Construction and application of service quality evaluation system in the preclinical research on cardiovascular implant devices.
Services for the preclinical development and evaluation of cardiovascular implant devices (CVIDs) is a new industry. However, there is still no indicator system for quality evaluation. Our aim is to construct a service for quality evaluation system for the preclinical research and development of CVIDs based on Fuzzy Analytical Hierarchy Process (FAHP). First, we reviewed the related literature to identify and select possible factors. Second, we developed an analytic hierarchy process framework. Third, we developed a questionnaire based on pairwise comparisons and invited 10 experienced specialists to rate these factors. We then used FAHP to compute the weights of these factors and prioritize them. Finally, to demonstrate the effectiveness of the proposed indicator system, a case study was performed as a practical example. Four main indicators (professionalism, functionality, stability and security) and 15 subindicators were selected to form the service evaluation system based on literature review and expert's proposals. According to the weight calculation data, the order of primary indicators by importance, is professionalism (0.6457), security (0.1193), functionality (0.0958) and stability (0.0596) in sequence. Top five secondary indices are personnel's technical ability, facility and equipment attractiveness, data auditability, confidentiality capability and professional service procedures. In the case study, FW's final actual effectiveness value was 0.9076, which is the same as the actual situation. The indicator system established in this study is comprehensive, reasonable, reliable and with strong practicality. It is worth popularizing and applying. The implementation of this evaluation system can provide measurable evidence for service demander and a way to improve service quality for suppliers.


Impaired vision and hip fracture. The Framingham Study.
Falls affect a large proportion of the elderly and can result in a variety of injuries, including hip fractures. Several studies have suggested that visual impairment contributes to falls, but studies have not used standardized definitions of visual impairment and have not examined injurious falls or fractures. We looked at the risk of hip fracture associated with visual impairment in those members of the Framingham Study Cohort who took part in the Framingham Eye Study in 1973-75. Of 2,633 subjects followed for 10 years after the eye exam, 110 sustained hip fractures. The fracture rates in those with moderately impaired (20/30 to 20/80) vision (8.5%) and poor (20/100 or worse) vision (11.3%) were higher than in those with good (20/25 or better) vision (3.0%). After adjustment for age, sex, weight, alcohol consumption, and (in women) estrogen use, the relative risk of fracture in those with moderate impairment was 1.54 (95% CI = 0.95-2.49), while for those with poor vision, the relative risk was 2.17 (95% CI = 1.24-3.80). Of note, those with moderately impaired vision in one eye and good vision in the other had a higher risk of fracture (relative risk = 1.94) than those with a similar degree of binocular impairment (relative risk = 1.11). Poor vision in one or both eyes was linked to an elevated fracture risk. This suggests that good stereoscopic vision may be necessary to prevent falls. The risk of fracture with poor and moderately impaired vision combined was increased in women (relative risk = 1.96, 95% CI = 1.23-3.11) but not in men (relative risk = 0.79, 95% CI = 0.23-2.72).(ABSTRACT TRUNCATED AT 250 WORDS)


Balance of Autonomic Nervous Activity, Exercise, and Sleep Status in Older Adults: A Review of the Literature.
While older people are frequently known to experience sleep disturbances, there are also many older people who have a good quality of sleep. However, little is known about the balance of autonomic nervous activity, exercise habits, and sleep status in healthy older adults. This study reviews the literature regarding balance of the autonomic nervous activity, exercise, and sleep in healthy older adults. Relevant articles were searched from electronic databases using the combination of the following keywords: "Autonomic nervous activity", "sleep status", "sleep", "healthy older adults", "aging", "heart rate variability (HRV)" and "exercise". Articles were included if they met inclusion criteria: (1) Published in English, (2) Article types: research and review articles, (3) Main outcome was related to the autonomic nervous activity, lifestyle, sleep, and/or healthy aging, and (4) Fully accessed. From 877 articles that were identified, 16 articles were included for review. Results showed that the autonomic nervous activity changes with increasing age, particularly a constant decline in cardiac vagal modulation due to the significant decrease in the nocturnal parasympathetic activity. In addition, the autonomic nervous activity was also related to sleep status and lifestyle, particularly the capability to exercise. In preparing older people toward a healthy aging, maintaining good sleep quality and exercise is suggested.


Gastric tube perforation penetrating the pericardium after esophagectomy that needed surgical repair.
As the prognosis of esophageal cancer surgery has improved, reports on postoperative complications of gastric tubes have increased. Among them, gastric tube ulcer perforation is infrequent but often severe and difficult to treat. A 73-year-old man had undergone thoracoscopic subtotal esophagectomy and laparoscopic-assisted gastric tube reconstruction via the retrosternal route for thoracic esophageal cancer 8 years previously. He was transferred to our hospital with a diagnosis of gastric tube ulcer perforation, penetrating the pericardium. Emergency surgery was performed to remove the gastric tube, followed by immediate reconstruction by right colon interposition. The patient was discharged on postoperative day 142. We report a rare complication of gastric tube ulcer perforation, penetrating the pericardium, after esophagectomy for esophageal cancer. It was successfully treated with appropriate surgical management.


T-cell responses during pig-to-primate xenotransplantation.
Xenotransplantation using porcine organs may resolve a chronic shortage of donor organs for clinical transplantation if significant immunological barriers can be overcome. To determine the potential role of T lymphocytes in Xenograft (Xg) rejection, we transplanted transgenic hCD46 porcine hearts heterotopically into baboon recipients. Recipients were treated to deplete anti-Gal antibody with a non-antigenic alpha-Gal polyethylene glycol polymer (TPC) (n = 2), TPC plus rituximab (anti-CD20) (n = 1) or were untreated (n = 1). None of the recipients received T-cell immunosuppression. All Xgs failed within 7 days and showed evidence of a mixed humoral and cellular rejection process. Cellular infiltration consisting primarily of CD4+ T cells and few CD8+ T cells. Proliferation and cytotoxicity assays showed sensitization of CD4+ and CD8+ T cells that reacted with porcine IFN-gamma (pIFN-gamma)-stimulated porcine aortic endothelial cells (PAEC). The CD4+ lymphocytes displayed greater cytotoxicity than CD8+ cells. An increased frequency of PAEC-specific interleukin (IL) 2 and IFN-gamma-secreting T cells was observed, suggesting a Th1 cytokine bias. An increase in the percentage of circulating CD4+CD28- cells was observed at the time of rejection and over 50% of the CD4+ cells recovered from residual pig tissue at necropsy lacked CD28 expression. These findings show that lymphocytes are efficiently stimulated by PAEC antigens and can mediate direct tissue destruction. These studies (1) provide an insight into the potential of cellular-mediated cardiac Xg rejection, (2) show for the first time the induction of cytotoxic pig-specific CD4+CD28- lymphocytes and (3) provide a rational basis for determining different modes of immunosuppression to treat Xg rejection.


Dose-dependent pharmacokinetics of probenecid in the rat.
The basic pharmacokinetics of probenecid was studied by administration of three different i.v. bolus doses (50, 75, and 100 mg kg-1) to rats. The protein binding of probenecid in pooled rat serum was estimated by equilibrium dialysis. The unbound fraction was found to increase non-linearly with increasing total concentration, yielding a maximum free fraction of 49 per cent. The plasma concentration data obtained were described by a two-compartment model with Michaelis-Menten elimination. The maximal rate of elimination (Vm) remained unchanged between different doses irrespective of whether it was calculated in total or free concentrations (mean 187.2 +/- 8.3 (SD) microgram min-1). The Michaelis-Menten constant (Km) decreased slightly with increasing dose, while the unbound Michaelis-Menten constant (Km,u) did not change between the doses (mean 37.1 +/- 1.3 (SD) microgram ml-1). The volume of distribution of the central compartment (Vc) did not alter when the dose was increased from 50 to 100 mg kg-1 (mean 56.5 +/- 4.3 (SD) ml), but the unbound volume of distribution of the central compartment (Vc,u) decreased from 186.5 +/- 15.6 (SD) to 89.8 +/- 6.9 (SD) ml, which is in accordance with the reduction to be expected for drugs that only distribute in the extracellular fluid.


Costs of syringe vending machines in Tbilisi, Georgia.
Syringe vending machines (SVM) can improve access to sterile injecting equipment, but they have not been widely implemented or evaluated. We evaluate the cost of SVM installed between July 2019-December 2020 in Tbilisi, Georgia. The SVM were stocked with several kit types, including injecting equipment for opioid or stimulant users, naloxone, male and female condoms, and pregnancy tests. We gathered financial data from the project to estimate fixed (staff time, start-up costs, equipment, running costs, and consumables) and variable (harm reduction kits) costs. We calculated the full cost of the SVM intervention, cost per user, cost per additional syringe accessed by SVM users, and cost per kit distributed (2020 Euros). SVM access cards were issued to 1132 users, and 29,238 kits were distributed through SVM, total cost €204,358. Staff costs were 51% of total, consumable costs 28%, equipment 10%, and start up, recurrent costs, and overheads 5% or less each. Opioid and stimulant kits were most accessed (35% and 32% of total). Cost per user was €66/year, and cost per transaction €7, of which €5 fixed costs and €2 variable. If monthly transactions increased from the average of 1622/month to highest monthly usage (4714), fixed costs per transaction would decrease to < €1. It cost €0.55 per additional syringe accessed/user/month. This study provides evidence for governments about the cost of SVM, a novel harm reduction intervention. This is particularly relevant where Global Fund is withdrawing and harm reduction services need to be incorporated into national budgets.


