The Potential Migrated Mechanism of Water-Soluble Components in Pellets Prepared by Wet Extrusion/Spheronization: Effect of Drying Rate.
At present, there are numerous researches on the migration of components in tablets and granules, however, the investigation in the pharmaceutical literatures concerning the effect of drying rate on the migration of water-soluble components of pellets is limited. Temperature and Relative Humidity (RH) are crucial parameters during the drying process, which is an essential step in the preparation of pellets via wet extrusion/spheronization. To quantify these variables, the water loss percentage of pellets per minute is defined as the drying rate. The study aimed to investigate the influence of drying rate on the migration of water-soluble components in wet pellets and the potential migrated mechanism. The pellets containing tartrazine as a water-soluble model drug and microcrystalline cellulose as a matrix former were prepared by extrusion/spheronization and dried at four different drying temperatures and relative humidity. Afterwards, the extent of migrated tartrazine was assessed regarding appearance, in-vitro dissolution test, Differential Scanning Calorimetry, X-Ray Powder Diffraction, Attenuated total reflectance Fourier transform infrared spectroscopy and Confocal Raman Mapping. Results demonstrated that red spots of tartrazine appeared on the surface of pellets and more than 40% tartrazine were burst released within 5 minutes when pellets were dried at 60°C/RH 10%. When pellets were dried at 40°C/RH 80%, none of these aforementioned phenomena were observed. In conclusion, the faster the drying rate was, the more tartrazine migrated to the exterior of pellets. Adjusting drying temperature and relative humidity appropriately could inhibit the migration of water-soluble components within wet extrusion/spheronization pellets.


Global resources in the fight against tuberculosis.
Tuberculosis continues to be a significant cause of mortality and morbidity worldwide, particularly in developing countries. Diagnosis and treatment of paediatric patients presents a challenge that can only be improved by the joint efforts of the international community, working together in cooperation and partnership. This article reviews global resources available to doctors and healthcare professionals in the fight against TB, including international programmes, policies and healthcare pathways. Special attention is paid to the role of international paediatric radiology in improving diagnostics, including available educational resources and support on a global, regional, national and individual level.


Heavy metals in the gold mine soil of the upstream area of a metropolitan drinking water source.
Pinggu District is adjacent to the county of Miyun, which contains the largest drinking water source of Beijing (Miyun Reservoir). The Wanzhuang gold field and tailing deposits are located in Pinggu, threatening Beijing's drinking water security. In this study, soil samples were collected from the surface of the mining area and the tailings piles and analyzed for physical and chemical properties, as well as heavy metal contents and particle size fraction to study the relationship between degree of pollution degree and particle size. Most metal concentrations in the gold mine soil samples exceeded the background levels in Beijing. The spatial distribution of As, Cd, Cu, Pb, and Zn was the same, while that of Cr and Ni was relatively similar. Trace element concentrations increased in larger particles, decreased in the 50-74 μm size fraction, and were lowest in the <2 μm size fraction. Multivariate analysis showed that Cu, Cd, Zn, and Pb originated from anthropogenic sources, while Cr, Ni, and Sc were of natural origin. The geo-accumulation index indicated serious Pb, As, and Cd pollution, but moderate to no Ni, Cr, and Hg pollution. The Tucker 3 model revealed three factors for particle fractions, metals, and samples. There were two factors in model A and three factors for both the metals and samples (models B and C, respectively). The potential ecological risk index shows that most of the study areas have very high potential ecological risk, a small portion has high potential ecological risk, and only a few sampling points on the perimeter have moderate ecological risk, with higher risk closer to the mining area.


Brain ischemia with Alzheimer phenotype dysregulates Alzheimer's disease-related proteins.
There are evidences for the influence of Alzheimer's proteins on postischemic brain injury. We present here an overview of the published evidence underpinning the relationships between β-amyloid peptide, hyperphosphorylated tau protein, presenilins, apolipoproteins, secretases and neuronal survival/death decisions after ischemia and development of postischemic dementia. The interactions of above molecules and their influence and contribution to final ischemic brain degeneration resulting in dementia of Alzheimer phenotype are reviewed. Generation and deposition of β-amyloid peptide and tau protein pathology are essential factors involved in Alzheimer's disease development as well as in postischemic brain dementia. Postischemic injuries demonstrate that ischemia may stimulate pathological amyloid precursor protein processing by upregulation of β- and γ-secretases and therefore are capable of establishing a vicious cycle. Functional postischemic brain recovery is always delayed and incomplete by an injury-related increase in the amount of the neurotoxic C-terminal of amyloid precursor protein and β-amyloid peptide. Finally, we present here the concept that Alzheimer's proteins can contribute to and/or precipitate postischemic brain neurodegeneration including dementia with Alzheimer's phenotype.


Clinical Improvement of Alpha-mannosidosis Cat Following a Single Cisterna Magna Infusion of AAV1.
Lysosomal storage diseases (LSDs) are debilitating neurometabolic disorders for most of which long-term effective therapies have not been developed. Gene therapy is a potential treatment but a critical barrier to treating the brain is the need for global correction. We tested the efficacy of cisterna magna infusion of adeno-associated virus type 1 (AAV1) expressing feline alpha-mannosidase gene in the postsymptomatic alpha-mannosidosis (AMD) cat, a homologue of the human disease. Lysosomal alpha-mannosidase (MANB) activity in the cerebrospinal fluid (CSF) and serum were increased above the control values in untreated AMD cats. Clinical neurological signs were delayed in onset and reduced in severity. The lifespan of the treated cats was significantly extended. Postmortem histopathology showed resolution of lysosomal storage lesions throughout the brain. MANB activity in brain tissue was significantly above the levels of untreated tissues. The results demonstrate that a single cisterna magna injection of AAV1 into the CSF can mediate widespread neuronal transduction of the brain and meaningful clinical improvement. Thus, cisterna magna gene delivery by AAV1 appears to be a viable strategy for treatment of the whole brain in AMD and should be applicable to many of the neurotropic LSDs as well as other neurogenetic disorders.


Spotted fever group rickettsiae and Anaplasma phagocytophilum in Borrelia burgdorferi sensu lato seropositive individuals with or without Lyme disease: A retrospective analysis.
The Ixodes ricinus tick is the main vector of Borrelia burgdorferi and tick-borne encephalitis virus in Switzerland. Spotted fever group Rickettsiae (SFG) and Anaplasma phagocytophilum have been detected in Swiss ticks, however, information about the extent and clinical presentation of these infections in humans is scant. Indirect fluorescent antibody tests for SFG rickettsiae and Anaplasma phagocytophilum were performed on serum samples of 121 Borrelia burgdorferi seropositive patients with and without Lyme disease and 43 negative controls. Out of 121 Borrelia burgdorferi seropositive individuals, 65 (53.7%) were seropositive for IgG and 15 (12.4%) for IgM antibodies to SFG rickettsiae. IgM antibodies were detected more frequently in early-than in late-stage of Lyme disease (12 out of 51 and 2 out of 49; respectively; p = 0.0078). Significantly higher IgG antibody titers against SFG rickettsiae were found in patients with late-stage compared to patients with early-stage Lyme disease (mean titer 1:261 and 1:129, respectively; p = 0.038). This difference was even more pronounced in patients with acrodermatitis chronica atrophicans compared to patients with early stage of Lyme disease (mean titer 1:337 and 1:129, respectively; p = 0.009).In patients presenting with fatigue, headache and myalgia, the prevalence of IgG antibodies against SFG rickettsiae was significantly higher (7 out of 11; 63.6%) than in Borrelia burgdorferi seropositive individuals without clinical illness (1 out of 10; 10%; p = 0.024). IgG antibodies to Anaplasma phagocytophilum were detected in 12 out of 121 individuals (9.9%), no IgM antibodies were found. Infections with SFG rickettsiae and Anaplasma phagocytophilum are underdiagnosed and should be ruled out after a tick bite. Further studies are needed to elucidate the possible causative role of SFG rickettsiae for myalgia, headache and long-lasting fatigue after a tick bite and to determine the necessity for an antibiotic treatment.


Aerobic composting remediation of petroleum hydrocarbon-contaminated soil. Current and future perspectives.
This article provides a comprehensive review on aerobic composting remediation of soil contaminated with total petroleum hydrocarbons (TPHs). The studies reviewed have demonstrated that composting technology can be applied to treat TPH contamination (as high as 380,000 mg kg-1) in clay, silt, and sandy soils successfully. Most of these studies reported more than 70% removal efficiency, with a maximum of 99%. During the composting process, the bacteria use TPHs as carbon and energy sources, whereas the fungi produce enzymes that can catalyze oxidation reactions of TPHs. The mutualistic and competitive interactions between the bacteria and fungi are believed to sustain a robust biodegradation system. The highest biodegradation rate is observed during the thermophilic phase. However, the presence of a diverse and dynamic microbial community ensures that TPH degradation occurs in the entire composting process. Initial concentration, soil type, soil/compost ratio, aeration rate, moisture content, C/N ratio, pH, and temperature affect the composting process and should be monitored and controlled to ensure successful degradation. Nevertheless, there is insufficient research on optimizing these operational parameters, especially for large-scale composting. Also, toxic and odorous gas emissions during degradation of TPHs, usually unaddressed, can be potential air pollution sources and need further insightful characterization and mitigation/control research.


Block by extracellular divalent cations of Drosophila big brain channels expressed in Xenopus oocytes.
Drosophila Big Brain (BIB) is a transmembrane protein encoded by the neurogenic gene big brain (bib), which is important for early development of the fly nervous system. BIB expressed in Xenopus oocytes is a monovalent cation channel modulated by tyrosine kinase signaling. Results here demonstrate that the BIB conductance shows voltage- and dose-dependent block by extracellular divalent cations Ca(2+) and Ba(2+) but not by Mg(2+) in wild-type channels. Site-directed mutagenesis of negatively charged glutamate (Glu(274)) and aspartate (Asp(253)) residues had no effect on divalent cation block. However, mutation of a conserved glutamate at position 71 (Glu(71)) in the first transmembrane domain (M1) altered channel properties. Mutation of Glu(71) to Asp introduced a new sensitivity to block by extracellular Mg(2+); substitutions with asparagine or glutamine decreased whole-cell conductance; and substitution with lysine compromised plasma membrane expression. Block by divalent cations is important in other ion channels for voltage-dependent function, enhanced signal resolution, and feedback regulation. Our data show that the wild-type BIB conductance is attenuated by external Ca(2+), suggesting that endogenous divalent cation block might be relevant for enhancing signal resolution or voltage dependence for the native signaling process in neuronal cell fate determination.


