclear. Our studies on B-lymphocytes permanently harboring the cancer-causing Epstein-Barr virus (EBV) have shown that SZF1, a KRAB-ZFP, binds to several lytic/replicative phase genes to silence them, thereby promoting the latent/quiescent phase of the virus. As a result, unless SZF1 and its binding partners are displaced from target regions on the viral genome, EBV remains dormant, i.e. refractory to lytic phase-inducing triggers. As SZF1 also heterochromatinizes the cellular genome, we performed in situ footprint mapping on both viral and host genomes in physically separated B-lymphocytes bearing latent or replicative/active EBV genomes. By analyzing footprints, we learned that SZF1 recognizes the host genome through a repeat sequence-bearing motif near centromeres. Remarkably, SZF1 does not use this motif to recognize the EBV genome. Instead, it uses distinct binding sites that lack obvious similarities to each other or the above motif, to silence the viral genome. Virus mutagenesis studies show that these distinct binding sites are not only key to maintaining the established latent phase but also silencing the lytic phase in newly-infected cells, thus enabling the virus to establish latency and transform cells. Notably, these binding sites on the viral genome, when also present on the human genome, are not used by SZF1 to silence host genes during latency. This differential approach towards target site recognition may reflect a strategy by which the host silences and regulates genomes of persistent invaders without jeopardizing its own homeostasis.


Glycerol Monolaurate, an Analogue to a Factor Secreted by Lactobacillus, Is Virucidal against Enveloped Viruses, Including HIV-1.
The vaginal microbiota influences sexual transmission of human immunodeficiency virus type 1 (HIV-1). Colonization of the vaginal tract is normally dominated by Lactobacillus species. Both Lactobacillus and Enterococcus faecalis may secrete reutericyclin, which inhibits the growth of a variety of pathogenic bacteria. Increasing evidence suggests a potential therapeutic role for an analogue of reutericyclin, glycerol monolaurate (GML), against microbial pathogens. Previous studies using a macaque vaginal simian immunodeficiency virus (SIV) transmission model demonstrated that GML reduces transmission and alters immune responses to infection in vitro Previous studies showed that structural analogues of GML negatively impact other enveloped viruses. We sought to expand understanding of how GML inhibits HIV-1 and other enveloped viruses and show that GML restricts HIV-1 entry post-CD4 engagement at the step of coreceptor binding. Further, HIV-1 and yellow fever virus (YFV) particles were more sensitive to GML interference than particles "matured" by proteolytic processing. We show that high-pressure-liquid-chromatography (HPLC)-purified reutericyclin and reutericyclin secreted by Lactobacillus inhibit HIV-1. These data emphasize the importance and protective nature of the normal vaginal flora during viral infections and provide insights into the antiviral mechanism of GML during HIV-1 infection and, more broadly, to other enveloped viruses.IMPORTANCE A total of 340 million sexually transmitted infections (STIs) are acquired each year. Antimicrobial agents that target multiple infectious pathogens are ideal candidates to reduce the number of newly acquired STIs. The antimicrobial and immunoregulatory properties of GML make it an excellent candidate to fit this critical need. Previous studies established the safety profile and antibacterial activity of GML against both Gram-positive and Gram-negative bacteria. GML protected against high-dose SIV infection and reduced inflammation, which can exacerbate disease, during infection. We found that GML inhibits HIV-1 and other human-pathogenic viruses (yellow fever virus, mumps virus, and Zika virus), broadening its antimicrobial range. Because GML targets diverse infectious pathogens, GML may be an effective agent against the broad range of sexually transmitted pathogens. Further, our data show that reutericyclin, a GML analog expressed by some lactobacillus species, also inhibits HIV-1 replication and thus may contribute to the protective effect of Lactobacillus in HIV-1 transmission.


Visualizing numbers in the mind's eye: the role of visuo-spatial processes in numerical abilities.
In the study of numerical and arithmetical abilities, there is compelling evidence demonstrating that number and space representations are connected to one another. Historically the first source of support came more than a century ago, when Galton's investigations on mental imagery suggested that the internal representation of numbers may evoke a stable, linear space. In the past few decades, empirical evidence lent further support to the hypothesis that numerical representation is spatially coded into a non-verbal 'mental number line', which in turn lead to considering this representation as the core of number meaning. Visuo-spatial processing is intuitively involved in various aspects of number processing and calculation: For instance, the meaning of a digit in a multi-digit number is coded following spatial information, given its association to its relative position within the number; similarly, to solve a complex written multiplication one has to know the correct location of the intermediate results. In this review behavioral, neuropsychological, and neuroimaging data concerning the close relationship between numerical abilities and visuo-spatial processes are considered.