Validated high-performance thin-layer chromatography method for determination of trigonelline in herbal extract and pharmaceutical dosage form.
A new, simple, sensitive, selective, precise and robust high-performance thin-layer chromatographic (HPTLC) method for analysis of trigonelline was developed and validated for the determination of trigonelline in herbal extracts and in pharmaceutical dosage forms. Analysis of trigonelline was performed on TLC aluminium plates pre-coated with silica gel 60F-254 as the stationary phase. Linear ascending development was carried out in twin trough glass chamber saturated with mobile phase consisting of n-propanol-methanol-water (4:1:4, v/v/v) at room temperature (25+/-2 degrees C). Camag TLC scanner III was used for spectrodensitometric scanning and analysis in absorbance mode at 269 nm. The system was found to give compact spots for trigonelline (R(f) value of 0.46+/-0.02). The linear regression analysis data for the calibration plots showed good linear relationship with r2=0.9991+/-0.0002 in the concentration range 100-1200 ng spot(-1) with respect to peak area. According to the International Conference on Harmonization (ICH) guidelines the method was validated for precision, recovery, robustness and ruggedness. The limits of detection and quantification were determined. The trigonelline content of herbal extracts quantified and estimated from the formulation was found to be well within limits (+/-5% of the labeled content of the formulations). Statistical analysis of the data showed that the method is reproducible and selective for the estimation of trigonelline.


Lipoxygenases: potential starting biocatalysts for the synthesis of signaling compounds.
Lipoxygenases (LOXs) have attracted a great deal of attention as potential starting biocatalysts for synthesizing signaling compounds. Significant advances during the past decade include the discovery of regiospecific LOXs and structural investigation for their diverse regiospecificity. Eight regiospecific (5-, 8-, 9-, 10-, 11-, 12-, 13-, and 15-) LOXs catalyze positional-specific dioxygenation of polyunsaturated fatty acids, forming positional-specific hydroperoxy fatty acids that are further metabolized into signaling compounds. The LOX-derived signaling compounds can be applied not only for clinical uses but also for industrial uses. For example, animal lipoxin LXA4, plant jasmonic acids, plant green leaf volatiles, and bacterial lactones have been used as anti-inflammatory agents, anti-pest agents, flavors, and food additives, respectively. Prostaglandins, as controllers of hormone regulation and cell growth, are also suggested as LOX-derived compounds in corals.


Interaction of polysorbate 80 with erythropoietin: a case study in protein-surfactant interactions.
The cause of antibody positive pure red cell aplasia associated with the subcutaneous administration of EPREX to patients with chronic kidney failure has been determined to be due to the leaching of weakly adjuvant compounds from the uncoated rubber stoppers that were formerly used in prefilled syringes. Other researchers have suggested that polysorbate 80 micelles containing erythropoietin may be a causative factor. The purpose of this work was to repeat previously published studies in a more controlled manner and to define the precise nature of the interactions between polysorbate 80 and erythropoietin. The contents of EPREX prefilled syringes and laboratory-prepared, well-characterized formulations of EPREX were analyzed by size exclusion chromatography. Fractions were analyzed for the presence of erythropoietin by ELISA. EPREX formulations prepared with increasing amounts of polysorbate 80 were analyzed by light scattering. Well-controlled chromatographic studies showed that when EPREX formulations containing no aggregate were analyzed by high-performance liquid chromatography, erythropoietin monomer could not be detected under the polysorbate 80 peak. Dimer and oligomers of erythropoietin coeluted under the polysorbate 80 peak as the molecular weights overlapped on the size exclusion chromatogram. Solution light scattering indicated that polysorbate 80 associates with erythropoietin in a defined stoichiometric ratio of 1:12. Based on controlled studies, previous results suggesting that EPREX contains micelle-associated erythropoietin were incorrect. As with other surfactants and proteins, polysorbate 80 associates with erythropoietin in a defined stoichiometric ratio.


Cholesterol-Containing Nuclease-Resistant siRNA Accumulates in Tumors in a Carrier-free Mode and Silences MDR1 Gene.
Chemical modifications are an effective way to improve the therapeutic properties of small interfering RNAs (siRNAs), making them more resistant to degradation in serum and ensuring their delivery to target cells and tissues. Here, we studied the carrier-free biodistribution and biological activity of a nuclease-resistant anti-MDR1 cholesterol-siRNA conjugate in healthy and tumor-bearing severe combined immune deficiency (SCID) mice. The attachment of cholesterol to siRNA provided its efficient accumulation in the liver and in tumors, and reduced its retention in the kidneys after intravenous and intraperitoneal injection. The major part of cholesterol-siRNA after intramuscular and subcutaneous injections remained in the injection place. Confocal microscopy data demonstrated that cholesterol-siRNA spread deep in the tissue and was present in the cytoplasm of almost all the liver and tumor cells. The reduction of P-glycoprotein level in human KB-8-5 xenograft overexpressing the MDR1 gene by 60% was observed at days 5-6 after injection. Then, its initial level recovered by the eighth day. The data showed that, regardless of the mode of administration (intravenous, intraperitoneal, or peritumoral), cholesterol-siMDR efficiently reduced the P-glycoprotein level in tumors. The designed anti-MDR1 conjugate has potential as an adjuvant therapeutic for the reversal of multiple drug resistance of cancer cells.


Molecular pharmacology of aromatase and its regulation by endogenous and exogenous agents.
Aromatase (estrogen synthase) is the cytochrome P450 enzyme complex that converts C19 androgens to C18 estrogens. Aromatase activity has been demonstrated in breast tissue in vitro, and expression of aromatase is highest in or near breast tumor sites. Thus, local regulation of aromatase by both endogenous factors as well as exogenous medicinal agents will influence the levels of estrogen available for breast cancer growth. The prostaglandin E2 (PGE2) increases intracellular cAMP levels and stimulates estrogen biosynthesis, and our recent studies have shown a strong linear association between CYP19 expression and the sum of COX-1 and COX-2 expression in breast cancer specimens. PGE2 can bind to four receptor subtypes, EP1-EP4, which are coupled to different intracellular signaling pathways. In primary human breast stromal cell cultures, aromatase activity was significantly induced by PGE2, dexamethasone, and agonists for the EP1 and EP2 receptor subtypes. An EP1 antagonist, SC-19220, inhibited the induction of enzyme activity by PGE2 or 17-phenyltrinor-PGE2, an EP1 agonist. Sulprostone, an EP3 agonist, did not alter aromatase activity levels. Investigations are also underway on the regulation of aromatase by exogenous medicinal agents. Selective steroidal and nonsteroidal agents are effective in inhibiting breast tissue aromatase. The benzopyranone ring system is a molecular scaffold of considerable interest, and this scaffold is found in certain flavonoid natural products that have weak aromatase inhibitory activity. Our novel synthetic route for benzopyranones utilizes readily available salicylic acids and terminal alkynes as starting materials. The synthesis of flavones with diversity on the benzopyranone moiety and at the C-2 position occurs with good to excellent yields using these reaction conditions, resulting in an initial benzopyranone library of thirty compounds exhibiting enhanced and differential aromatase inhibition. Current medicinal chemistry efforts focus on diversifying the benzopyranone scaffold and utilizing combinatorial chemistry approaches to construct small benzopyranone libraries as potential aromatase inhibitors.


Impaired polyfunctionality of CD8+ T cells in severe sepsis patients with human cytomegalovirus reactivation.
Human cytomegalovirus (HCMV) establishes a lifelong chronic latent infection and often reactivates in immunocompromised patients. In addition, HCMV reactivates in patients with sepsis or other critical illnesses, particularly in patients with poor prognoses. However, the immunological characteristics of sepsis patients with HCMV reactivation have not been elucidated. In the present study, we examined T-cell responses in severe sepsis patients with and without HCMV reactivation. First, HCMV pp65-specific T-cell functions were assessed by intracellular cytokine staining (ICS) for IFN-γ, TNF-α, and MIP-1β and by CD107a staining. We analyzed the ICS data for each function individually and found no difference between the patient groups. However, the relative frequency of polyfunctional CD8+ T cells was significantly decreased in sepsis patients with HCMV reactivation. Next, we examined programmed cell death protein 1 (PD-1) expression. It was significantly increased in the CD8+ T-cell population in severe sepsis patients with HCMV reactivation, indicating CD8+ T-cell exhaustion. Interestingly, the frequency of PD-1+ cells in the CD8+ T-cell population was inversely correlated with the relative frequency of polyfunctional CD8+ T cells. Herein, we demonstrate that HCMV reactivation in severe sepsis patients is associated with PD-1 expression and impaired polyfunctionality of CD8+ T cells.


The pursuit of further miniaturization of screen printed micro paper-based analytical devices utilizing controlled penetration towards optimized channel patterning.
One of the main objectives of microfluidic paper-based analytical devices is to present solutions particularly, for applications in low-resource settings. Therefore, screen-printing appears to be an attractive fabrication technique in the field, due to its overall simplicity, affordability, and high-scalability potential. Conversely, the minimum feature size attained using screen-printing is still rather low, especially compared to other fabrication methods, mainly attributed to the over-penetration of hydrophobic agents, underneath defined patterns on masks, into the fiber matrix of paper substrates. In this work, we propose the use of the over-penetration to our advantage, whereby an appropriate combination of hydrophobic agent temperature and substrate thickness, allows for the proper control of channel patterning, rendering considerably higher resolutions than prior arts. The implementation of Xuan paper and nail oil as novel substrate and hydrophobic agent, respectively, is proposed in this work. Under optimum conditions of temperature and substrate thickness, the resolution of the screen-printing method was pushed up to 97.83 ± 16.34 μm of channel width with acceptable repeatability. It was also found that a trade-off exists between achieving considerably high channel resolutions and maintaining high levels of repeatability of the process. Lastly, miniaturized microfluidic channels were successfully patterned on pH strips for colorimetric pH measurement, demonstrating its advantage on negligible sample-volume consumption in nano-liter range during chemical measurement and minimal interference on manipulation of precious samples, which for the first time, is realized on screen-printed microfluidic paper-based analytical devices.


High cortisol levels are associated with cognitive impairment no-dementia (CIND) and dementia.
This study aimed to compare serum cortisol concentrations in cognitively healthy elderly and in subjects with cognitive impairment no dementia (CIND) and dementia, besides to evaluate these concentrations according to apolipoprotein E genotype (APOE). Three-hundred and nine elderly enrolled in the Pietà Study (Brazil) were divided in 3 groups: control (n=158), CIND (n=92) and dementia (n=59) and had concentrations of morning serum cortisol measured. Hormone concentrations were measured by chemiluminescence and APOE genotypes were determined by PCR followed by restriction fragment length polymorphism (RFLP). Medians of cortisol concentrations (μg/dl) for the groups were 12.14 (interquartile range - IQR 6.34) for control, 13.65 (IQR 5.88) for CIND and 14.47 (IQR 7.35) for dementia. Significant differences were observed for control vs. CIND (P=0.003), control vs. dementia (P=0.001), but not for CIND vs. dementia (P=0.269). No association was observed between cortisol concentrations and APOE genotype among the groups (P=0.348). The elevation in cortisol concentrations is associated with dementia, independently of APOE genotypes. Further studies are required to understand if elevation of cortisol is an initial event and how hippocampal damage and the loss of hypothalamus-pituitary-adrenal (HPA) axis inhibition may affect its concentrations.