Crowding Effects Dominate Demographic Attributes in COVID-19 Cases.
With an eye toward possible public policy implications, our objective is to identify the socio-economic and demographic factors that drive the large variation in COVID-19 incidence rates observed within relatively compact geographic regions, and to quantify the relative impact of each of these factors. We use international comparisons as a starting point. New York City, consisting of some 175 zip codes, is an ideal arena to pursue the above study given the large variation in case incidence rates across zip codes. We conducted systematic regression studies employing data with zip code granularity. Our model specifications are based on a well-established epidemiologic model that explains the effects of household sizes on R0. Average household size emerges as the single most important driver behind the large variation in COVID-19 incidence rates. It independently explains 62% of the variation. The percentage of the population above the age of 65 and the percentage below the poverty line are also strongly positively associated with zip code incidence rates. As to ethnic/racial characteristics, the percentages of African Americans, Hispanics and Asians within the population are significantly associated, but the magnitude of the impact is smaller. (The proportion of Asians within a zip code has a negative association.) Contrary to common belief, population density, by itself, does not have a significantly positive impact (other than when a high population is driven by large household sizes). Our findings support implemented and proposed policies to quarantine patients and separate infected individuals from families or dormitories; they also support newly revised nursing home admission policies.


Symptom patterns in the daily life of PSC patients.
Patients with primary sclerosing cholangitis (PSC) may suffer from complaints such as pruritus, right upper abdominal quadrant pain (RUQ-A) and fatigue. However, the severity of these complaints, daily and/or seasonal patterns and other factors of influence in PSC are largely unknown. The aim of this study is to assess daily symptoms and patterns thereof in PSC patients in their natural setting. A mobile application was designed according to the experience sampling method. Push notifications with a response time of max 4 h were sent during tiers of 3 months. Questions comprised VAS scales on degree of pruritus, fatigue, RUQ-A, time of the day these symptoms were worst, as well as time of intake of medication. Linear mixed modelling was used to identify patient- and external factors associated with pruritus, fatigue and RUQ-A pain. A total of 6713 questionnaires were completed by 137 patients. Fatigue was the most prevalent symptom among PSC patients being reported in a striking 71% of measurements, followed by pruritus (38%). Both increased during the day and were associated with longer disease duration. A highly significant correlation between pruritus and day temperature was observed (ρ = -0.14, p = .000), and itch was generally worse during winter (p = .000). Patient preference for the tool was high. Pruritus and fatigue are prevalent symptoms in the daily life of PSC patients and show a distinct diurnal pattern. This may have implications for efficient dosing of anti-pruritic agents. The level of pruritus is highly correlated with day temperature, which may have several implications.


European versus North American cardioplegia: comparison of Bretschneider's and Roe's cardioplegic solutions in a canine model of cardiopulmonary bypass.
Roe's and Bretschneider's crystalloid cardioplegic solutions were compared in a canine model of total cardiopulmonary bypass with 4.5 hours of hypothermic (27 degrees C) ischemic arrest and 60 minutes of reperfusion. Bretschneider's solution (Group I, six dogs) preserved tissue adenosine triphosphate (ATP) near control levels and maintained coronary effluent pH near 7.0 throughout the ischemic interval, while Roe's solution (Group II, six dogs) allowed progressive acidosis and depletion of ATP (P less than 0.005 versus control). Group I had supranormal left ventricular function during reperfusion (greater than 100% of pre-arrest function) but Group II regained only 40-75% of pre-arrest function. Group I had 2.82% +/- 3.61% necrosis of heart mass and Group II 9.33% +/- 8.26 (P less than 0.10). We conclude that Bretschneider's solution provided better myocardial protection than Roe's solution. The development of acidosis in the Roe group suggests that the more effective buffering of Bretschneider's solution with histidine is the probable basis for its superiority.


Evaluation for the ecological quality status of coastal waters in East China Sea using fuzzy integrated assessment method.
This research presented an evaluation for the ecological quality status (EcoQS) of three semi-enclosed coastal areas using fuzzy integrated assessment method (FIAM). With this method, the hierarchy structure was clarified by an index system of 11 indicators selected from biotic elements and physicochemical elements, and the weight vector of index system was calculated with Delphi-Analytic Hierarchy Process (AHP) procedure. Then, the FIAM was used to achieve an EcoQS assessment. As a result of assessment, most of the sampling stations demonstrated a clear gradient in EcoQS, ranging from high to poor status. Among the four statuses, high and good, owning a ratio of 55.9% and 26.5%, respectively, were two dominant statuses for three bays, especially for Sansha Bay and Luoyuan Bay. The assessment results were found consistent with the pressure information and parameters obtained at most stations. In addition, the sources of uncertainty in classification of EcoQS were also discussed.


Relationship between L-lactate dehydrogenase and multidrug resistance in Staphylococcus xylosus.
Staphylococcus xylosus is a gram-positive bacterium that has attracted much attention due to its increasing clinical appearance, frequently associated with serious multidrug resistance cases. L-lactate dehydrogenase (LDH) has been related to drug resistance in several bacterial species. However, the mechanism of multidrug resistance in S. xylosus remains unclear as well as the involvement of LDH in such resistance. To explore the relationship between multidrug resistance and LDH in S. xylosus, we used tylosin-resistant S. xylosus as the parent strain to construct ldh knockout and complemented strains. Then, we tested their resistance to macrolides, lincosamides, tetracyclines, and aminoglycosides. In addition, the enzyme activity, metabolite content, and transcriptional level of key genes involved in the TCA cycle and thioredoxin system were determined to clarify the mechanism of resistance. We observed that the resistance to multiple antibiotics increased significantly after ldh knockout, especially that to lincomycin, whereas antibiotic sensitivity was partially restored in the complemented strain. The levels of pyruvate, nicotinamide adenine dinucleotide, and reactive oxygen species decreased significantly upon ldh knockout, and the activity of isocitrate dehydrogenase and malate dehydrogenase decreased. These results indicate that the lack of LDH promotes multidrug resistance in S. xylosus by inhibiting the TCA cycle and regulating the thioredoxin system.


Detection of Drug-Responsive T-Lymphocytes in a Case of Fatal Antituberculosis Drug-Related Liver Injury.
Antituberculosis (TB) drug exposure is associated with a mild elevation of liver enzymes that occasionally develops into severe liver injury. Herein, we identify ethambutol- and rifampicin-specific CD4+ and CD8+ T-cell clones in a patient with fatal anti TB-related liver injury. The clones were activated to proliferate and secrete IFN-γ, Il-13, and granzyme B following drug treatment. Drug-responsive T-cells may contribute to the pathogenesis of antituberculosis-related liver failure.


The effect of glycerol as a cryoprotective agent in the cryopreservation of adipose tissue.
Long-term preservation of adipose tissue is crucial for clinical applications. Researchers should consider both efficiency and biosafety when choosing a cryoprotective agent (CPA) for adipose tissue preservation. Glycerol has been applied as a nontoxic CPA for multiple tissues but not adipose tissue. We aimed to evaluate the efficacy of glycerol as a CPA for adipose tissue cryopreservation. Fresh human adipose tissues were obtained from patients who underwent liposuction and divided into 1 mL samples. Each sample was randomly mixed with 1 mL of CPA: 60-100% glycerol, 0.25 mol/L trehalose or DMSO + FBS and cryopreserved in - 196 °C liquid nitrogen for one month. After thawing and elution, the tissues were immediately evaluated for activity and structural integrity in vitro. Then, 0.2 mL of each sample was transplanted subdermally to the nude mouse dorsum and harvested after one month for histological examination to assess the effect of the cryopreserved fat in transplantation. After cryopreservation, the samples treated with DMSO + FBS, trehalose, 60% and 70% glycerol had a more integrated structure than the samples in other groups. Tissues preserved with 70% glycerol had the highest G3PDH activity of 24.41 ± 0.70, comparable to 24.76 ± 0.48 in fresh tissue (p > 0.05). Adipose-derived stem cells (ASC) viability, proliferation and differentiation capability were also better preserved in 70% glycerol group. In vivo analysis showed that tissue preserved with 70% glycerol had a retention rate of 52.37 ± 7.53%, significantly higher than other groups. Histological observation demonstrated better structural integrity and viability in 70% glycerol group. Compared to the DMSO + FBS and trehalose groups, the glycerol groups showed lower tissue inflammation. Glycerol (70%) is efficient in adipose tissue cryopreservation. Glycerol-based CPAs, which are nontoxic and show biosafety, are a promising solution for clinical tissue cryopreservation.


The effect of complete dentures on head posture.
This study investigated possible changes in head posture after insertion of complete dentures in patients who had been edentulous for at least 6 months. The craniovertical angle was measured with a plastic ruler and protractor assembly, which was aligned with dots made on the skin over the zygomatic arch. Readings were made before denture insertion, immediately after insertion, and 15 and 30 minutes later. Two-way ANOVA was used to analyze the results. When the predenture insertion values were included, statistically significant changes (p less than 0.01) in head posture were found. However, when the predenture values were excluded, no statistically significant differences were found. The results support the conclusions that head posture is significantly altered immediately after insertion of dentures in edentulous patients but within the next 30 minutes there is no statistically significant alteration in head posture.


BRCA1 in breast and ovarian cancer predisposition.
Women carrying one mutated BRCA1 allele are at increased risk of developing breast and ovarian cancer but tumor initiation requires the loss of the wild-type allele indicating that it is a tumor suppressor gene. In the 10 years since the cloning of BRCA1, a function for the gene product in the DNA damage response has been established. However, identifying the exact biochemical activities of BRCA1 has been a more difficult task. Our current understanding suggests that the molecular functions mediated by the terminal ends of BRCA1, which include an E3 ubiquitin ligase activity at the N-terminus and a protein-protein interaction surface at the C-terminus, are critical to the function of this protein in the response to DNA damage.


Topological quantum computing with a very noisy network and local error rates approaching one percent.
A scalable quantum computer could be built by networking together many simple processor cells, thus avoiding the need to create a single complex structure. The difficulty is that realistic quantum links are very error prone. A solution is for cells to repeatedly communicate with each other and so purify any imperfections; however prior studies suggest that the cells themselves must then have prohibitively low internal error rates. Here we describe a method by which even error-prone cells can perform purification: groups of cells generate shared resource states, which then enable stabilization of topologically encoded data. Given a realistically noisy network (≥10% error rate) we find that our protocol can succeed provided that intra-cell error rates for initialisation, state manipulation and measurement are below 0.82%. This level of fidelity is already achievable in several laboratory systems.