Relationship between Brain Age-Related Reduction in Gray Matter and Educational Attainment.
Inter-subject variability in age-related brain changes may relate to educational attainment, as suggested by cognitive reserve theories. This voxel-based morphometry study investigated the impact of very low educational level on the relationship between regional gray matter (rGM) volumes and age in healthy elders. Magnetic resonance imaging data were acquired in elders with low educational attainment (less than 4 years) (n = 122) and high educational level (n = 66), pulling together individuals examined using either of three MRI scanners/acquisition protocols. Voxelwise group comparisons showed no rGM differences (p<0.05, family-wise error corrected for multiple comparisons). When within-group voxelwise patterns of linear correlation were compared between high and low education groups, there was one cluster of greater rGM loss with aging in low versus high education elders in the left anterior cingulate cortex (p<0.05, FWE-corrected), as well as a trend in the left dorsomedial prefrontal cortex (p<0.10). These results provide preliminary indication that education might exert subtle protective effects against age-related brain changes in healthy subjects. The anterior cingulate cortex, critical to inhibitory control processes, may be particularly sensitive to such effects, possibly given its involvement in cognitive stimulating activities at school or later throughout life.


Morphoea profunda presenting with atrophic skin lesions in a 26 year old female: a case report.
Morphoea Profunda is a rare variant of Morphoea that presents clinically as a solitary fibrotic plaque. Morphoea Profunda presenting with atrophic lesions has rarely been reported in literature. We report the case of a 26 year old Nepalese lady who presented to us with multiple non-inflammatory atrophic lesions on her body without significant skin induration, pigmentation and texture change. The findings on histopathology confirmed a diagnosis of Morphoea Profunda. Hence, Morphoea Profunda should be considered in the differential diagnosis of anyone presenting with asymptomatic atrophy of the skin.


Hierarchy of membrane-targeting signals of phospholipase D1 involving lipid modification of a pleckstrin homology domain.
The amino terminus of phospholipase D1 (PLD1) contains three potential membrane-interacting determinants: a phox homology (PX) domain, a pleckstrin homology (PH) domain and two adjacent cysteines at positions 240 and 241 within the PH domain that are fatty acylated in vivo. To understand how these determinants contribute to membrane localization, we have mutagenized critical residues of the PLD1 PH domain in the wild type or palmitate-free background in the intact protein, in a fragment that deletes the first 210 amino acids including the PX domain, and in the isolated PH domain. Mutants were expressed in COS-7 cells and examined for membrane residence, intracellular localization, palmitoylation, and catalytic activity. Our results are as follows. 1) Mutagenesis of critical residues of the PH domain results in redistribution of PLD1 from membranes to cytosol, independently of fatty acylation sites. Importantly, PH domain mutants in the wild type background showed greatly reduced fatty acylation, despite the presence of all relevant cysteines. 2) The isolated PH domain did not co-localize with PLD1 and was not palmitoylated. 3) The PX deletion mutant showed similar distribution and palmitoylation to the intact protein. Interestingly, PH domain mutants in this background showed significant palmitoylation and incomplete cytosolic redistribution. 4) PH domain mutants in the wild type or palmitate-free background maintained catalytic activity. We propose that membrane targeting of PLD1 involves a hierarchy of signals with a functional PH domain allowing fatty acylation leading to strong membrane binding. The PX domain may modulate function of the PH domain.


Clinicopathological study of a patient with procainamide-induced systemic lupus erythematosus.
A patient who developed a multisystem involvement of systemic lupus erythematosus (SLE) after 9 years of procainamide therapy, during which time he ingested enormous amounts of the drug, is described. The patient first suffered from recurrent episodes of pleuritis and arthritis, after which he developed a characteristic SLE nephritis associated with a high level of antinative DNA antibodies and a low level of complement. He finally died from a complication of a nonbacterial endocarditis. Autopsy showed polyserositis and typical deposits of electron-dense material on the glomerular basement membrane, and confirmed the clinical diagnosis of Libman-Sacks endocarditis. The possibility that procainamide-induced SLE might have all the clinical, immunological, and pathological features of spontaneous SLE, especially in patients exposed to large doses of the drug for many years, is discussed.