Skeletal muscle ventricle aortic counterpulsation: function during chronic heart failure.
Skeletal muscle ventricles (SMVs) are pumping chambers formed from latissimus dorsi muscle. The SMV aortic counterpulsator model has been proven to be stable in the long term and provide effective diastolic pressure augmentation in normal dogs. This study seeks to prove that the aortic counterpulsator model can function effectively in chronic heart failure. In 6 dogs, pericardium-lined SMVs were created from latissimus dorsi muscle and electrically conditioned for fatigue resistance. Each SMV was attached to the descending thoracic aorta with a two-limb bifurcated graft and the aorta ligated between the limbs. The SMV was stimulated to contract during cardiac diastole at 1:2 to 1:3 ratio. Rapid ventricular pacing was initiated at 220 to 230 beats/min for 7 weeks to induce chronic heart failure. SMV contraction resulted in augmentation of the diastolic pressure time-index by 12.1% (32.8+/-15.4 versus 36.1+/-14.7 mm Hg-s, p < 0.05) at baseline, then by 33.6% (12.9+/-4.4 versus 16.8+/-4.3 mm Hg-s, p < 0.05) after 7 weeks of rapid ventricular pacing. After 7 weeks of rapid ventricular pacing, SMV counterpulsation provided significant afterload reduction with increases in peak left ventricular ejection velocity and stroke volume of 22.7% (142+/-55 versus 168+/-45 mL/s, p < 0.05) and 6.2% (13.0+/-5.1 versus 13.7+/-5.2 mL, p < 0.05), respectively. Coronary blood flow was measured in 3 animals at the 7-week measurement; augmentation averaged 47.6% (0.357+/-0.29 versus 0.432+/-0.26 mL/beat, p < 0.05). The SMV aortic counterpulsator provides improved cardiac assistance relative to the failing heart.


Experience and lessons from health impact assessment for human rights impact assessment.
As globalisation has opened remote parts of the world to foreign investment, global leaders at the United Nations and beyond have called on multinational companies to foresee and mitigate negative impacts on the communities surrounding their overseas operations. This movement towards corporate impact assessment began with a push for environmental and social inquiries. It has been followed by demands for more detailed assessments, including health and human rights. In the policy world the two have been joined as a right-to-health impact assessment. In the corporate world, the right-to-health approach fulfils neither managers' need to comprehensively understand impacts of a project, nor rightsholders' need to know that the full suite of their human rights will be safe from violation. Despite the limitations of a right-to-health tool for companies, integration of health into human rights provides numerous potential benefits to companies and the communities they affect. Here, a detailed health analysis through the human rights lens is carried out, drawing on a case study from the United Republic of Tanzania. This paper examines the positive and negative health and human rights impacts of a corporate operation in a low-income setting, as viewed through the human rights lens, considering observations on the added value of the approach. It explores the relationship between health impact assessment (HIA) and human rights impact assessment (HRIA). First, it considers the ways in which HIA, as a study directly concerned with human welfare, is a more appropriate guide than environmental or social impact assessment for evaluating human rights impacts. Second, it considers the contributions HRIA can make to HIA, by viewing determinants of health not as direct versus indirect, but as interrelated.


Identification of alkaloid constituents from Fangchi species using pH control liquid-liquid extraction and liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.
Fangchi (F.) species from four different origins have been widely used to treat or prevent diseases, and their main constitutes are several types of alkaloids. Identification of alkaloids in F. species is a necessary step to understand the therapeutic properties of each different origin, but this has not yet been fully performed. Several types of alkaloids were extracted from F. species using ultrasonication with 70% CH(3)OH and the extract was partitioned at pH 2 and 12 to enrich alkaloid constituents and to remove interferences. The separation of alkaloids in the Fangchi extract was performed on a C18 column using gradient elution and their tandem mass spectra were obtained by quadrupole time-of-flight tandem mass spectrometry (QTOF-MS/MS) to perform accurate mass measurements of fragment ions for the alkaloid constituents. Several types of alkaloids were successfully separated and identified by LC/ESI-MS/MS. The structural assignment of individual alkaloids was performed based on convergence of MS/MS spectral data, pH partitioning behavior, LC retention behavior, and accurate mass measurements. The pH partition of the extract provided structural information about unknown alkaloids extracted from Fangchi species. A total of 28 compounds were identified and tentatively characterized, and of these 10 alkaloids were reported for the first time in the investigated F. species. The chemical profiling of alkaloids in F. species with different origins was performed for the first time and provided diagnostic ions for diverse alkaloids in F. species. Marker compounds were suggested based on the 28 characterized compounds for quality evaluation and the differentiation of Fangchi species with four different origins.


Atypical neuropsychological profiles and cognitive outcome in mesial temporal lobe epilepsy.
Patients with left mesial temporal lobe epilepsy (MTLE) have deficits in verbal memory processes, while patients with right MTLE have visuospatial memory impairment. However, atypical cognitive phenotypes among patients with MTLE may occur. In this study, we analyzed preoperative memory deficits in a cohort of 426 right-handed patients with unilateral MTLE. We also evaluated the cognitive outcome after anterior temporal lobectomy (ATL) of patients with atypical profiles in comparison with those with typical memory profile. We found that 25% of our patients had a typical cognitive profile, with verbal memory deficits associated with left side hippocampal sclerosis (HS) and visuospatial memory deficits associated with right side HS. However, 75% of our patients had atypical memory profiles. Despite these atypical profiles, patients submitted to right ATL had no significant cognitive deficit after surgery. In patients submitted to left ATL, the higher the presurgical scores on verbal memory and naming tests, the higher the cognitive decline after surgery.


Facility- and Patient-Level Factors Associated with Esophageal Variceal Screening in the USA.
The American Association for the Study of Liver Disease (AASLD) recommends screening for esophageal varices (EV) by esophagoduodenoscopy (EGD) in patients with cirrhosis to guide decisions regarding primary prophylaxis for EV hemorrhage. We aimed to identify patient and facility factors associated with EV screening in veterans with hepatitis C (HCV)-associated cirrhosis. This was a population-based cohort study. Veterans with HCV and newly diagnosed cirrhosis between 1/1/2004 and 12/31/2005 and followed until 12/31/2011 were included. The primary outcome was receipt of EGD within 1 year of cirrhosis diagnosis. Patient- and facility-level factors associated with EV screening were determined. A total of 4230 patients with HCV cirrhosis were identified. During median follow-up of 6.1 years (IQR: 4.0-8.0), 21.5 % developed a decompensating event, and 38.3 % died. Fifty-four percent received an EGD, and 33.8 % had an EGD within guidelines. Median time from cirrhosis diagnosis to EGD was 72 days (IQR: 12-176). Factors independently associated with receipt of EV screening were a decompensation event (OR 1.16, CI 1.01-1.32) and gastroenterology/hepatology clinic access (OR 2.1, CI 1.73-2.46), whereas cardiovascular (OR 0.81, CI 0.69-0.95), mental health (OR 0.79, CI 0.68-0.91), and respiratory (OR 0.85, CI 0.72-0.99) comorbidities were associated with reduced likelihood of EV screening. EV screening per AASLD guidelines occurs in only one-third of patients. This missed opportunity was strongly associated with access to gastroenterology/hepatology specialty care. Additionally, providers may be relying on clinical cues (i.e., decompensation) to prompt referral for endoscopy suggesting education to improve compliance with guidelines is needed.


Prediction of platelet counts with ROTEM-sigma in cardiac surgery.
Excessive bleeding is common after cardiac surgery. According to transfusion algorithms based on ROTEM results (TEM International Inc., Munich, Germany), platelet transfusion is recommended when FIBTEM amplitude is normal and EXTEM amplitude is reduced. The aim of this study was to evaluate whether ROTEM (TEM International Inc.) parameters may predict accurately platelet counts in cardiac surgery patients, and to determine which of these parameters is the most useful for predicting platelet counts. In this retrospective single center study data from 83 patients who underwent cardiac surgery were reviewed. We analyzed the results of patients for whom ROTEM (TEM International Inc.) and conventional laboratory tests were performed simultaneously. The derived ROTEM (TEM International Inc.) parameter PLTEM was used to estimate platelet count; PLTEM is calculated by subtracting FIBTEM from EXTEM. Correlation between ROTEM (TEM International Inc.) variables and platelet counts were determined. Logistic regression analyses were performed to predict platelet counts. ROTEM A5 values show a high linear correlation with MCF values. PLTEM has a strong linear correlation with platelet counts. According to our results for PLTEM A5<32 mm the probability of platelet count <150×109/L is 100%, for PLTEM A5<27 mm the probability of platelet count <100×109/L is nearly 80%, and for PLTEM A5<22 the probability of platelet count <75×109/L is 70%. This study demonstrates the reliability of considering early ROTEM (TEM International Inc.) results and the feasibility of using PLTEM A5 to predict platelet counts and so, improve our ability to decide the need of platelet transfusion in cardiac surgery patients.