Focal hepatic lesions characterisation by different sonographic techniques: a prospective analysis.
Ultrasound is usually the first diagnostic investigation for the assessment of liver lesions. Apart from conventional sonography (CS), new grey-scale sonographic techniques have been developed which have increased the application of ultrasound in liver imaging. The present study was undertaken to compare image quality of CS, real-time compound sonography (RTCS), tissue harmonic sonography (THS) and tissue harmonic compound sonography (THCS) in focal liver lesions. 100 patients with focal hepatic lesions were enroled. Lesions were divided into solid and cystic group. Solid lesions were evaluated for lesion conspicuity and elimination of artefacts. For cystic lesions, lesion conspicuity, posterior acoustic enhancement and internal echoes within the lesion were evaluated. Grading was done using 3-5-point scales. Overall image quality was assessed depending on the total points. 78 solid and 22 cystic liver lesions were included. THCS showed superior results for lesion conspicuity, elimination of artefacts and overall image quality in solid lesions. RTCS showed similar results as THCS for lesion conspicuity and overall image quality in solid lesions. THS gave better results in cystic lesions for all imaging parameters. Results of THCS though slightly inferior, showed no significant difference from THS, in cystic lesions. CS was found to have least diagnostic value in characterisation. For evaluation of focal hepatic lesions, a combination of compound and harmonic sonography, i.e. THCS, is the preferred sonographic technique.


Bony increased-offset reverse shoulder arthroplasty vs. metal augments in reverse shoulder arthroplasty: a prospective, randomized clinical trial with 2-year follow-up.
Reverse shoulder arthroplasty (RSA) is rapidly being adopted as the standard procedure for a growing number of shoulder pathologies. Lateralization of the glenoid component is known to reduce the incidence of scapular notching and possibly improve postoperative range of motion. A number of methods are used for glenoid component lateralization, including bony increased-offset reverse shoulder arthroplasty (BIO-RSA) and porous metal-augmented baseplates. Presently, there exists little comparative literature on bone vs. metal lateralization. Therefore, the purpose of this study was to compare BIO-RSA to metal-augmented glenoid baseplates by assessing clinical outcomes and baseplate migration using model-based radiostereometric analysis. A power analysis indicated 40 patients would be required for this radiostereometric study. Therefore, 41 shoulders were prospectively randomized to receive either glenoid bone grafting (BIO-RSA) or a porous metal-augmented wedge-shaped titanium baseplate for primary reverse shoulder arthroplasty. At the time of primary surgery, all patients also underwent implantation of 8 tantalum marker beads in the glenoid and coracoid. Following surgery, participants were imaged using a calibrated, stereo radiographic technique. Radiographs were acquired at 6 weeks (baseline), 3 months, 6 months, 1 year, and 2 years postoperatively. Migration of the prosthesis was compared between bone and metal lateralization groups at each time point using a mixed effects model with Bonferroni test for multiple comparisons. Outcome measures were acquired preoperatively and 2 years postoperatively. No significant differences were observed along any translation or rotation axis at any time point for either glenoid fixation group (P ≥ .175). Mean total glenoid component translation (± standard deviation) 2 years postoperatively was 0.4 ± 0.2 mm and 0.5 ± 0.3 mm for BIO-RSA and metal-augmented baseplates, respectively (P = .784). No significant differences were observed between groups in active range of motion; pain; American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form score; Simple Shoulder Test score; Disabilities of the Arm, Shoulder, and Hand score; Constant Shoulder score; or Subjective Shoulder Value (P ≥ .117), with the exception of increased active external rotation in the BIO-RSA cohort (P = .036). This randomized clinical trial assessed reverse shoulder arthroplasty glenoid component migration using model-based radiostereometric analysis. At 2-year follow-up, our results indicate both BIO-RSA and porous metal wedge augmented baseplates provide stable initial fixation, which is maintained at 2 years' follow-up, with no substantial differences in clinical outcomes.


Echo-Doppler (duplex) ultrasonic scanning.
The combination of pulsed echo with pulsed Doppler provides a system that is capable of imaging peripheral arteries and veins and evaluating velocity patterns across suspected areas of narrowing. The method has been most widely applied to the evaluation of carotid artery disease for the detection and grading of lesions in the carotid bulb. Recent experience has suggested that the technique may also be applied to the vessels of the limb, the abdominal aorta, visceral arteries, and the deep veins. The use of this method is indicated for screening purposes and long-term follow-up of patients who have or have not had surgery.


Computed Tomography-Based 3-Dimensional Finite Element Analyses of Various Types of Plates Placed for a Virtually Reduced Unilateral Condylar Fracture of the Mandible of a Patient.
This study was performed to evaluate stresses in various types of plates placed for a virtually reduced unilateral condylar fracture of the mandible using computed tomography-based 3-dimensional finite element (FE) models of a patient to select the optimal plate system. A computed tomography-based FE model of the mandible of a patient with a unilateral condylar fracture was constructed. The fracture was virtually reduced and fixed with 1 straight titanium plate; 2 straight titanium plates; 2 straight poly-L-lactic acid plates; and 4-hole (box), 5-hole (strut), and 7-hole (lambda) condylar plates. Stresses developing in these plates were analyzed by applying 478.1 N of bite force at the first molar of the contralateral side of the mandible. The magnitudes of tensile stress were within the tensile strength in all types of plates. However, the magnitudes of compressive stress in 1 straight titanium plate and 2 straight poly-L-lactic acid plates were beyond the compressive strength. The tensile and compressive stresses of the 5-hole (strut) plate were the smallest among the 3 types of condylar plates. Fixation by 2 straight titanium plates or any type of condylar plate was biomechanically indicated for the condylar fracture of this patient. Among these plates, the 5-hole (strut) plate was considered optimal. FE analysis is useful in selecting the optimal fixation method in the individual patient.


[Birth defects in the Czech Republic--the prenatal diagnostic].
An analysis of the efficiency of prenatal diagnostic of selected birth defects in the Czech Republic and its dynamics in past 30 years according to birth defect type and prenatal diagnostic methods. Retrospective epidemiological analysis of selected birth defects, prenatal diagnostics efficiency. Data from the National Birth Defect Register (Institute for Health Information and Statistics) in the Czech Republic in the 1975 - 2005 period were used along with data on prenatally diagnosed and terminated pregnancies from the same period. Mean prenatal diagnostic efficiency values of selected types of defects were analyzed in 5-year periods and minimal/maximal values were assessed. During 1975 - 2005 period, totally 3,935,209 children were born, out of which 83,970 were with a birth defect. Mean incidence was 213.38 per 10,000 live births (with the highest value of 414.58 in 2003). In 1985 - 2005, 7,398 cases of prenatally detected birth defects (resulting in pregnancy terminations) were registered, which made (in relative numbers) a span from 4.9 defects per 10,000 live births in 1985 to 65.2 per 10,000 live births in the year 2005. During this period, an important increase of diagnostics of prenatally detectable defects occurred. The study gives results of relative efficiency of prenatal diagnostics of particular birth defects. The highest efficiency was in anencephaly and encephalocele (100%), the other defects showed the following numbers: spina bifida 81%, congenital hydrocephalus 67%, omfalocele 67%, gastroschisis 92%, cystic kidney 59%, renal agenesis 50%, diaphragmatic hernia 35% and Down syndrome 74%.


Health literacy and quality of life of patients with coronary heart disease in Tibet, China: The mediating role of self-efficacy and self-management.
The disease burden of coronary heart disease patients in Tibet, China, ranks high in the country. Due to the local culture and environment, patients with coronary heart disease have increased risk factors for the disease, and their survival is worrisome. The purpose of this study was to determine the relationship between health literacy and quality of life for patients with coronary heart disease in Tibet, China, and to explore the mediating roles of self-efficacy and self-management. A cross-sectional study was conducted from August 2020 to July 2021 in Tibet. A total of 258 patients with coronary heart disease in Tibet participated. Self-reported questionnaires were used to assess health literacy, self-efficacy, self-management, and quality of life. Pearson correlation analysis and the SPSS PROCESS macro were used to analyze the data. The mean total score for the health literacy of patients with coronary heart disease in Tibet was 3.59 ± 0.80 points, showing the existence of a limited level of literacy. The quality of life was of an average level, with scores of 57.20 ± 21.70 points and 63.63 ± 20.66 points for physical and mental status, respectively. Self-efficacy and self-management mediated the relationship between health literacy and quality of life. Self-efficacy and self-management mediate the relationship between health literacy and quality of life. Targeted interventions for health literacy, self-efficacy, and self-management skills are important to improve the quality of life of Tibetan patients with coronary heart disease.


Orexin 1 receptor activation attenuates neurogenic dural vasodilation in an animal model of trigeminovascular nociception.
The pathophysiology underlying the pulsating quality of the pain of a migraine attack is not fully understood, although trigeminal vascular afferents containing the sensory neuropeptide calcitonin gene-related peptide (CGRP) must have a role. Antimigraine drugs, such as triptans, serotonin 5-hydroxytryptamine(1B/1D) receptor agonists, reproducibly block neurogenic vasodilation associated with CGRP release. We examined the effects of the hypothalamic neuropeptides orexin A and orexin B on neurogenic dural vasodilation, dissecting out the receptor pharmacology with the novel orexin 1 (OX1) receptor antagonist N-(2-methyl-6-benzoxazolyl)-N''-1,5-naphthyridin-4-yl urea (SB-334867). Electrical stimulation of dural afferents (50-300 microA) resulted in reproducible dural vasodilation of 136 +/- 9%. Orexin A 30 microg kg(-1), but not 3 and 10 microg kg(-1), inhibited the dilation brought about by electrical stimulation over 60 min and maximally after 15 min by 60% (t7= 7.138; P < 0.001; n = 8). This response was reversed by pretreatment with the OX1 receptor antagonist SB-334867. Addition of CGRP(8-37) at the point of maximal effect of orexin A produced a further significant decrease in neurogenic dural vasodilation compared with orexin A only. CGRP administration (1 microg kg(-1)) produced a reproducible dural blood vessel dilation of 145 +/- 7% that was not inhibited by intravenous administration of orexin A (30 microg kg(-1)). Orexin B had no significant effect even at the highest dose. The current study demonstrates that orexin A is able to inhibit neurogenic dural vasodilation via activation of the OX1 receptor, resulting in inhibition of prejunctional release of CGRP from trigeminal neurons.