Relationship between body composition and blood pressure in Bahraini adolescents.
The objective of the present study was to examine the relationship between body composition and blood pressure (BP) in Bahraini adolescents. A sample of 504 Bahraini schoolchildren aged 12-17 years (249 boys and 255 girls) was selected using a multi-stage stratified sampling procedure. BP measurements were performed on the students. Anthropometric data including weight, height, waist circumference (WC), hip circumference, and triceps, subscapular and medial calf skinfold thicknesses were also collected. BMI, percentage body fat, waist:hip (WHR), and subscapular:triceps skinfold ratio were calculated. Mean systolic BP and mean diastolic BP were higher in males than in females. Weight and height in boys and weight only in girls were significantly associated with systolic BP independent of age or percentage fat. Nearly 14 % of the adolescents were classified as having high BP. BMI and percentage body fat were significantly and positively associated with the risk of having high BP in the boys and girls. Adolescents with high WHR or WC, as indicators for central obesity, tended to have higher BP values. The results from the present study indicate that obesity influences the BP of Bahraini adolescents and that simple anthropometric measurements such as WHR and WC are useful in identifying children at risk of developing high BP. These findings together with the known tracking of BP from adolescence into adulthood underline the importance of establishing intervention programmes in order to prevent the development of childhood and adolescent obesity.


[Combined treatment of genital human papillomavirus infection in men].
This study aimed to assess the efficacy of treatment of genital human papillomavirus infection in 107 men. Patients in group 1 (n=51) underwent laser ablation of genital warts, patients in group 2 (n=56) were treated with laser ablation in conjunction with the administration of an immune system medication izoprinozin. During the first 9 months post-treatment, human papillomavirus infection relapse rate in group 1 was 23,5% and in group 2 - 5,4%. It was likewise observed that the combined treatment of genital warts resulted in reduced incidence of infective complications and the time of wound epithelialization after laser papilloma ablation.


Characterization of the coding sequence of the normal M4 alpha 1-antitrypsin gene.
The nucleotide sequences of the common normal "M" family of alpha 1-antitrypsin (alpha 1AT) variants are known, including M1(Val213), M1(Ala213), M2 and M3. Less common, but also migrating with the "M" family on isoelectric focusing gels, is the normal M4 allele. Being relatively rare, the M4 allele is usually found in heterozygous combination with another alpha 1AT allele making sequence characterization more difficult. To facilitate analysis of the coding exons of the alpha 1AT M4 allele, a method was developed to combine blood monocyte RNA extraction, reverse transcription of the alpha 1AT mRNA, amplification with the polymerase chain reaction and direct sequencing. This analysis demonstrated that the M4 allele differs from the M1(Val213) allele by a single nucleotide substitution G--greater than A, causing the amino acid substitution Arg101 CGT--greater than His101 CAT. This same mutation is also a part of the M2 gene suggesting that this region of the alpha 1AT gene may be one of increased mutational activity.


Feasibility of a CT-based lymph node radiomics nomogram in detecting lymph node metastasis in PDAC patients.
To investigate the potential value of a contrast enhanced computed tomography (CECT)-based radiological-radiomics nomogram combining a lymph node (LN) radiomics signature and LNs' radiological features for preoperative detection of LN metastasis in patients with pancreatic ductal adenocarcinoma (PDAC). In this retrospective study, 196 LNs in 61 PDAC patients were enrolled and divided into the training (137 LNs) and validation (59 LNs) cohorts. Radiomic features were extracted from portal venous phase images of LNs. The least absolute shrinkage and selection operator (LASSO) regression algorithm with 10-fold cross-validation was used to select optimal features to determine the radiomics score (Rad-score). The radiological-radiomics nomogram was developed by using significant predictors of LN metastasis by multivariate logistic regression (LR) analysis in the training cohort and validated in the validation cohort independently. Its diagnostic performance was assessed by receiver operating characteristic curve (ROC), decision curve (DCA) and calibration curve analyses. The radiological model, including LN size, and margin and enhancement pattern (three significant predictors), exhibited areas under the curves (AUCs) of 0.831 and 0.756 in the training and validation cohorts, respectively. Nine radiomic features were used to construct a radiomics model, which showed AUCs of 0.879 and 0.804 in the training and validation cohorts, respectively. The radiological-radiomics nomogram, which incorporated the LN Rad-score and the three LNs' radiological features, performed better than the Rad-score and radiological models individually, with AUCs of 0.937 and 0.851 in the training and validation cohorts, respectively. Calibration curve analysis and DCA revealed that the radiological-radiomics nomogram showed satisfactory consistency and the highest net benefit for preoperative diagnosis of LN metastasis. The CT-based LN radiological-radiomics nomogram may serve as a valid and convenient computer-aided tool for personalized risk assessment of LN metastasis and help clinicians make appropriate clinical decisions for PADC patients.