Prevalence of bovine rotavirus among cattle in mainland China: A meta-analysis.
Bovine rotavirus is the primary pathogen causing diarrhea in cattle and can be transmitted vertically through the placenta. It mainly presents with clinical signs such as depression, loss of appetite, diarrhea, vomiting, and dehydration. A systematic review and meta-analysis were conducted to assess the prevalence of BRV infection in mainland China. We conducted a literature search on the prevalence of BRV infection in pigs between Jan 1, 1979 and Dec 31, 2021 in English and Chinese databases, including PubMed, Google Scholar, Cochrane library, Clinical Trials, VIP, CNKI, and WanFang database. Selections were made based on the title and the abstract of the paper, Search strings included if they reported the cattle samples of more than 15 cattle and provided information that allowed us to establish the prevalence of BRV. Moreover, we excluded repeated studies, reviews, other hosts. Finally, we extracted the number of cattle with BRV infection from the obtained studies and provided information that permitted us to estimate the prevalence of BRV infection in cattle in mainland China. The data of 29 articles (including data on 10677 cattle) are compliant with the standards. The pooled prevalence of BRV in cattle in China was 46%(6635/10677), the pooled prevalence of BRV in cattle from Northeast China (40%) was significantly lower than those from other regions. In addition, the prevalence of BRV was associated with publication time of paper, detection methods, age of cattle, and clinical symptoms(diarrhea, etc.). Our findings suggest that BRV infection is common among cattle in China. It is, therefore, necessary to carry out further research and monitor the prevalence of BRV infection. Furthermore, powerful and effective regulatory measures should be taken to prevent the transmission and spread of BRV among cattle populations.


Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells.
Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.


Patterns and trajectories of children's maltreatment experiences in Taiwan: Latent transition analysis of a nationally representative longitudinal study.
Little is known about the patterns of child maltreatment change over time and vary according to gender and child protective services (CPS) experience in Taiwan. To examine the latent status and the trajectories of child maltreatment and to identify effects that gender and CPS have on these statuses and trajectories in Taiwan. A national proportionately stratified sample of 6233 4th-grade students were recruited from 314 elementary schools in Taiwan, and followed up at 6th and 8th graders. A total of 1908 students completed valid data at all three time points was analyzed. Latent class analysis and latent transition analysis were used to identify the number of latent variables and the patterns of child maltreatment. Multiple-group model was used to test with gender difference. Four latent maltreatment statuses were identified: high all maltreatment, high psychological maltreatment, high neglect, and no/low maltreatment. A reduction in maltreatment severity occurred over time was found. The percentage of students in the "high all maltreatment" and "high neglect" groups decreased whereas those in the "high psychological maltreatment" and "no/low maltreatment" groups increased. Differences in the transition probabilities of latent maltreatment status by gender was revealed. The percentage of CPS recipients in the "high all maltreatment" decreased over time. This study highlighted the dynamic nature of child maltreatment and described the timing, continuity, and change that characterizes children's exposure to maltreatment in Taiwan. Policies and interventions geared toward early detection, mitigation, and prevention of child maltreatment are needed.


Unrecognized coronary vasospasm in patients referred for percutaneous coronary intervention: Intracoronary nitroglycerin, the forgotten stepchild of cardiovascular guidelines.
The goal of this study was to demonstrate the importance of intracoronary nitroglycerin (IC NTG) administration during diagnostic coronary angiography and prior to percutaneous coronary intervention (PCI). PCI has been a mainstay treatment for patients with symptomatic coronary artery disease. While current guidelines emphasize the importance of periprocedural antithrombotic medications, they fail to mention the use of nitroglycerin prior to PCI. Retrospective chart and angiographic review was performed to identify patients referred for PCI who had significant angiographic stenoses that resolved after administration of IC NTG. The study group consisted of 6 patients (3 men, 3 women) with mean age 52 ± 4years (range 46-57 years). All had anginal symptoms and significant (>70%) stenosis on diagnostic coronary angiography. None had documented ST segment elevation. The median interval between diagnostic and staged PCI procedures was 3 days. IC NTG was not administered to any of the patients at the time of diagnostic coronary angiography. In each case, repeat coronary angiography following administration of IC NTG (155 ± 46 mcg) before planned PCI demonstrated resolution of the target stenosis. PCI was deferred and all patients were successfully managed medically. Coronary artery spasm is an under-recognized cause of chest pain in patients with significant angiographic lesions. Coronary spasm should be suspected especially in younger patients (less than 60 years old) with apparent single vessel disease. IC NTG should be routinely administered during diagnostic angiography and before PCI to avert unnecessary coronary interventions. © 2017 Wiley Periodicals, Inc.


Posterior wall isolation in persistent atrial fibrillation. Long-term outcomes of a repeat procedure strategy.
Posterior wall isolation (PWI) added to pulmonary vein isolation (PVI) is increasingly used in ablation for persistent atrial fibrillation (PeAF) despite limited evidence of clinical benefit. We investigated the 5-year outcomes of a PVI + PWI ablation strategy with mandatory repeat procedures in PeAF. Twenty-four patients with PeAF participated in this single-arm prospective study and underwent radiofrequency ablation (RFA) with wide area circumferential ablation (WACA), roof, and inferior lines for PVI + PWI which was reinforced if required during mandated repeat procedures after 6 months. Then, patients were followed for 60 months using continuous heart rhythm monitoring by implanted cardiac monitors (ICM) and atrial fibrillation effect on quality-of-life scoring (AFEQT; range: 20-100 points) for the initial 30 months. ICM-verified cumulated AF recurrence was 54% after 30 months but the ensuing AF burden was only median 0‰ [0 to 4.8‰] overall and 1‰ [0 to 8 ‰] among patients with any recurrence. AFEQT scores increased from baseline 60 points [48 to 72] to 93 points [84 to 96] at repeat procedures P < 0.0001 and further to 96 points [93 to 99] P = 0.03 after 30 months. After 60 months, at least one episode of AF had been documented in 63% and two patients (8%) were in permanent AF. Reinforced PVI + PWI was associated with low long-term AF burden and corresponding improvements in quality-of-life. Reinforced (or durable) PVI + PWI appears to be a promising strategy to treat PeAF. ClinicalTrials.gov. Identifier: NCT05045131.


A Prospective Follow-up Study on Risk Factors to Predict the Progression of Unruptured Intracranial Aneurysms on Enhanced HR-MRI.
To prospectively investigate the potential correlation between qualitative and quantitative assessment of aneurysm wall enhancement (AWE) on initial enhanced high-resolution magnetic resonance imaging (HR-MRI) and aneurysm progression during follow-up. From June 2016 to January 2021, we prospectively recruited patients with unruptured intracranial aneurysms (UIAs) for enhanced HR-MRI examination. The patients' demographic and clinical data and aneurysm characteristics, including AWE features, were collected and analyzed. Follow-up images were compared to evaluate IA progression. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify the risk factors associated with aneurysm progression. Seventy-seven patients with 95 UIAs met our research criteria, and the median follow-up time was 15.7 months. Progression was observed in 18 aneurysms; the remaining 77 remained stable. Progressive UIAs were larger in size, more frequently displayed obvious AWE and showed a higher enhancement ratio (ER) than nonprogressive UIAs. Multivariate Cox regression analysis showed that both ER (hazard ratio, 6.304, p < 0.001) and aneurysm size (hazard ratio, 1.343, p = 0.014) were independent risk factors for aneurysm progression. The combination of ER and aneurysm size had an area under the curve of 0.920 for the prediction of aneurysm progression, with a sensitivity of 88.9% and specificity of 87.0%. A higher ER value of the aneurysm wall and a larger aneurysm size on initial HR-MRI may predict an increased risk of aneurysm progression, which suggests that closer monitoring by imaging or preventive intervention may be required for the clinical management of these aneurysms.


Nonsmoking grain handlers in Saskatchewan: airways reactivity and allergic status.
This study was carried out to determine whether respiratory disease in Saskatchewan grainhandlers was or was not due to hypersensitivity to grain dust. Sixty nonsmoking grainhandlers, half of whom had low FEV1/FVC ratios and half of whom had high, were studied. The findings in grainhandlers were compared with those in 30 age-matched, nonsmoking teachers. In the group of grainhandlers with low FEV1/FVC ratios, one had developed asthma associated with exposure to grain dust. The majority were healthy, had FEV1/FVC ratios of 70% or greater, and had less evidence of allergic respiratory disease than had age-matched teachers. The studies suggest that non-atopic, nonsmoking men can work in grain elevators without developing respiratory disability, though they may develop a small but significant increase in nonspecific bronchial reactivity to histamine.


Ribonucleotide reductase--new twists in an old tale.
Although they are proliferatively quiescent, the cells in the intact adult rat liver express the gene coding for the M1 subunit of ribonucleotide reductase. But since they do not need deoxyribonucleotides, they promptly inactivate the 88 to 90 kDa M1 products and degrade them into 40 kDa fragments. Partial hepatectomy signals the remaining cells to start proliferating. Two hours before the onset of DNA replication, around 16 to 18 hr after partial hepatectomy, the cells start accumulating a large pool of functional ribonucleotide reductase M2 subunits. Near the end of the G1 build-up the cells step up M1 gene expression, stop inactivating, and reduce the degradation of the M1 products. The accumulating functional 88 to 90 kDa M1 subunits, each with more than one catalytic site, couple with functional M2 subunits to produce active ribonucleotide reductase holoenzyme which accumulates in the outer nuclear membrane from which they supply deoxyribonucleotide precursors to intranuclear replication enzymes. At the end of the S phase, the cell reduces M1 gene expression and resumes degrading 88 to 90 kDa M1 subunits. At least some of the 40 kDa M1 fragments are still active and can form partially active "holoenzymes" when mixed with a standard preparation of functional M2 subunits. The M1 control mechanism appears not to operate in hepatoma cells and Ehrlich ascites tumor cells, both of which maintain a pool of undegraded 88 to 90 kDa M1 components.


Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: Insights into a challenging symptom.
More than half of patients who recover from COVID-19 experience fatigue. We studied fatigue using neuropsychological and neurophysiological investigations in post-COVID-19 patients and healthy subjects. Neuropsychological assessment included: Fatigue Severity Scale (FSS), Fatigue Rating Scale, Beck Depression Inventory, Apathy Evaluation Scale, cognitive tests, and computerized tasks. Neurophysiological examination was assessed before (PRE) and 2 min after (POST) a 1-min fatiguing isometric pinching task and included: maximum compound muscle action potential (CMAP) amplitude in first dorsal interosseous muscle (FDI) following ulnar nerve stimulation, resting motor threshold, motor evoked potential (MEP) amplitude and silent period (SP) duration in right FDI following transcranial magnetic stimulation of the left motor cortex. Maximum pinch strength was measured. Perceived exertion was assessed with the Borg-Category-Ratio scale. Patients manifested fatigue, apathy, executive deficits, impaired cognitive control, and reduction in global cognition. Perceived exertion was higher in patients. CMAP and MEP were smaller in patients both PRE and POST. CMAP did not change in either group from PRE to POST, while MEP amplitudes declined in controls POST. SP duration did not differ between groups PRE, increased in controls but decreased in patients POST. Patients' change of SP duration from PRE to POST was negatively correlated to FSS. Abnormal SP shortening and lack of MEP depression concur with a reduction in post-exhaustion corticomotor inhibition, suggesting a possible GABAB-ergic dysfunction. This impairment might be related to the neuropsychological alterations. COVID-19-associated inflammation might lead to GABAergic impairment, possibly representing the basis of fatigue and explaining apathy and executive deficits.