Lentivirus Production and Purification.
Lentiviral (LV) vectors offer unique advantages over other gene delivery systems, namely the ability to integrate transgenes into the genome of both dividing and nondividing cells. Detailed herein is a simple protocol for the production LV vectors, describing the triple transfection of an LV transfer vector and LV helper plasmids into HEK-293 cells, and the subsequent purification of virions from the cellular media. The current protocol is versatile, and can be easily modified to fit the specific needs of the researcher in order to produce relatively high-titer LV vectors which can be used to transduce a wide variety of cells both in vitro and in vivo.


HHsenser: exhaustive transitive profile search using HMM-HMM comparison.
HHsenser is the first server to offer exhaustive intermediate profile searches, which it combines with pairwise comparison of hidden Markov models. Starting from a single protein sequence or a multiple alignment, it can iteratively explore whole superfamilies, producing few or no false positives. The output is a multiple alignment of all detected homologs. HHsenser's sensitivity should make it a useful tool for evolutionary studies. It may also aid applications that rely on diverse multiple sequence alignments as input, such as homology-based structure and function prediction, or the determination of functional residues by conservation scoring and functional subtyping.HHsenser can be accessed at http://hhsenser.tuebingen.mpg.de/. It has also been integrated into our structure and function prediction server HHpred (http://hhpred.tuebingen.mpg.de/) to improve predictions for near-singleton sequences.


Estimation of fetal weight with the use of head, body, and femur measurements--a prospective study.
In utero estimates of fetal weight were evaluated prospectively in 109 fetuses with the use of sonographic models developed in a previous study. This report confirms that the best in utero weight estimates result from the use of models based on measurements of head size, abdominal size, and femur length. Since the accuracy of these models (1 SD = 7.5%) is significantly better than those based on measurements of head and body (e.g., biparietal diameter, abdominal circumference), we recommend routine use of such models in obstetric sonography.


Emotional activation of obese and normal women due to imagery and food content of verbal stimuli in a memory task.
The aim of this study is to look for correlation between a physiological variable (skin conductance, SCL) and cognitive variables (reaction time, RT and productivity score) obtained in a memory task. Subjects were 17 females, including 7 patients and 10 controls. Patients were recruited among women who went to a clinic for alimentary disorders because of obesity and volunteered for this study; controls were normal women of comparable age without any alimentary problem. Tonic variations of SCL were recorded by a computerized polygraph during the execution of the cognitive task, which consisted of a computerized presentation of frequent, everyday used words evenly divided according to an alimentary/nonalimentary content and to a high/low imagery quality. The acquisition session was followed by an immediate recognition session where subjects were asked to identify the previously presented words among an equal number of similar words not included in the acquisition list. The two session series (acquisition and recognition) were repeated three times to evaluate the learning curve and habituation. This same procedure was separately performed with high imagery alimentary/nonalimentary words and with another list of low imagery alimentary/nonalimentary words. During the recognition tasks, both RT and productivity scores were recorded. A correlation analysis between cognitive and physiological variables was carried out to explore how subjects with different attitudes to food react in cognitive and somatic terms when exposed to verbal stimuli concerning this topic and to neutral verbal stimuli. Results show that obese patients have a different emotional activation in front of these verbal stimuli where both the cognitive activity and the somatic responses are affected by their involvement with the verbal stimuli. On the contrary, the imagery effect does not seem to be influenced by the content and by the idiosyncratic reactions to it of the specific groups of subjects.


Berry curvature generation detected by Nernst responses in ferroelectric Weyl semimetal.
The quest for nonmagnetic Weyl semimetals with high tunability of phase has remained a demanding challenge. As the symmetry-breaking control parameter, the ferroelectric order can be steered to turn on/off the Weyl semimetals phase, adjust the band structures around the Fermi level, and enlarge/shrink the momentum separation of Weyl nodes which generate the Berry curvature as the emergent magnetic field. Here, we report the realization of a ferroelectric nonmagnetic Weyl semimetal based on indium-doped Pb1- x Sn x Te alloy in which the underlying inversion symmetry as well as mirror symmetry are broken with the strength of ferroelectricity adjustable via tuning the indium doping level and Sn/Pb ratio. The transverse thermoelectric effect (i.e., Nernst effect), both for out-of-plane and in-plane magnetic field geometry, is exploited as a Berry curvature-sensitive experimental probe to manifest the generation of Berry curvature via the redistribution of Weyl nodes under magnetic fields. The results demonstrate a clean, nonmagnetic Weyl semimetal coupled with highly tunable ferroelectric order, providing an ideal platform for manipulating the Weyl fermions in nonmagnetic systems.


Parameter optimization of double-blade normal milk processing and mixing performance based on RSM and BP-GA.
Temperature stability was taken as the evaluation index of processing performance, and the three factors that influence normal milk processing and mixing performance were optimized by response surface analysis and BP-GA neural network algorithm. Analysis results showed the influence order of the factors on temperature stability was as follows: shape > height > rotating speed. In the optimization by response surface methodology (RSM), when rotating speed was 30 r/min, height was 31 mm, and blade shape was a full trapezoid, predicted value and actual value of variable coefficient were 0.0046 and 0.0044 respectively, with relative error of 4.5%. In the optimization by BP-GA neural network algorithm, when rotating speed was 34 r/min, height was 25 mm, and blade shape was a full trapezoid, the predicted value and actual value of variable coefficient were 0.0036 and 0.0035 respectively, with relative error of 2.9%. The predicted root-mean-square error of the model by the BP-GA neural network algorithm was 0.0013, determination coefficient was 0.9960, and relative percent deviation was 8.4961, which showed better performance than the RSM model. Thus, the BP-GA neural network algorithm has better fitting performance, and then, the optimal working parameter combination was confirmed, which could provide reference to improving double-blade normal milk processing and mixing device design and milk processing quality.


Antiphospholipid antibodies in chronic hypertension: the value of screening during pregnancy.
To determine if screening for antiphospholipid antibodies in gravid chronic hypertension patients is warranted, we performed a retrospective cohort study to test the association between antiphospholipid antibodies and perinatal outcome in this group of women. The primary outcome we compared was adverse perinatal outcome, defined as delivery <37 weeks' gestation secondary to maternal or fetal indications, intrauterine or neonatal death, birth weight <10th percentile for gestational age, early-onset severe preeclampsia, or placental abruption. Our sample size allowed for the detection of a 60% reduction in the relative risk of adverse perinatal outcome in patients who were antiphospholipid antibody screen negative (80% power, P = 0.05). No increased risk of adverse perinatal outcome was demonstrated among patients with positive serum antiphospholipid antibodies (33.3%, 5/15) versus patients with negative screening (40.0%, 22/55) in our cohort (RR 0.88, 95% Cl 0.38-1.83). Furthermore, antiphospholipid antibody status was not associated with adverse perinatal outcome after controlling for classic indications for antibody screening (RRMH 0.63, 95% Cl 0.30-1.33). In conclusion, chronic hypertension patients with positive antiphospholipid antibody screening are not at increased risk for adverse perinatal outcome compared to those with negative screening. Therefore, screening for antiphospholipid antibodies in chronic hypertension patients without classic indications for screening is not warranted.


BCGitis and BCGosis in children with primary immunodeficiency - imaging characteristics.
When administered to an immune-compromised patient, BCG (Bacille Calmette-Guérin) can cause disseminated and life-threatening infections. To describe the imaging findings in children with primary immunodeficiency and BCG-related infections. We reviewed the imaging findings of children with primary immunodeficiency treated at a children's hospital during 2012-2014 with localized or disseminated BCG infection. Imaging modalities included US, CT and radiography. Nine children with primary immunodeficiency had clinical signs of post-vaccination BCGitis; seven of these children showed disseminated disease and two showed only regional lesions with characteristic ipsilateral lymphadenopathy. Overall, lymphadenopathy was the most prevalent feature (n = 8) and characteristically appeared as a ring-enhancing hypodense (CT) or hypoechoic (US) lesion. Visceral involvement with multiple abscesses appeared in the spleen (n = 2), liver (n = 1) and bones (n = 1). All lesions regressed following appropriate anti-tuberculosis treatment. BCG infection needs to be considered in children with typical findings and with suspected primary immunodeficiency.


New score indicating placental vascular resistance.
Umbilical artery Doppler velocimetry is a routine method for fetal surveillance in high-risk pregnancy. Uterine artery Doppler seems to give comparable information, but it can be difficult to interpret as there are two arteries, which might show notching and/or increased pulsatility index (PI) as signs of increased vascular impedance. Combining the information on vascular resistance on both sides in a new score might simplify and improve evaluation of placental circulation. Uterine and umbilical artery Doppler velocimetry was evaluated in 633 high-risk pregnancies. The managing clinician was informed only about the umbilical artery flow. The umbilical artery flow spectrum was semiquantitatively divided into four blood flow classes (BFC), expressing signs of increasing vascular resistance. The uterine artery Doppler flow spectrum was divided into five uterine artery scores (UAS), taking into account presence/absence of notching and/or increase in PI. By adding UAS to BFC, a new placental score (PLS) was constructed with values ranging from 0 to 7, indicating general placental vascular resistance. The scores were related to three outcome variables: small-for-gestational age (SGA), premature delivery (<37 weeks), and cesarean section. All three score systems showed a significant relationship between signs of increasing vascular resistance and outcome. The new PLS showed the best association to adverse outcomes, with optimal cut-off at values exceeding score 3. Doppler velocimetry on both sides of the placenta showed a strong relationship to an adverse outcome of pregnancy. The new PLS showed a better relationship to adverse perinatal outcome than the BFC and the UAS. The PLS can simplify evaluation of uteroplacental and fetoplacental Doppler velocimetry.