Transcervical radiofrequency ablation of fibroids that are 5 cm or larger in women with abnormal uterine bleeding.
Fibroids are the most common benign uterine tumors. Transcervical radiofrequency ablation with the Sonata® System offers a minimally invasive, incisionfree, organ-preserving therapy, with intraoperative visualization of fibroids using intrauterine ultrasound guidance. To demonstrate the effectiveness of transcervical radiofrequency ablation of fibroids that are 5 cm or larger using the Sonata® System, this retrospective analysis was collected. 151 patients have been treated with this method in our department up to the time of this analysis. Only patients with at least one fibroid of ≥5 cm and with bleeding symptoms, who were treated with the Sonata® System were included in this retrospective study. A total of 50 patients were included in the study and 57 fibroids were treated. A total of 57 fibroids were detected and treated, however FIGO 1 and 2 fibroids (in total three fibroids were excluded). The smallest fibroid was 4 cm and the largest fibroid was 12 cm. A single ablation was performed in 18 cases, two ablation steps in 16 cases, three ablation steps in 13 cases, and more than three ablation steps in three cases. Depending on ablation steps, the shortest ablation time was 3 min 15 s and the longest ablation time was 25 min 6 s, with an average time of 9 min 12 s. 86% of patients reported an improvement of symptoms Conclusion: Thus, the Sonata® System is a simple, minimally invasive, rapid and successful method that shows significant improvement of symptoms even in large myomas from ≥5 cm.


One click, two clicks: the past shapes the future in auditory cortex.
What are the synaptic and cellular mechanisms by which stimulus context shapes cortical responses? In this issue of Neuron, Wehr and Zador describe intracellular recordings of responses to click pairs in rat primary auditory cortex (A1) and offer new insights into the successive roles of inhibition and synaptic depression in suppressing responses to the second click in many A1 neurons.


[Sociotherapeutic innovations in the care system].
What are sociotherapeutic innovations? How can humanities be introduced and recognised in the French health care system? This set of practices and techniques differ from biomedical medicine. It is a matter of understanding the values they convey and the way they compare with evidence-based medicine.


Witkop's syndrome: A case report.
Witkop's syndrome is a rare autosomal dominant disorder characterized by tooth and nail abnormalities. It is a variant of ectodermal dysplasia, which is thought to occur in approximately 1 in 100,000 live births. Thus, such a low occurrence and paucity of clearly delineating features make its identification in general population a real challenge. This case report aims to add to the existing literature a commonsense approach of identifying the uncommon thing.


Role of the processing pore of the ClpX AAA+ ATPase in the recognition and engagement of specific protein substrates.
ClpX binds substrates bearing specific classes of peptide signals, denatures these proteins, and translocates them through a central pore into ClpP for degradation. ClpX with the V154F po e mutation is severely defective in binding substrates bearing C-motif 1 degradation signals and is also impaired in a subsequent step of substrate engagement. In contrast, this mutant efficiently processes substrates with other classes of recognition signals both in vitro and in vivo. These results demonstrate that the ClpX pore functions in the recognition and catalytic engagement of specific substrates, and that ClpX recognizes different substrate classes in at least two distinct fashions.


The effect of the amount of protrusion built into the bionator on condylar growth and displacement: a clinical study.
To evaluate the treatment effects of a variable degree of forward posturing of the mandible incorporated into the Bionator, a study was undertaken on 14 patients with Class II, Division 1 malocclusion, treated for 1 year with a Bionator, maintaining the mandible in an edge-to-edge incisal position (Be group). This group was compared with a matched group of patients treated with the Bionator in whom the mandible was maintained in a "functional maxipropulsion" (Bmax group). Both groups were subdivided further according to sex for selected parameters. Twenty-nine measurements on cephalometric x-ray films taken before and after 1 year of treatment were statistically analyzed. According to this study, "edge-to-edge" protrusion is superior to "functional maxipropulsion" in increasing ramal height. The difference in increase in corpus length after treatment (greater in boys than in girls) was sex related rather than dependent on appliance characteristics. When studying the effect of functional appliances, it is suggested that a patient group be subdivided by sex. After treatment a repositioning of the condyle was found in a more downward and possibly slightly forward direction relative to sella point (S) in both groups. A relocation of the condyle should be considered as another treatment effect of functional appliances. The more important lowering of the condyle found in the Bmax group may partly explain the significant increase in SNB, the 1.6-fold larger decrease in overbite, and the highly significant increase in anterior lower facial height in this group.(ABSTRACT TRUNCATED AT 250 WORDS)


Myocardial uptake of encainide and its two major metabolites, O-demethyl encainide and 3-methoxy-O-demethyl encainide, in the dog.
Encainide is a new antiarrhythmic agent which is currently undergoing clinical evaluation. Two metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide (MODE), have been identified. We have investigated the myocardial accumulation of these three compounds in an anesthetized open-chested dog model. We also considered the degree of plasma protein binding and the oil/water partitioning characteristics of these three compounds to see if they explained differences in myocardial accumulation. Each compound was administered by intravenous infusion to a group of five dogs. Blood and myocardial biopsy samplings were carried out under steady-state conditions. The myocardial/plasma concentration ratios for encainide, ODE, and MODE were 8.4, 5.4, and 4.8, respectively. The ratios were compared with a completely randomized analysis of variance followed by multiple comparisons. The myocardial/plasma concentration ratio for encainide was significantly greater (p less than .05) than the ratios of the metabolites; however, the difference between ODE and MODE was not significant. Myocardial uptake of encainide, ODE, and MODE was quite rapid, and the myocardial concentration-time course of each compound followed its time course in plasma closely. Encainide and its two metabolites are only moderately bound to plasma proteins. The mean (+/- SD) percent bound for encainide, ODE, and MODE are 49 +/- 10, 55 +/- 19, 44 +/- 18, respectively. The whole blood/plasma concentration ratios are 1.04 +/- 0.16, 1.08 +/- 0.23, and 1.06 +/- 0.08 for encainide, ODE, and MODE, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Predictors of unprotected sex among young sexually active African American, Hispanic, and White MSM: the importance of ethnicity and culture.
Despite the recognized need for culturally tailored HIV prevention interventions for gay, bisexual, and questioning youth, few studies have examined if predictors of unprotected sex vary for youth from different ethnic groups. This study reports on a sample of 189 gay, bisexual, and questioning youth (age 15-22) from three racial/ethnic backgrounds (African American, Hispanic, and White) recruited in Chicago, IL and Miami-Dade and Broward Counties, Florida. For African American youth, being in a long-term relationship, having been kicked out of the home for having sex with men, and younger age at initiation of sexual behavior were associated with unprotected sex. For Hispanic youth, higher ethnic identification and older age at initiation of sexual behavior were associated with unprotected sex. For White youth, no predictors were associated with unprotected sex. Our findings point to the importance of understanding the varying predictors of unprotected sex and integrating them into tailored prevention interventions.


Full-endoscopic lumbar discectomy via lateral superior articular process approach for treating far lateral lumbar disc herniation: a retrospective study and technical note.
This study aims to evaluate the efficacy and safety of the full-endoscopic lumbar discectomy (FELD) via lateral superior articular process (LSAP) approach and full-endoscopic transforaminal discectomy (FETD) for treating far lateral lumbar disk herniation (FFLDH). From January 2020 to June 2022, patients who were diagnosed as FLLDH underwent the FELD via LSAP approach or FETD. The operation time, estimated blood loss, length of hospital stays, and complications were recorded. The visual analog scale (VAS) for back pain, VAS for leg pain, and the Oswestry Disability Index (ODI) scores was measured during preoperative and postoperative follow-up. Thirty-two patients were enrolled in this study, of which 12 patients were treated with the FELD via LSAP approach (LSAP-FELD group) and 20 patients underwent FETD (FETD group). The LSAP-FELD group exhibited significantly shorter operation times and hospital stays compared to the FETD group, while no statistically significant differences were observed in intraoperative blood loss and complication rates. There were no significant differences in the VAS for back pain, the VAS for leg pain, and the ODI score between the two groups preoperatively and three days, three months, and the last follow-up postoperatively. Both the FELD via LSAP approach and FETD have demonstrated favourable clinical efficacy in the treatment of FLLDH. Notably, the FELD via LSAP approach shows the advantages of shorter operation time and hospital stays.


Synthesis and A1-adenosine receptors affinities of purino[7,8-c]quinazoline-8,10(9H,11H)-diones as rigid analogues of 8-arylxanthines.
Title compounds were prepared by a cyclocondensation reaction between 8-(2-aminophenyl)xanthines and trialkyl orthoesters. Some of them showed activities as A1-adenosine receptor antagonists with binding values in the micromolar range. Results are discussed with reference to 1,3-dialkyl-8-arylxanthines. Considerations on the role played by both electronic and conformational factors are also reported.


Estrogens and postprandial lipid metabolism.
Women with angiographically proven coronary heart disease (CAD) had higher postprandial concentrations of small chylomicron-remnants, measured as IDL apo B48, than women without CAD. Fasting TG concentrations were not different and within the normal range. Thus, the postprandial concentration of small chylomicron-remnants could identify women at high CAD risk within a normolipidemic population. Replacement therapy with 17beta-estradiol improved the clearance of chylomicron-remnants by 41% and attenuated the postprandial reduction in HDL-cholesterol by 66%. This improvement in postprandial lipid metabolism can explain part of the protective effect of estrogens against CAD.


Managing the three-rivers headwater region, china: from ecological engineering to social engineering.
The three-rivers headwater region (THRHR) of Qinghai province, China plays a key role as source of fresh water and ecosystem services for central and eastern China. Global warming and human activities in the THRHR have threatened the ecosystem since the 1980s. Therefore, the Chinese government has included managing of the THRHR in the national strategy since 2003. The State Integrated Test and Demonstration Region of the THRHR highlights the connection with social engineering (focus on improving people's livelihood and well-being) in managing nature reserves. Based on this program, this perspective attempts a holistic analysis of the strategic role of the THRHR, requirements for change, indices of change, and approaches to change. Long-term success of managing nature reserves requires effective combination of ecological conservation, economic development, and social progress. Thus, the philosophy of social engineering should be employed as a strategy to manage the THRHR.


Subjective, psychomotor, and analgesic effects of oral codeine and morphine in healthy volunteers.
The subjective, psychomotor, and physiological effects of analgesic doses of oral codeine and morphine were examined in 12 healthy volunteers. Subjects ingested placebo, morphine 20 or 40 mg, or codeine 60 or 120 mg in a randomized, double-blind, crossover design. The smaller and larger doses of each drug were putatively equianalgesic, and the cold-pressor test was included to test this assumption. Codeine and morphine increased ratings of "feel drug effect" but had little effect on other subjective measures, including the Addiction Research Center Inventory, visual analog scales, and adjective checklists. The few subjective effects that were observed were modest and were dose-related for morphine but not for codeine. The drugs did not affect performance on Maddox-Wing, digit-symbol substitution, coordination, auditory reaction, reasoning, and memory tests. Dose-related decreases in pupil size (miosis) were observed following codeine and morphine. Ratings of pain intensity decreased in a dose-related manner for morphine but not for codeine. Plasma codeine and morphine levels varied as an orderly function of dose. These results suggest that oral codeine and morphine are appropriate drugs for outpatient pain relief because they are effective analgesics at doses that have only modest effects on mood, produce few side effects, and do not impair performance. The results also suggest a possible ceiling effect of codeine on analgesia and subjective effects.


Presence of opiate receptors on striatal serotoninergic nerve terminals.
After degeneration of serotoninergic neurons induced by either transection of the ascending neuronal pathways originating from the nucleus raphe dorsalis or intraventricular 5,6-dihydroxytryptamine administration, the number of binding sites for [3H]D-Ala2, Met5-enkephalinamide was significantly reduced. This decrease in binding sites does not seem to be related to the opiate receptors present on dopaminergic terminals, nor is it due to a simple decrease in serotoninergic neuronal tone, since after p-chlorophenylalanine (100 mg/kg X 4 days) the number of striatal binding sites for the opiate ligand was not diminished. On the other hand, shortly after mechanical interruption of the raphe-striatal serotoninergic fibers, at a time when the metabolic processes are still functioning in the lesioned neurons, morphine still increased the striatal content of 5-hydroxyindoleacetic acid. These results suggest the presence of opiate receptors on striatal serotoninergic terminals, where they may modulate the presynaptic activity of these neurons.


Electrolyte disturbances and risk factors of acute kidney injury patients receiving dialysis in exertional heat stroke.
Exertional heat stroke (EHS) is a life-threatening illness and leads to multi-organ dysfunction including acute kidney injury (AKI). The clinical significance of abnormal electrolytes and renal outcomes in ESH patients has been poorly documented. We aim to exhibit the electrolyte abnormalities, renal outcomes and risk factors of patients with AKI receiving dialysis in EHS. A retrospective cohort study in EHS patients between 2003 and 2014 were conducted. Clinical and laboratory outcomes including serum and urine electrolytes, AKI and dialysis were assessed on admission, during hospitalization and at the time of their discharge from the hospital. A logistic regression analysis was performed for risk factors of acute dialysis. All 66 subjects with mean age 22.1 ± 4.3 years were included. On admission, the common electrolyte disturbances were hypokalemia (71.2 %), hypophosphatemia (59.1 %), hyponatremia (53.0 %), hypocalcemia (51.5 %), and hypomagnesemia (34.9 %). Electrolytes depletion was confirmed as renal loss (potassium loss; 54.2 %, phosphate loss; 86.7 %, sodium loss; 64.7 % and magnesium loss; 83.3 %). During hospitalization ranging from 2 to 209 days, 90.9 % patients suffered from AKI with 16.7 % receiving acute dialysis, and 3 % patients died. At discharge, AKI and electrolyte abnormalities had dramatically improved. The prognosis factors for AKI receiving dialysis were identified as neurological status, renal function and serum muscle enzyme at time of admission. The study suggests that hypoelectrolytemia and AKI are frequently observed in patients with EHS. Neurological impairment, impaired renal function, and increased serum muscle enzyme should be considered risk factors of acute dialysis.


Associations of retinal artery occlusion and retinal vein occlusion to mortality, stroke, and myocardial infarction: a systematic review.
Retinal vascular events are perceived to be related to various cardiovascular complications. We conducted a systematic review to assess the relationship between retinal artery/vein occlusions (RAO/RVO) and the incidence of mortality, stroke, and myocardial infarction (MI). A comprehensive electronic literature search selected 93 relevant studies between 1992-2015: 16 articles qualified for inclusion (7 for mortality rate and MI, 11 for stroke). No published articles examined associations of RAO to mortality or MI, but only to stroke. Because of the heterogeneity of studies, no meta-analysis was performed. The association with mortality risk was highest at ~34.7% in RVO subgroup; whereas for MI, the risk was comparatively lower at 3.9-5.7% for RVO. There was no significant difference in stroke rate when comparing central and branch RVO subgroups (6.5%), but was significantly higher at 19.6-25% in RAO. There is a positive association of retinal vascular events to mortality, stroke, and MI. RAO is associated with a higher risk of stroke. Given that RAO and RVO patients would generally present to ophthalmologists, their high cardiovascular risk should include a referral for cardiovascular assessment as part of their management protocol.


New T1 classification.
The IASLC staging and Prognostic Factor Committee proposed new changes to the descriptors for the 8th edition of the Tumour Node Metastasis Staging for Lung Cancer. The T1 descriptor changes include (1) T1 tumours are subclassified into T1a (< 1 cm), T1b (> 1 to < 2 cm), T1c (> 2 to < 3 cm). The corresponding changes are introduced to the overall staging: T1aN0M0 = Stage IA1; T1bN0M0 = Stage IA2; T1cN0M0 = Stage IA3. (2) The introduction of the pathological entities Adenocarcinoma-In-Situ (AIS), Minimally Invasive Adenocarcinoma, and Lepidic Predominant Adenocarcinoma. The corresponding changes on the T descriptor are as follows: Adenocarcinoma-in situ is coded as Tis (AIS); Minimally Invasive Adenocarcinoma is coded as T1a(mi). In this review, the basis for these changes will be described, and the implications on clinical practice will be discussed.


CS-NO suppresses inhibits glycolysis and gastric cancer progression through regulating YAP/TAZ signaling pathway.
Gastric cancer (GC) is a significant contributor to global mortality and is recognized for its elevated prevalence and fatality rates. Nitric Oxide (NO) plays a role in multiple aspects of cancer metastasis and progression. CS-NO is a polysaccharide-based biomaterial with NO-releasing properties that shows promising therapeutic potential. Nonetheless, the action mechanism of CS-NO in GC is still largely unclear. The present study employed various experimental techniques, including CCK-8 assay, colony formation assay, EdU staining, and transwell assays, to evaluate the proliferation, migration, and invasion of GC cells. Additionally, ELISA was utilized to measure glucose uptake, lactate production, and cellular ATP levels in GC cells. In vivo investigations on nude mice were conducted to validate the in vitro results. The present study aimed to examine the potential anti-tumor properties of CS-NO on GC through in vitro and in vivo investigations, while also exploring the underlying mechanisms involved. Our data suggested that CS-NO might prevent GC cell invasion and migration. Decreased expressions of GLUT1, HK2, and LDHA further demonstrated that CS-NO significantly suppressed aerobic glycolysis in GC cells. The administration of CS-NO resulted in a significant reduction of YAP and TAZ levels in GC cells. Our data further show that CS-NO treatment could inhibit GC cancer growth in mice, consistent with the significant decrease in Ki67, GLUT1 and YAP expression levels. These findings could reveal the good effects of CS-NO therapy on inhibiting GC.


The oxytocin challenge test: an ominous pattern associated with severe fetal growth retardation.
Four cases of a rare atypical fetal heart pattern obtained during the oxytocin challenge test are described. In all cases, there were marked oligohydramnios and fetal growth retardation with a severely compromised fetus, and in 3 cases the fetuses died.


Head and neck hemorrhage: Technical tools and tricks.
The purpose of the present work is to provide a fresh, simple, and accessible document for all surgeons who treat traumatic hemorrhage from the head and neck. This article arose from the work of a consortium of experienced trauma surgeons who collaborated to produce a first-of-its-kind surgical course for multifocal hemorrhage control. The "Bloody Simple Hemorrhage control masterclass course" has been offered at national and international venues since 2019 and has been both well received by participants and well regarded in academic trauma surgical circles. This paper-and the series of articles which accompany it-was meant to be a literature companion to or extension of the Bloody Simple course, a way to distill and digest the hemorrhage control strategies espoused therein but in the form of a journal article. The result of this work is a succinct and experience-based set of principles for conquering life-threatening, traumatic bleeding from a variety of sources in the head and neck. This article translates experience and evidence into a simple and digestible format that will provide a sound approach for any surgeon facing traumatic hemorrhage from the head and neck.


Synthesis of 5,12-Diazapentacenes and Their Properties.
An efficient synthesis via a precursor route to a new class of linear dialkyldiaminoazapentacenes is reported. The synthetic route involves the coupling of 4-substituted aniline derivatives to 2,5-dibromoterephthalonitrile via Buchwald-Hartwig amination followed by an acid-mediated cyclization to furnish the diazapentacenes. These reactions occur under short reaction times (<2 h), provide high yields (77-99%), and do not require column chromatography for purification. The electrochemical and optical properties of the diazapentacenes were evaluated, and the values indicate that these molecules are promising n-type materials for organic electronic devices. The photostability of these molecules was significantly greater than unsubstituted acenes. Their method of degradation via endoperoxide generation was confirmed by X-ray crystallography and mass spectrometry.