[Posterior tibial tendon dysfunction: what other structures are involved in the development of acquired adult flat foot?].
To evaluate the association of posterior tibial tendon dysfunction and lesions of diverse ankle structures diagnosed at MRI with radiologic signs of flat foot. We retrospectively compared 29 patients that had posterior tibial tendon dysfunction (all 29 studied with MRI and 21 also studied with weight-bearing plain-film X-rays) with a control group of 28 patients randomly selected from among all patients who underwent MRI and weight-bearing plain-film X-rays for other ankle problems. In the MRI studies, we analyzed whether a calcaneal spur, talar beak, plantar fasciitis, calcaneal bone edema, Achilles' tendinopathy, spring ligament injury, tarsal sinus disease, and tarsal coalition were present. In the weight-bearing plain-film X-rays, we analyzed the angle of Costa-Bertani and radiologic signs of flat foot. To analyze the differences between groups, we used Fisher's exact test for the MRI findings and for the presence of flat foot and analysis of variance for the angle of Costa-Bertani. Calcaneal spurs, talar beaks, tarsal sinus disease, and spring ligament injury were significantly more common in the group with posterior tibial tendon dysfunction (P<.05). Radiologic signs of flat foot and anomalous values for the angle of Costa-Bertani were also significantly more common in the group with posterior tibial tendon dysfunction (P<.001). We corroborate the association between posterior tibial tendon dysfunction and lesions to the structures analyzed and radiologic signs of flat foot. Knowledge of this association can be useful in reaching an accurate diagnosis.


A high-resolution staining method for examination of mammalian cell surfaces in the light microscope.
A simple light-microscopic method for the examination of fine details on cell surfaces is described. When cell specimens on platinum-coated glass or plastic surfaces are stained with 3,3'-diaminobenzidine tetrahydrochloride and hydrogen peroxide, fine cytoplasmic processes that cannot be detected using conventional staining techniques for the light microscope are revealed. It is suggested the new technique be applied instead of the scanning electron microscope when the limited resolution of the light microscope is sufficient.


Computerized Cytomorphometric and Cytomorphological Analysis of Canine Transmissible Venereal Tumours.
Canine transmissible venereal tumour (CTVT) has three cytomorphological types: plasmacytic, lymphocytic and mixed type. Cytomorphometry, a method of computerized image analysis, has been used recently in veterinary medicine. This study compared the nuclear and cellular morphometric parameters (i.e. radius, diameter, perimeter and area) in different types of CTVT with other canine round cell tumours including lymphoma, mast cell tumour (MCT) and histiocytic tumour (HCT). We also evaluated the relationship between clinical information and the different CTVT cytomorphologic types. CTVT cells from 44 dogs revealed that the measured parameters were significantly different between different round cell tumours and among the CTVT cytomorphological types. CTVT had the largest cells, followed by HCTs, MCTs and lymphomas. The mixed type of CTVT had the largest nuclear and cellular size, followed by the plasmacytic and lymphocytic types. Lymphocytic CTVTs had less aggressive biological behaviour than the other types. Mixed type CTVTs were more likely to show malignant behaviour including metastasis and resistance to chemotherapy; however, there was no significant correlation between cytomorphological type of CTVT and response to chemotherapy.


The effect of shear forces externally applied to skin surface on underlying tissues.
The effects of shear forces externally applied to the skin surface on the underlying tissues have been investigated. An analysis of the internal stresses and strains was conducted using a simplified model incorporating elasticity theory. Skin blood flow was measured using laser Doppler flowmetry while variable shear forces over a range of 0-250 g were applied to the skin surface. The theoretical model predicts that the application of surface shear forces alters the internal stress distribution and makes the shear and compressive components of stresses increase ahead of the surface force application point. The force resulting from concomitant application of shear and normal force determines the internal maximum stress and strain. Theoretically, the shear force should have the same effects on the underlying tissues as normal force. The experimental investigations revealed that the skin blood flow decreased roughly linearly with the increase of shear forces. When a shear force equal to the normal force was applied, the flux decreased by 45%, nearly equal to the increasing magnitude (41%) of resultant of normal and shear forces.


Relationship between lipoprotein(a) levels, oxidative stress, and blood pressure levels in patients with essential hypertension.
High plasma levels of lipoprotein(a) [Lp(a)] are considered a risk factor for the development of coronary artery disease. In vitro experiments have shown that oxidized Lp(a) is able to impair the arterial endothelium-dependent dilation, thus suggesting a possible role of Lp(a) in the genesis of essential hypertension. The aim of our work was to investigate the correlation of blood pressure levels with plasma Lp(a) concentration, apo(a) isoform size, and peroxidative stress in patients with essential hypertension. The study was performed in 54 untreated hypertensive patients whose blood pressure was monitored for 24 h by ambulatory blood pressure monitoring. Lp(a) concentration was measured by a double monoclonal antibody-based enzyme immunoassay demonstrated to be insensitive to apo(a) size heterogeneity. Apo(a) isoforms were determined by a high-resolution SDS-agarose gel electrophoresis followed by immunoblotting. A significant correlation was found between Lp(a) levels and the night-time systolic and diastolic pressures (r=0.32, P<0.05 and r=0.30, P<0.05, respectively), as well as with the mean night-time fall in systolic and diastolic blood pressures (r=-0.28, P<0.05 and r=-0.29, P<0.05, respectively). These relationships were further potentiated when peroxidative stress data were taken into consideration (r=0.37 and r=0.40, P<0.01 for the night-time systolic and diastolic pressures, respectively and r=-0.34 and r=-0.38, P<0.01 for the night-time fall in systolic and diastolic blood pressures, respectively). Apo(a) isoform size did not affect these relationships. Our data suggest that Lp(a) and peroxidative stress may be involved as cofactors in essential hypertension, with a mechanism that remains to be elucidated.


GTP-binding protein-independent potentiation by mastoparan of IL-1beta-induced nitric oxide release from insulin-secreting HIT-T15 cells.
Our recent data implicated small molecular weight G-proteins (e.g., H-Ras) in interleukin 1beta (IL 1beta)-induced metabolic dysfunction and apoptotic demise of the islet beta cell (Tannous et al., Biochem Pharmacol 2001; 62:1459-1468, Kowluru and Morgan, Biochem Pharmacol, 2002; 63:1027-1035, Chen et al. Biochem Pharmacol, 2003; 66:1681-1694). Recently, we have shown that mastoparan, a tetradecapeptide from wasp venom, has been shown to directly activate islet endogenous G-proteins and regulate islet function (Amin et al., Endocrinology 2003; 144: 4508-4518). Herein, we investigated potential contributory roles, if any, of mastoparan (Mas)-sensitive G-proteins in IL-induced nitric oxide (NO) release from insulin-secreting HIT-T15 cells. While, ineffective by itself, Mas significantly potentiated IL-induced NO release from HIT-T15 cells. Interestingly, Mas-17, an inactive analog of Mas, also potentiated IL-induced NO release, suggesting that the potentiating effect of Mas may not involve activation of specific G-proteins. Such potentiating effects on IL-induced NO release were also demonstrable in the presence of another polycationic compound, melittin. Together, these findings suggest that Mas-induced potentiation of IL-induced NO release may in part be due to its amphiphilic and polycationic nature. These data also warrant caution in the use of Mas to study its regulation of cellular function without the use of an appropriate negative control, such as Mas-17.


Nicaraven inhibits TNFα-induced endothelial activation and inflammation through suppression of NF-κB signaling pathway.
Inflammation-induced activation and dysfunction of endothelial cells play an important role in the pathology of multiple vascular diseases. Nicaraven, a potent hydroxyl radical scavenger, has recently been found to have anti-inflammatory roles; however, the mechanism of its action is not fully understood. Here we investigated the effects of Nicaraven on tumor necrosis factor α (TNFα) - induced inflammatory response in human umbilical vein endothelial cells and we explore the underlying mechanisms related to the nuclear factor-κB (NF-κB) signaling pathway. Our results showed that Nicaraven significantly reduced the reactive oxygen species production after TNFα stimulation. Nicaraven suppressed TNFα-induced mRNA expression of multiple adhesion molecules and pro-inflammatory cytokines, including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E-selectin, MCP-1, TNFα, interleukin-1β (IL-1β), IL-6, and IL-8. In addition, Nicaraven inhibited monocyte adhesion and reduced the protein levels of VCAM-1 and ICAM-1. Mechanistically, Nicaraven prevented TNFα-induced activation of NF-κB signaling pathway by suppressing the phosphorylation of NF-κB p65, IκBα, and IκB kinase (IKK)α/β, stabilizing IκBα, and inhibiting the translocation of p65 from cytosol to nucleus. Finally, we showed that Nicaraven improved the functions of endothelial cells, seen as the upregulation of endothelial nitric oxide synthase and increased nitric oxide levels. Our findings indicated that Nicaraven effectively inhibits TNFα-induced endothelial activation and inflammatory response at least partly through inhibiting NF-κB signaling pathway.


Local field potential (LFP) power and phase-amplitude coupling (PAC) changes in the striatum and motor cortex reflect neural mechanisms associated with bradykinesia and rigidity during D2R suppression in an animal model.
Impairments in motor control are the primary feature of Parkinson's disease, which is caused by dopaminergic imbalance in the basal ganglia. Identification of neural biomarkers of dopamine D2 receptor (D2R) suppression would be useful for monitoring the progress of neuropathologies and effects of treatment. Male Swiss albino ICR mice were deeply anesthetized, and electrodes were implanted in the striatum and motor cortex to record local field potential (LFP). Haloperidol (HAL), a D2R antagonist, was administered to induce decreased D2R activity. Following HAL treatment, the mice showed significantly decreased movement velocity in open field test, increased latency to descend in a bar test, and decreased latency to fall in a rotarod test. LFP signals during HAL-induced immobility (open field test) and catalepsy (bar test) were analyzed. Striatal low-gamma (30.3-44.9 Hz) power decreased during immobility periods, but during catalepsy, delta power (1-4 Hz) increased, beta1(13.6-18 Hz) and low-gamma powers decreased, and high-gamma (60.5-95.7 Hz) power increased. Striatal delta-high-gamma phase-amplitude coupling (PAC) was significantly increased during catalepsy but not immobility. In the motor cortex, during HAL-induced immobility, beta1 power significantly increased and low-gamma power decreased, but during HAL-induced catalepsy, low-gamma and beta1 powers decreased and high-gamma power increased. Delta-high-gamma PAC in the motor cortex significantly increased during catalepsy but not during immobility. Altogether, the present study demonstrated changes in delta, beta1 and gamma powers and delta-high-gamma PAC in the striatum and motor cortex in association with D2R suppression. In particular, delta power in the striatum and delta-high-gamma PAC in the striatum and motor cortex appear to represent biomarkers of neural mechanisms associated with bradykinesia and rigidity.