[Study on therapeutic effect of carnitine on hepatic steatosis caused by total parenteral nutrition in rats].
To study the hepatic steatosis-minimizing effects of carnitine supplemented total parenteral nutrition (TPN). Eighteen normal Wistar rats and nineteen cirrhotic Wistar rats were randomly divided into three groups, respectively: group A (12), chow and libitum; group B (13), TPN for one week group C (12), TPN with carnitine. Liver functions were tested at the seventh day, and also, the liver was resected for histological studies and lipid content determination. Hepatic lipid content was significantly elevated and hepatic steatosis was noted in group B. Hepatic lipid content and hepatic lipid deposit were significantly lowered when carnitine was added to the TPN solution. Carnitine can minimize hepatic steatosis caused by TPN.


The Bare Area of the Proximal Ulna: An Anatomic Study With Relevance to Chevron Osteotomy.
A chevron osteotomy of the ulna is widely used to obtain intra-articular access to the elbow in the treatment of type C distal humerus fractures. The trochlear notch of the proximal ulna is divided into 2 articular parts by the "bare area." Ideally, the olecranon osteotomy should be centered on the bare area to minimize damage to the joint cartilage. The goals of this study were to describe the anatomy of the bare area and design an ideal chevron-shaped osteotomy. We dissected 38 cadaver elbows and measured the width of the bare area, the distance between the tip of the triceps insertion and the area on the olecranon cortex corresponding to the bare area. We then designed a chevron osteotomy to stay within the bare area and measured the distance from the tip of the triceps insertion to the osteotomy apex as well as the angle of the osteotomy plane and the angle of the chevron cuts. The bare area existed in all 38 cadavers. The mean longitudinal and transverse widths were 4.0 mm (range, 1.0-8.6 mm) and 19.0 mm (range, 16.9-23.8 mm), respectively. The mean distance between the tip of the triceps insertion and the area on the olecranon cortex corresponding to the bare area was 19.0 mm (range, 16.0-23.0 mm). The mean transverse and longitudinal widths of the cortical notch were 3.0 mm (range, 1.6-4.5 mm) and 8.0 mm (range, 6.5-14.8 mm), respectively. The mean distance between the tip of the triceps insertion and the osteotomy apex was 22.0 mm (range, 18.0-24.0 mm) and the mean angle between the osteotomy surface and the vertical plane corresponding to the tangent plane was 20° (range, 10° to 25°). The mean angle of the V shape was 140° (range, 130° to 150°). Using the narrowest edge lacking cartilage (lateral or medial side) as a point of reference to locate the bare area, the designed chevron osteotomy entered the joint in the bare area in most specimens and decreased associated damage to the joint cartilage. This study describes the anatomy of the bare area and the design of the ideal chevron-shaped osteotomy to treat type C distal humerus fractures.


Pharmacopeial specifications and analytical data from post-marketing quality sampling and testing programs: A perspective beyond out-of-specification results.
Ensuring that marketed medicines meet acceptable standards (safety, quality, and efficacy) involves aspects of product development, compliance with good manufacturing practices, and monitoring and testing of these products already on the market. Pharmacopeias are one of the main tools used by regulatory authorities in the analytical testing for quality assessment; there are almost 60 pharmacopeias in the world. Thus, this research evaluated the potential impacts of the differences between the pharmacopeial specifications in the quality assessment of these products. It also assessed the use of analytical data to strengthen these surveillance systems. The pharmacopeial specifications for assay determination and dissolution test from United States Pharmacopeia (USP), British (BP), Brazilian (FB), Portuguese (FP), Argentine (FA), and International (Ph. Int.) Pharmacopeias were compared. The quality control reports and results of the Brazilian conformity assessment program were used to support the research. The possibility of selection of medicines or manufacturers for monitoring, sampling, and testing, as well as good manufacturing practice inspections based on analytical data were observed, even considering compliant cases or those within the tolerance limits. An important impact of acceptance criteria given in the individual monographs of different pharmacopeias regarding quality testing was also observed. Strengthening of the pharmacopeial harmonization projects and universalization of the requirements provided by the individual monographs can help in supporting the internationalization of the pharmaceutical market and improving access to medicines.


Urine activity of cathepsin B, collagenase and urine excretion of TGF-beta 1 and fibronectin in membranous glomerulonephritis.
In 30% of cases nephrotic syndrome is caused by membranous glomerulonephritis (MG). Protein accumulation in glomeruli leads to progressive loss of kidney function and damage of structure in MG. The role of tissue proteolytic systems and growth factors in this process is not known. The purpose of the study was to estimate urine cathepsin B, collagenase activity and urine excretion of TGF-beta 1 and fibronectin in MG. Cathepsin B activity was greater in the urine of MG patients than in the control group (10.58 +/- 8.73 pmol AMC/mg creatinine per min-1 vs control 7.11 +/- 2.05 pmol AMC/mg creatinine per min-1; P < 0.05). Urine collagenase activity was higher in the group of patients than in the control group (8.59 +/- 4.26 pmol AMC/mg creatinine per min-1 vs control 3.84 +/- 2.09 pmol AMC/mg creatinine per min-1 P < 0.02). Urine excretion of fibronectin (45.60 ng/mg creatinine vs control 10.30 ng/mg creatinine; P < 0.04) and TGF-beta 1 levels in the urine were higher than in controls (283.55 +/- 248.13 pg/ml vs 36.11 +/- 48.01 pg/ml; P < 0.01). Results suggest glomerular overproduction of TGF-beta 1 and urinary leak of proteolytic enzymes (PE). This may result in decreased glomerular PE activity in MG and, with time, may lead to protein accumulation in renal glomeruli and to progressive loss of kidney function and damage of structures as the course of MG progresses. PE urine composition as well as ECM protein and cytokine urine excretion may allow noninvasive glomerulopathy course monitoring in humans in the future.


General requirements for protein secretion by the F-like conjugation system R1.
Bacterial conjugation disseminates genes among bacteria via a process requiring direct cell contact. The cell envelope spanning secretion apparatus involved belongs to the type IV family of bacterial secretion systems, which transport protein as well as nucleoprotein substrates. This study aims to understand mechanisms leading to the initiation of type IV secretion using conjugative plasmid paradigm R1. We analyze the general requirements for plasmid encoded conjugation proteins and DNA sequence within the origin of transfer (oriT) for protein secretion activity using a Cre recombinase reporter system. We find that similar to conjugative plasmid DNA strand transfer, activation of the R1 system for protein secretion depends on binding interactions between the multimeric, ATP-binding coupling protein and the R1 relaxosome including an intact oriT. Evidence for DNA independent protein secretion was not found.


A quantitative comparison of the mutagenicity of carcinogenic polycyclic hydrocarbon derivatives in cultured mammalian cells.
The mutagenicity of a series of reactive polycyclic hydrocarbon derivatives has been studied using Chinese hamster (V79) cells in culture and, as a mutational marker, resistance to the purine analogue 8-azaguanine. The compounds were compared by relating mutation frequency to the dose applied (mutagenic effectiveness) to induced cytotoxicity (mutagenic efficiency) and to the extent of reaction of the hydrocarbon with DNA (absolute mutagenic efficiency). In each case anti-benzo(alpha)pyrene (BP)-7,8 dihydrodiol-9,10 oxide, the suspected ultimate carcinogenic form of benzo(alpha)pyrene, was by far the most potent of the compounds tested. Furthermore, the mutagenicity of the syn- and anti-BP-diolepoxide isomers correlated positively with their documenrences in the ability of each derivative to form a carbonium ion. Variations in mutagenic efficiency and absolute mutagenic efficiency were more difficult to explain. The latter findings are discussed in relation to the types of hydrocarbon-DNA product obtained with each compound and also to the possibility of a variable cellular response to more subtle differences in the chemistry of the hydrocarbon-DNA interaction.


Controversies of total mesorectal excision for rectal cancer in elderly patients.
The cornerstone of treatment for rectal cancer is resectional treatment according to the principles of total mesorectal excision (TME). However, population-based registries show that improvements in outcome after resectional treatment occur mainly in younger patients. Furthermore, 6-month postoperative mortality is significantly increased in elderly patients (> or = 75 years of age) compared with younger patients (< 75 years of age). Several confounding factors, such as treatment-related complications and comorbidity, are thought to be responsible for these disappointing findings. Thus, major resectional treatment is not advantageous for all older patients with rectal cancer. However, the Dutch TME trial showed a good response to a short course of neoadjuvant radiotherapy in elderly patients. Biological responses to cancer treatment seem to change with age, and, therefore, individualised cancer treatments should be used that take into account the heterogeneity of ageing. For elderly patients who retain a good physical and mental condition, treatment that is given to younger patients is deemed appropriate, whereas for those with diminished physiological reserves and comorbid conditions, alternative treatments that keep surgical trauma to a minimum and optimise the use of radiotherapy might be more suitable.


Long-term incidence of urinary tract infection after ureteral reimplantation for primary vesicoureteral reflux.
To determine the incidence of urinary tract infection (UTI) after ureteral reimplantation (UR) for primary vesicoureteral reflux (VUR). In this retrospective review, the pyelonephritis-free survival of patients with primary VUR who underwent open UR from January 1990 to December 2002 was assessed using a Cox proportional hazards analysis. 1076 patients underwent open UR for primary VUR. 73.0% were female; median age was 4.7 years. 80.1% presented with UTI. Clinical success rate for non-tapered UR was 96.5%. Median follow-up was 2.9 years. 21.8% had at least one postoperative UTI. 6.5% had postoperative pyelonephritis (POP) at a median of 21 months postoperatively. On multivariate survival analysis female gender (OR 9.97, 95% CI 3.07-32.34), preoperative VUR grade ≥ 3 (2.14, 1.25-3.69), breakthrough preoperative UTI (2.00, 1.22-3.25), and preoperative renal scarring (1.86, 1.15-2.99) were associated with POP. POP is rare on long-term follow-up, suggesting that UR is effective in reducing pyelonephritis in this population.