Outcomes of breast conserving therapy: Recurrence, imaging findings and histological correlation.
Breast conserving therapy (BCT) is the mainstay therapy in patients with early breast cancer and selected patients with locally advanced breast cancer. No formal audit has been performed on BCT at our institution. To determine the incidence and risk factors for ipsilateral breast tumour recurrence (IBTR). Study the imaging features of IBTR. Determine adherence to the proposed annual mammographic surveillance schedule. Clinical, radiological and histopathological records of patients who underwent BCT from 01 January 2011 to 31 December 2015 were reviewed. Patients were followed up for at least 5 years. Ninety-two patients were included in the study with a mean age of 54.3 years. Eighty of the 92 (87.0%) patients were imaged within 1-year post-BCT. Ipsilateral breast tumour recurrence was 6/92 (6.5%) with mean time to IBTR of 34.4 months. One of the 92 (1.0%) patients had a contralateral metachronous recurrence with no IBTR and 11/92 (12.0%) had distant metastases only. Pathological tumour size and extent (pT2) (68.5%) and pathological lymph node (pN0) (65.2%) were the most common locoregional staging. Infiltrating ductal carcinoma was the most common histological type (88%). Age < 35 years was associated with breast cancer recurrence (p < 0.01). Imaging findings of recurrence were microcalcification (odds ratio [OR]: 4), asymmetric density (OR: 4) and skin thickening (OR: 2.5). The occurrence of IBTR following BCT in our unit is acceptable and comparable to local and international units. The accuracy of assessing the post-BCT breast for IBTR is in keeping with international standards. Improved radiological imaging interpretation of the post-BCT breast.


Modeling mitochondrial protein evolution using structural information.
We present two new models of protein sequence evolution based on structural properties of mitochondrial proteins. We compare these models with others currently used in phylogenetic analyses, investigating their performance over both short and long evolutionary distances. We find that our models that incorporate secondary structure information from mitochondrial proteins are statistically comparable with existing models when studying 13 mitochondrial protein data sets from eutherian mammals. However, our models give a significantly improved description of the evolutionary process when used with 12 mitochondrial proteins from a broader range of organisms including fungi, plants, protists, and bacteria. Our models may thus be of use in estimating mitochondrial protein phylogenies and for the study of processes of mitochondrial protein evolution, in particular for distantly related organisms.


A unique insight for energy metabolism disorders in depression based on chronic unpredictable mild stress rats using stable isotope-resolved metabolomics.
Depression is currently the main disease which endangers human health and emotion. However, the existing antidepressants have the disadvantages of slowly taking effect and high recurrence rate. Numerous studies have shown that depression causes disorders in energy metabolism, but the specific metabolic pathways remain unclear. The stable isotope-resolved metabolomics (SIRM) can clarify the specific metabolic pathways of energy metabolism disorders in depression and provide a strong basis for the pathogenesis of depression and new targets for the development of new antidepressants. We applied this method to the chronic unpredictable mild stress (CUMS) model, and the metabolites related to energy metabolism were comprehensively analyzed on HILIC and T3 columns through LC-MS. Conventional untargeted metabolomics found 50 differential metabolites, and most of them were focused on the energy metabolism pathway. SIRM exhibited that 78 metabolites related to energy metabolism were labeled, and 28 of them were observed significantly changed in the model group compared with control. Our results revealed depression inhibited TCA cycle and activated gluconeogenesis pathway, and abnormally increased pyruvic acid may participate in pyrimidine biosynthesis, phospholipid synthesis, and amino acid metabolism pathways. Pyruvate carboxylase (PC), pyruvate dehydrogenase (PDH), aspartate aminotransferase (AST) and phosphoenolpyruvate carboxykinase (PEPC) may be the new targets for depression. We established a SIRM method at animal level. To the best of our knowledge, it is the first time to apply the method for the study of depression. The method is of great significance and value for further explaining the pathogenesis of depression and the development of antidepressants.


Relationship between wild-caught organisms for bioassays and sampling areas: Widespread serpulid early-development comparison between two distinct populations after trace element exposure.
Previous studies suggested the suitability of the brackish-water serpulid (Ficopomatus enigmaticus) to be used as model organism for both marine and brackish waters monitoring, by the performance of sperm toxicity and larval development assays. The present study focused on larval development after the exposure of two F. enigmaticus populations (Mediterranean and Atlantic, collected in Italy and Portugal, respectively) to different trace elements (copper, mercury, arsenic, cadmium, and lead) at different concentrations. Results of larval development assays were presented as the percentage of abnormal developed larvae. The effect, measured in terms of EC50 for all toxicants tested, showed that mercury was the most toxic metal for larvae of both populations. Specifically, the tested trace elements may be racked in the following order from the highest to the lowest toxicity: Mediterranean: mercury > copper > lead > arsenic > cadmium; Atlantic: mercury > copper > cadmium > arsenic > lead. Responses of both populations were similar for arsenic. Lead was the least toxic element for the Atlantic population, while cadmium showed the least toxicity for the Mediterranean population. These preliminary results demonstrate the sensitivity and suitability of the organisms to be used in ecotoxicological bioassays and monitoring protocols. Moreover, chemical analyses on soft tissues and calcareous tubes of collected test organisms and their sampling site water were performed, to identify and quantify the concentration of the tested trace elements in these 3 matrices. Populations exhibited less sensitivity to a certain element together with a relevantly higher concentration of the same element in soft tissues. This may indicate a certain resistance to particular contaminant toxic effects by organisms that tend to accumulate the same toxicant. This highlights the potential correlation between wild-caught test organisms' responses and a deep characterization of the sampling site to identify putative abnormalities or differences in model organism response during bioassay execution.


[Effect of colchicine on the morphogenesis and ultrastruct of Acetabularia mediterranea].
The effect of colchicine on morphogenesis of the regenerating nuclear fragments of Acetabularia mediterranea has been studied. Colchicine was shown to inhibit the formation of caps. The algae are most sensitive to colchicine at the early stages of regeneration. The breakdown of microtubules in the perinuclear cytoplasm of regenerating algae under the effect of colchicine was found under the electron microscopy. The breakdown of microtubules in this zone appears not to disturb the transport of morphogenetical substances in the apical cell part. Colchicine inhibits the morphogenesis, apparently, at the expense of protein inactivation in the zone of growth.


Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries.
A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.


Safe implementation of laparoscopic gastrectomy in a community-based general surgery practice.
This study reviewed a 3-year experience with the implementation of laparoscopic gastrectomy at a community hospital. A retrospective chart review identified all patients that underwent laparoscopic gastrectomy between January 2004 and March 2007. Patient demographics, tumor characteristics, length of stay, operative time, and short-term outcomes (postoperative complications and death) were examined. A total of 49 patients were identified; 25 (51%) were male. Median age was 68 years (range 31-90 years). Thirty-five (71%) and seven (14%) patients presented with adenocarcinoma and gastrointestinal stromal tumor (GIST), respectively. Median operative time was 169 min (range 23-387 min). Conversion to open laparotomy was necessary in six cases (12%). Median length of stay was 5 days (range 0-48 days). There were four (8.2%) postoperative deaths, and eight major complications, which included: myocardial infarction, pulmonary embolism, duodenal stump leak, bleeding, dehiscence, anastomotic leak, and obstruction. Of patients undergoing laparoscopic gastrectomy with curative intent, 36/38 (95%) underwent R0 resection. Median number of lymph nodes that were pathologically evaluated was 11 (range 1-27). To our knowledge, this is the first study to report on the implementation of laparoscopic gastrectomy in a community hospital setting. Laparoscopic gastrectomy can be performed safely in a community hospital setting with operative times and length of stay that are comparable to open cases. Our short-term outcomes are comparable with existing studies from academic/university centers.


Clinical study on correlation with the 60-min plasma phenolsulfonphthalein concentration and other renal function tests.
An analysis of the reliability of the 60-min plasma phenosulfonphthalein concentration (PSP60) as a renal function test has been made in 40 patients with or without urinary dead space. PSP60 correlates with 15-min urinary PSP excretion and 24-hour endogenous creatinine clearance in patients without urinary dead space. 15-min urinary PSP excretion showed unreliability as a renal function test in patients with urinary dead space. However, we confirmed that PSP60 and 24-hour endogenous creatinine clearance were reliable indicators of renal function in these patients.


3-D localization of non-radioactive strontium in osteoarthritic bone: Role in the dynamic labeling of bone pathological changes.
The study objective was to visualize regions of bone that undergo pathological mineralization and/or remodeling during pathogenesis of osteoarthritis, by employing non-radioactive strontium as a dynamic tracer of bone turnover. Post traumatic osteoarthritis was surgically induced in skeletally mature rats, followed by in vivo micro-CT imaging for 12 weeks to assess bone micro-structural changes. Rats either received strontium ranelate daily for the entire course of study or only last 10 days before euthanization. Distribution of strontium in bone was assessed in two and three dimensions, using electron probe micro-analysis (EPMA) and synchrotron dual energy K-edge subtraction micro-CT (SRμCT), respectively. Considerable early formation of osteophytes around the collateral ligament attachments and margins of articulating surfaces were observed, followed by subchondral sclerosis at the later stages. Accordingly, strontium was heavily incorporated by mineralizing osteophytes at 4, 8, and 12 weeks post-surgery, whereas subchondral bone only incorporated strontium between weeks 8-12.This study showed low dose stable strontium can effectively serve as a dynamic tracer of bone turnover to study pathological bone micro-structural changes, at resolution higher than nuclear medicine. Co-administration of strontium during therapeutic drug intervention may show enormous utility in assessing the efficacy of those compounds upon adaptive bone physiology.


Reliability of clinician rated physical effort determination during functional capacity evaluation in patients with chronic musculoskeletal pain.
Functional capacity evaluation (FCE) can be used to make clinical decisions regarding fitness-for-work. During FCE the evaluator attempts to assess the amount of physical effort of the patient. The aim of this study is to analyze the reliability of physical effort determination using observational criteria during FCE. Twenty-one raters assessed physical effort in 18 video-recorded FCE tests independently on two occasions, 10 months apart. Physical effort was rated on a categorical four-point physical effort determination scale (PED) based on the Isernhagen criteria, and a dichotomous submaximal effort determination scale (SED). Cohen's Kappa, squared weighted Kappa and % agreement were calculated. Kappa values for intra-rater reliability of PED and SED for all FCE tests were 0.49 and 0.68 respectively. Kappa values for inter-rater reliability of PED for all FCE tests in the first and the second session were 0.51, and 0.72, and for SED Kappa values were 0.68 and 0.77 respectively. The inter-rater reliability of PED ranged from κ = 0.02 to κ = 0.99 between FCE tests. Acceptable reliability scores (κ > 0.60, agreement ≥80 %) for each FCE test were observed in 38 % of scores for PED and 67 % for SED. On average material handling tests had a higher reliability than postural tolerance and ambulatory tests. Dichotomous ratings of submaximal effort are more reliable than categorical criteria to determine physical effort in FCE tests. Regular education and training may improve the reliability of observational criteria for effort determination.


Immunogenetic study on the polymorphism of serum alpha 2-lipoprotein in mink. III. Ld1 allotype of low-density lipoprotein.
Mink Ldl antigen of serum low-density lipoprotein was demonstrated by alloantibodies. No genetic relation was found between Ldl and the Lpm system of very-high-density lipoprotein. The existence of an autosomal dominant gene, coding for the new alloantigenic marker, is postulated on the basis of mink breeding data.


Heavy metals produce toxicity, oxidative stress and apoptosis in the marine teleost fish SAF-1 cell line.
The use of cell lines to test the toxicity of aquatic pollutants is a valuable alternative to fish bioassays. In this study, fibroblast SAF-1 cells from the marine gilthead seabream (Sparus aurata L.) were exposed for 24 h to the heavy metals Cd, Hg, MeHg (Methylmercury), As or Pb and the resulting cytotoxicity was assessed. Neutral red (NR), MTT-tetrazolio (MTT), crystal violet (CV) and lactate dehydrogenase (LDH) viability tests showed that SAF-1 cells exposed to the above heavy metals produced a dose-dependent reduction in the number of viable cells. Methylmercury showed the highest toxicity (EC50 = 0.01 mM) followed by As, Cd, Hg and Pb. NR was the most sensitive method followed by MTT, CV and LDH. SAF-1 cells incubated with each of the heavy metals also exhibited an increase in the production of reactive oxygen species and apoptosis cell death. Moreover, the corresponding gene expression profiles pointed to the induction of the metallothionein protective system, cellular and oxidative stress and apoptosis after heavy metal exposure for 24 h. This report describes and compares tools for evaluating the potential effects of marine contamination using the SAF-1 cell line.


Selection of DNA aptamers that bind to four organophosphorus pesticides.
Single-stranded DNA (ssDNA) aptamers against four organophosphorus pesticides (phorate, profenofos, isocarbophos and omethoate) were simultaneously isolated from an immobilized random ssDNA library by systematic evolution of ligands by exponential enrichment (SELEX) technique. After 12 rounds of in vitro selection, five ssDNA aptamer candidates were selected and their binding affinities were identified by a novel method using a molecular beacon. Two of the five ssDNA sequences, SS2-55 and SS4-54, demonstrated higher affinities and specificities to the four organophosphorus pesticides. They were defined as broad-spectrum aptamers binding to four different targets and their simulated secondary structures showed highly distinct features with typical stem and loop structures. The dissociation constant of SS2-55 and SS4-54 binding to the four organophosphorus pesticides ranged from 0.8 to 2.5 μM. These aptamers offered application potential in the analysis and/or neutralization of the residues of the four organophosphorus pesticides.


Presence of tracheal bronchus in children undergoing flexible bronchoscopy.
Tracheal bronchus (TB) is a rare congenital malformation of the lung tree with a bronchus originating from the trachea. Only a small number of publications have analyzed the frequency and diagnostic procedure of TB in children, based on a restricted sample of patients. In the present study, we analyze and discuss new aspects of prevalence, clinical presentation and associated malformations of TB based on a large pediatric cohort. Data from 5970 children having a flexible bronchoscopy for investigation of respiratory symptoms were selected. We analyzed the anaesthesic management, the presence of associated malformations, and all tracheobronchial anomalies observed during the endoscopic procedure. Fifty-seven cases of tracheal bronchus were identified (0.9%). In the majority of them, tracheal bronchus was a fortuitous discovery without clear clinical relevance. Statistical analysis revealed that the majority of TB originated from the middle and lower one third of the trachea (56%). 61.5% of patients had associated anomalies such as syndromic association (21%), cardiac malformations (19.2%) or tracheal stenosis (14%). Only 38.5% of children had no associated anomalies. Tracheal bronchus is a rare morphological anomaly of the tracheobronchial tree. Most often TB is associated with other birth defects such as another tracheo-bronchial tree malformation, vascular abnormality, congenital heart malformation or in the context of a syndromic pattern. A relationship between respiratory symptoms and the presence of TB is very rare and selective treatment is infrequent.


Neural differentiation increases expression of Alzheimer amyloid protein precursor gene in murine embryonal carcinoma cells.
Neural differentiation of the embryonal carcinoma P19 cell line markedly increased the abundance of mRNA encoding Alzheimer amyloid beta/A4-protein precursor (APP). In P19 cells treated with retinoic acid, the abundance of mRNA encoding APP695, which lacks the protease inhibitor domain, reached a maximum on days 2-4 and decreased thereafter, whereas the abundances of mRNAs encoding APP751 and APP770, both possessing the protease inhibitor domain, slowly increased to reach higher levels than APP695 mRNA at later stages of neural differentiation. The induction of APP695 mRNA was consistent with the appearance of neurons in the P19 cultures. A high abundance of APP695 mRNA was also detected in mouse brain at a stage of the period of neuroblast formation. Thus, neural differentiation of P19 cells may present a suitable model for studying the regulation of APP gene expression during early differentiation of brain cells in vivo.


The impact of Levilactobacillus brevis YSJ3 and Lactiplantibacillus plantarum JLSC2-6 co-culture on gamma-aminobutyric acid yield, volatile and non-volatile metabolites, antioxidant activity, and bacterial community in fermented cauliflower byproducts.
Co-culture fermentation is a novel technology for enhancing fermentation quality and promoting gamma-aminobutyric acid (GABA) yield. The purpose of this study was to evaluate the effects of Levilactobacillus brevis YSJ3 and Lactiplantibacillus plantarum JLSC2-6 co-culture on GABA yield, volatile and non-volatile metabolite profiles, and antioxidant activity in cauliflower byproducts. It was found that co-culture had the highest GABA yield (35.00 ± 1.15 mg/L) in fermented cauliflower stems. In total, 111 and 1264 volatile and non-volatile metabolites, respectively, were identified, of which 59 metabolites were significantly upregulated after co-culture fermentation. The results showed that 24 key upregulated metabolites were positively associated with hydroxyl radical-scavenging activity. Notably, Levilactobacills were positively correlated with the yield of GABA and key upregulated metabolites. Thus, these results suggest that Levilactobacillus brevis and Lactiplantibacillus plantarum can improve in key metabolites, GABA yield, and antioxidant activity following co-culture. This study provide a theoretical basis for developing GABA-rich cauliflower byproducts.


[Drug interactions in dermatological systemic treatment].
Severe pharmacological side effects have an occurrence of 5-7% and represent a frequent reason for hospital admission. The prevalence of undesired pharmacological side effects during hospitalization is even higher with approximately 11.5%. The causes are often interactions between drugs due to the polypharmacy of multimorbid older patients. On average, a 65-year-old male patient will simultaneously be taking 5 medications. Due to the increasing use of systemic drugs in dermatology and the simultaneously increasing polypharmacy, knowledge of interactions between medications is essential for dermatologists in order to avoid severe side effects of drugs. This article provides assistance in order to identify patients and medications with a high risk for severe interactions and, therefore, to avoid the occurrence of undesired effects or the reduction of the therapeutic effects of active substances. We would like to point out that this article deals with individual aspects and does not mean that the testing of individual drug interactions with interaction programs can be omitted. It should also not be neglected that in addition to prescription-only drugs, foodstuffs, dietary supplements and herbs can also lead to interactions with medications.


Yeast/E. coli shuttle vectors with multiple unique restriction sites.
Two yeast/E. coli shuttle vectors have been constructed. The two vectors, YEp351 and YEp352, have the following properties: (1) they can replicate autonomously in Saccharomyces cerevisiae and in E. coli; (2) they contain the beta-lactamase gene and confer ampicillin resistance to E. coli; (3) they contain the entire sequence of pUC18; (4) all ten restriction sites of the multiple cloning region of pUC18 including EcoRI, SacI, KpnI, SmaI, BamHI, XbaI, SalI, PstI, SphI and HindIII are unique in YEp352; these sites are also unique in YEp351 except for EcoRI and KpnI, which occur twice; (5) recombinant plasmids with DNA inserts in the multiple cloning region of YEp351 and YEp352 can be recognised by loss of beta-galactosidase function in appropriate E. coli hosts; (6) YEp351 and YEp352 contain the yeast LEU2 and URA3 genes, respectively, allowing for selection of these auxotrophic markers in yeast and E. coli; (7) both plasmids are retained with high frequency in yeast grown under non-selective conditions indicative of high plasmid copy number. The above properties make the shuttle vectors suitable for construction of yeast genomic libraries and for cloning of DNA fragments defined by a large number of different restriction sites. The two vectors have been further modified by deletion of the sequences necessary for autonomous replication in yeast. The derivative plasmids YIp351 and YIp352 can therefore be used to integrate specific sequences into yeast chromosomal DNA.


Differences in developmental changes in GABAergic response between bushy and stellate cells in the rat anteroventral cochlear nucleus.
Many mammalian central nervous system neuron responses mediated by GABA(A) receptors undergo a developmental transition from excitation to inhibition, but little is known about the time of this switch in specific cell types in the developing anteroventral cochlear nucleus (AVCN). In the present study, bushy and stellate cells, two major cell types in the AVCN, were identified according to their morphology and electrophysiology. The equilibrium potential of GABA-evoked currents (E(GABA)) was examined using the gramicidin-perforated patch-clamp technique. We found that the action of GABA in bushy and stellate cells switched from predominantly depolarizing to predominantly hyperpolarizing with respect to their resting membrane potential (V(rest)) at different postnatal ages. Such a switch in the GABA response of bushy cells occurred before the first postnatal week, whereas that in stellate cells happened at the end of the second postnatal week. Furthermore, we discovered that bushy cells had a more depolarized V(rest) than did stellate cells before the second postnatal week; however, the E(GABA) of bushy and stellate cells was not significantly different. Thus, the discrepancy in the timing of the developmental shift from depolarizing to hyperpolarizing GABA responses between bushy and stellate cells may be due to the difference in their V(rest), but not due to E(GABA) itself. These results suggest that GABAergic inhibition functions earlier in bushy than in stellate cells. In contrast, the longer excitatory action of GABA on stellate cells possibly renders them more vulnerable than bushy cells to excitotoxic substances during early development.


Number, activation, and differentiation of circulating fibrocytes correlate with asthma severity.
A biomarker that predicts poor asthma control would be clinically useful. Fibrocytes are bone marrow-derived circulating progenitor cells that have been implicated in tissue fibrosis and T(H)2 responses in asthmatic patients. We sought to test the hypothesis that the concentration and activation state of peripheral blood fibrocytes correlates with asthma severity. By using fluorescence-activated cell sorting analysis, fibrocytes (CD45(+) and collagen 1 [Col1](+)) were enumerated and characterized in the buffy coats of fresh peripheral blood samples from 15 control subjects and 40 asthmatic patients. Concentrations of peripheral blood total (CD45(+)Col1(+)), activated (the TGF-β transducing protein phosphorylated SMAD2/3 [p-SMAD2/3](+) or phosphorylated AKT [p-AKT](+)), and differentiated (α-smooth muscle actin [α-SMA](+)) fibrocytes were increased in asthmatic patients compared with control subjects. The increase in total and CD45(+)Col1(+)CXCR4(+) fibrocytes was primarily seen in patients with severe asthma (Global Initiative for Asthma steps 4-5) as opposed to those with milder asthma (Global Initiative for Asthma steps 1-3). In addition, numbers of circulating α-SMA(+) and α-SMA(+)CXCR4(+) fibrocytes were increased in asthmatic patients experiencing an asthma exacerbation in the preceding 12 months. A significant correlation (P < .05) was observed between CD45(+)Col1(+)CXCR4(+) fibrocytes and the activation phenotypes CD45(+)Col1(+)p-SMAD2/3(+) and CD45(+)Col1(+)p-AKT(+). There was correlation between circulating fibrocyte subsets and asthma severity, and there was an increased number of activated/differentiated fibrocytes in circulating blood of asthmatic patients experiencing an exacerbation in the preceding 12 months.


Transcriptional reprogramming of infiltrating neutrophils drives lung pathology in severe COVID-19 despite low viral load.
Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths confined to Black/African American (AA) patients in some areas. However, targeted studies on this vulnerable population are scarce. Here, we applied multiomics single-cell analyses of immune profiles from matching airways and blood samples of Black/AA patients during acute SARS-CoV-2 infection. Transcriptional reprogramming of infiltrating IFITM2+/S100A12+ mature neutrophils, likely recruited via the IL-8/CXCR2 axis, leads to persistent and self-sustaining pulmonary neutrophilia with advanced features of acute respiratory distress syndrome (ARDS) despite low viral load in the airways. In addition, exacerbated neutrophil production of IL-8, IL-1β, IL-6, and CCL3/4, along with elevated levels of neutrophil elastase and myeloperoxidase, were the hallmarks of transcriptionally active and pathogenic airway neutrophilia. Although our analysis was limited to Black/AA patients and was not designed as a comparative study across different ethnicities, we present an unprecedented in-depth analysis of the immunopathology that leads to acute respiratory distress syndrome in a well-defined patient population disproportionally affected by severe COVID-19.


The finite dose technique as a valid in vitro model for the study of percutaneous absorption in man.
An in vitro model of percutaneous absorption has been developed which permits close stimulation of conditions commonly associated with topical drug use in living man. Quantitative comparison of the absorption of selected compounds in the model and in living man was made to test the validity of the model. Excellent agreement has been found between the two sets of data, both with respect to the total amount absorbed and the kinetics of absorption.


Intrapleural endodermal sinus tumor arising from the diaphragm.
We report a primary endodermal sinus tumor (EST) of the right hemidiaphragm, presenting as a right-sided hemothorax in an 18-month-old female. Four operations were performed, the last three being indicated solely by an elevated level of serum alpha-fetoprotein (AFP). Cyclic chemotherapy with varying drug combinations together with irradiation therapy were not effective in controlling the disease. To our knowledge, this is the first instance of a primary EST arising from the diaphragm.


Two-stage posterior spinal fusion for early-onset scoliosis: Two case reports.
Fusionless techniques for early-onset scoliosis (EOS) have evolved to allow near-normal growth while maintaining the correction achieved during the initial surgery. However, such procedures require repeated surgeries and have increased complication rates. We have developed a 2-stage fusion technique using pedicle screws for EOS to reduce patient burden and complication risk. This series describes the clinical and radiological features of 2 patients with EOS who received 2-stage posterior spinal fusion. This surgical method for EOS represents the first of its kind. Case 1 was a 10-year-old girl who was diagnosed as having scoliosis with Prader Willi syndrome at the age of 2 years. Her preoperative major curve Cobb angle was 100 degrees at age 10 years. Case 2 was an 11-year-old boy who was found to have scoliosis with 22q11.2 deletion syndrome at the age of 4 years. His preoperative major curve Cobb angle was 77 degrees at age 11 years. Whole-spine radiographs were performed to diagnose scoliosis. Both patients received 2-stage posterior spinal fusion. Postoperative Cobb angle of the major curve improved to 46 and 48 degrees, respectively. Thoracic height respectively improved from 160 and 148 mm before surgery to 206 and 211 mm at final follow-up. Surgical outcome as evaluated by Scoliosis Research Society-22 patient questionnaires revealed acceptable results without any severe complications. Based on the present case report, 2-stage posterior spinal fusion for EOS achieves good radiological and clinical outcomes without severe complications.


Accommodative and pupillary responses to sinusoidal target depth movement.
We evaluated the accommodative and pupillary responses to sinusoidal target depth movement in 10 normal subjects and one patient by analysing frequency responses and associated Bode plots. The phase of the pupillary response significantly lagged behind that of accommodative response, which suggests that they are controlled by separate central nervous systems. We measured the baseline shift of each response trace using a regression line and found that they were larger at higher stimulation frequencies. A patient with severe asthenopia showed a considerable baseline shift in accommodative response. These analyses may be useful for the quantitative assessment of dynamic accommodation and pupillary response.


The blockage of the Nogo/NgR signal pathway in microglia alleviates the formation of Aβ plaques and tau phosphorylation in APP/PS1 transgenic mice.
Alzheimer's disease (AD) is characterized by extracellular β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and microglia-dominated neuroinflammation. The Nogo/NgR signal pathway is involved in AD pathological features, but the detailed mechanism needs further investigation. Our previous studies have confirmed that the activation of NgR on microglia by Nogo promotes the expression of proinflammatory cytokines and inhibits cell adhesion and migration behaviors. In the present study, we investigated the effects of Nogo/NgR signaling pathway on the pathological features of AD and possible mechanisms. After NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in amyloid precursor protein (APP)/PS1 transgenic mice, plaque load, tau phosphorylation, and inflammatory responses were determined. After primary mouse neurons were exposed to the conditioned medium from BV-2 microglia stimulated by Nogo, the production of Aβ and phosphorylation of tau was quantified by ELISA and western blot. Inhibition of the Nogo/NgR signaling pathway ameliorated pathological features including amyloid plaques and phosphorylated levels of tau in APP/PS1 mice. In addition, after treatment with the conditioned medium from BV-2 microglia stimulated by Nogo, Aβ production and tau phosphorylation in cultured neurons were increased. The conditioned medium also increased the expression of APP, its amyloidogenic processing, and the activity of GSK3β in neurons. The conditioned medium was also proinflammatory medium, and the blockage of the Nogo/NgR pathway improved the neuroinflammatory environment in APP/PS1 mice. Taken together, the neuroinflammation mediated by Nogo/NgR pathway in microglia could directly take part in the pathological process of AD by influencing the amyloidogenesis and tau phosphorylation. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying the progression of AD.


An integrated view of quantitative trait variation using tomato interspecific introgression lines.
Resolving natural phenotypic variation into genetic and molecular components is a major objective in biology. Over the past decade, tomato interspecific introgression lines (ILs), each carrying a single 'exotic' chromosome segment from a wild species, have exposed thousands of quantitative trait loci (QTL) affecting plant adaptation, morphology, yield, metabolism, and gene expression. QTL for fruit size and sugar composition were isolated by map-based cloning, while others were successfully implemented in marker-assisted breeding programs. More recently, integrating the multitude of IL-QTL into a single database has unraveled some unifying principles about the architecture of complex traits in plants.


Optic nerve coloboma, Dandy-Walker malformation, microglossia, tongue hamartomata, cleft palate and apneic spells: an existing oral-facial-digital syndrome or a new variant?
We report on a female infant with postaxial polydactyly of the hands, preaxial polydactyly of the right foot, cleft palate, microglossia and tongue hamartomata consistent with an oral-facial-digital syndrome (OFDS). The patient also had optic nerve colobomata, a Dandy-Walker malformation, micrognathia and apneic spells. This combination of clinical features has not been previously reported. This patient either expands the clinical features of one of the existing OFDS or represents a new variant. A review of the literature highlights the difficulties in making a specific diagnosis because of the different classification systems that exist in the literature.


Structure-function relationship in hemoproteins: the role of cytochrome c3 in the reduction of colloidal sulfur by sulfate-reducing bacteria.
Cytochromes c3 of different strains of sulfate-reducing bacteria have been purified and tested for their capacity to reduce colloidal sulfur to hydrogen sulfide. The results are in good agreement with the activities reported for the whole cells. Cytochrome c3 is the sulfur reductase of some strains of sulfate-reducing bacteria such as Desulfovibrio desulfuricans Norway 4 and sulfate-reducing bacterium strain 9974 from which the sulfur reductase activity can be purified with the cytochrome c3. In contrast, Desulfovibrio vulgaris Hildenborough cytochrome c3 is inhibited by the product of the reaction namely hydrogen sulfide. Chloramphenicol has no effect on the sulfur reductase activity of D. desulfuricans Norway 4 when resting cells grown on lactate-sulfate medium are put in the presence of colloidal sulfur. This shows that the sulfur reductase activity is constitutive and corresponds to the fact that colloidal sulfur grown cells do not contain more cytochrome c3 (or another sulfur reductase) than lactate-sulfate-grown cells.