Management of dredge material in the Republic of Ireland - A review.
As an island nation the Republic of Ireland's ports and harbours are key to the economic wellbeing of the country as they are the primary transport link to the United Kingdom, mainland Europe and beyond. This paper examines the main aspects of the Irish dredging industry with comparison to international practice and standards, including the source of the dredge material and volumes generated annually, the dredging plant employed and the management processes currently practised. Relevant European and Irish legislation governing dredging, disposal at sea and waste licensing are presented. The potential impacts of disposal at sea are discussed with the implications for the Irish dredging industry of recently introduced European Directives assessed. Beneficial use rates for dredge material and the techniques implemented in Ireland are examined and compared with international practice. Recent notable beneficial use projects for dredge material and proposed innovative dredge material management techniques for specific dredging projects in Ireland are presented. Proposals to encourage greater beneficial use of dredge material and minimise disposal at sea for Ireland are presented including the introduction of environmental credits, tax breaks and a grant system for pilot schemes. An alternative disposal at sea charge fee structure is also recommended to encourage alternative dredge material management practices. Ireland's management of contaminated sediment is also presented with recent projects described highlighting the current practice of primarily exporting contaminated sediment to mainland Europe. Alternative methods of treatment of contaminated sediment are assessed in an Irish context. Future issues and challenges facing the Irish dredging industry are assessed and a critical analysis of the current approaches to dredge material management is presented.


Role of glutamate receptors and an on-going protein synthesis in the regulation of phosphorylation of Ca2+/calmodulin-dependent protein kinase II in the CA3 hippocampal region in mice administered with kainic acid intracerebroventricularly.
In an immunohistochemical study, kainic acid (KA, 0.1 microg) administered intracerebroventricularly (i.c.v.) dramatically increased the expression of Ca2+/calmodulin-dependent protein kinase II (CaMK II) and the phosphorylation of CaMK II (p-CaMK II) in the CA3 hippocampal region of mice. Pre-treatment with cycloheximide (a protein synthesis inhibitor; 200 mg/kg) intraperitoneally prevented the expression of CaMK II and phosphorylation of CaMK II induced by KA. In addition, pre-treatment with MK-801 ((5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine; an NMDA receptor blocker, 1 microg, i.c.v.) or CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; a non-NMDA receptor blocker, 0.5 microg, i.c.v.) attenuated the p-CaMK II, but not CaMK II, expression induced by KA. Our results suggest that KA administered supraspinally induces CaMK II and the phosphorylation of CaMK II expression in the CA3 hippocampal region, for which an on-going protein synthesis is needed. Furthermore, both NMDA and non-NMDA receptors appear to be involved in supraspinally administered KA-induced phosphorylation of CaMK II.


Absence of black-white differences in sodium and calcium in platelets.
Consistent differences in sodium transport in red blood cells are observed in blacks compared to whites and have been the basis for speculation regarding physiologic differences in the vascular bed as well. The theoretical link between these metabolic markers and the risk of hypertension generally assumes a secondary effect on calcium. Calcium metabolism in red cells is difficult to study, however, so this proposition has never been tested directly. Given the growing importance of platelets in this area of research, and the availability of sensitive laboratory methods, we carried out a systematic examination of calcium and sodium homeostasis in this cell line among black and white normotensive subjects. No differences were noted in resting cytosolic calcium, mobilizable stores, agonist-induced response, or sodium-calcium exchange. In addition, resting sodium was not different between groups, nor was the increase in sodium induced by ouabain. A correlation of 0.3 was observed between blood pressure and both resting and stimulated cytosolic calcium (P < .05). Red cells may be atypical for studies of calcium and sodium homeostasis, and their relevance for interethnic studies of causal pathways in hypertension should be reconsidered.


Long-term follow-up and comparison of programmable and non-programmable ventricular cerebrospinal fluid shunts among adult patients with different hydrocephalus etiologies: a retrospective cohort study.
Programmable valve (PV) has been shown as a solution to the high revision rate in pediatric hydrocephalus patients, but it remains controversial among adults. This study is to compare the overall revision rate, revision cause, and revision-free survival between PV and non-programmable valve (NPV) in adult patients with different hydrocephalus etiologies. We reviewed the chart of all patients with hydrocephalus receiving index ventricular cerebrospinal fluid (CSF) shunt operations conducted at a single institution from January 2017 to December 2017. Patients included in the study were followed up for at least 5 years. Statistical tests including independent t-test, chi-square test, and Fisher's exact test were used for comparative analysis, and Kaplan-Meier curve using log-rank test was performed to compare the revision-free survival between the PV and NPV groups. A total of 325 patients were included in the study, of which 181 patients were receiving PVs and 144 patients receiving NPV. There were 23 patients (12.8%) with PV and 22 patients (15.3%) with NPV receiving initial revision. No significant statistical difference in the initial revision rate was observed between the two groups (p = 0.52). No survival difference was found between the PV and NPV groups. However, better revision-free survival was noted in the PV group among idiopathic normal pressure hydrocephalus (iNPH) (p = 0.0274) and post-traumatic hydrocephalus (p = 0.017). The combination of the different etiologies of hydrocephalus and the features of PV and NPV results in different outcomes-revision rate and revision-free survival. PV use might be superior to NPV in iNPH and post-traumatic hydrocephalus patients. Further studies are needed to clarify the indications of PV use in adult hydrocephalus patients.


Erythrocyte glutathione is a novel biomarker of Diamond-Blackfan anemia.
Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia with mutations in ribosomal protein (RP) genes. Elevated activity of erythrocyte adenosine deaminase (eADA) has been utilized as a biomarker of DBA. We examined erythrocyte reduced glutathione (GSH) as well as eADA in 22 patients in 18 DBA families, in whom RP gene mutations had been identified. Simultaneous evaluation of both eADA and GSH demonstrated that all examined DBA patients showed elevated values of either eADA or GSH, whereas presence of both eADA and GSH elevation was able to distinguish DBA patients from 34 normal controls and 14 unaffected members of the DBA families. Furthermore, a support vector machines analysis using both eADA and GSH levels yielded a formula to differentiate DBA from both normal controls and non-DBA family members. To confirm the usefulness of the formula, we analyzed additional 7 patients diagnosed by the clinical criteria. Although eADA showed within normal values in 3 patients, all of these patients were diagnosed as 'DBA' by use of the formula. Because extensive analysis of the RP genes failed to detect no causative mutation in approximately 40% of clinically diagnosed DBA patients, GSH may be useful an additional biomarker for diagnosis of DBA.


Bayesian optimization of comprehensive two-dimensional liquid chromatography separations.
Comprehensive two-dimensional liquid chromatography (LC×LC), is a powerful, emerging separation technique in analytical chemistry. However, as many instrumental parameters need to be tuned, the technique is troubled by lengthy method development. To speed up this process, we applied a Bayesian optimization algorithm. The algorithm can optimize LC×LC method parameters by maximizing a novel chromatographic response function based on the concept of connected components of a graph. The algorithm was benchmarked against a grid search (11,664 experiments) and a random search algorithm on the optimization of eight gradient parameters for four different samples of 50 compounds. The worst-case performance of the algorithm was investigated by repeating the optimization loop for 100 experiments with random starting experiments and seeds. Given an optimization budget of 100 experiments, the Bayesian optimization algorithm generally outperformed the random search and often improved upon the grid search. Moreover, the Bayesian optimization algorithm offered a considerably more sample-efficient alternative to grid searches, as it found similar optima to the grid search in far fewer experiments (a factor of 16-100 times less). This could likely be further improved by a more informed choice of the initialization experiments, which could be provided by the analyst's experience or smarter selection procedures. The algorithm allows for expansion to other method parameters (e.g., temperature, flow rate, etc.) and unlocks closed-loop automated method development.


Chromogenic peptide substrate assays for determining components of the plasma kallikrein system.
Methods for plasma prekallikrein, kallikrein like activity, kallikrein inhibitors and inhibitors of beta FXIIa using chromogenic peptide substrates are outlined. Results with these assays are described and discussed. Substrates for alpha and beta FXIIa are also described and the possibilities of a direct chromogenic substrate assay for FXII are discussed.


Age-related alterations in superoxide anion generation in mouse peritoneal macrophages studied by repeated stimulations and heat shock treatment.
The ability of thioglycollate-elicited peritoneal macrophages (PM) from young and senescent mice to generate superoxide anions (O2-) under repeated stimulation or thermal stress was studied using either zymosan, opsonized zymosan (OZ), or phorbol myristate acetate (PMA). A diminished capacity to recover from repeated stimulation was found with aging. When stimulated for a second time 24 hours after the primary stimulation, PM from young animals generated 80% of the initial O2- responses to either zymosan, or OZ. Under the same conditions, PM from senescent mice generated 62% of the initial O2- produced in response to zymosan, and 45% in response to OZ. In both age groups the response to a second PMA stimulation comprised only 10% of the primary response. A considerably diminished capacity to generate O2- was also demonstrated in PM from senescent mice after recovery from exposure to thermal stress. Exposure to 42.5 degrees C for 20 minutes was found to be the threshold temperature for irreversible loss of activity in senescent PM, whereas at this temperature, PM from young animals recovered up to 70% of their O2- generating activity. Since NADPH oxidase and superoxide dismutase activities were only mildly affected by the hyperthermia in all age groups, they could not account for the age-related decline in the recovery from stress. Age-related alterations in signal transduction or receptor alterations could possibly play a primary role in this decline.


A penalty on photosynthetic growth in fluctuating light.
Fluctuating light is the norm for photosynthetic organisms, with a wide range of frequencies (0.00001 to 10 Hz) owing to diurnal cycles, cloud cover, canopy shifting and mixing; with broad implications for climate change, agriculture and bioproduct production. Photosynthetic growth in fluctuating light is generally considered to improve with increasing fluctuation frequency. Here we demonstrate that the regulation of photosynthesis imposes a penalty on growth in fluctuating light for frequencies in the range of 0.01 to 0.1 Hz (organisms studied: Synechococcus elongatus and Chlamydomonas reinhardtii). We provide a comprehensive sweep of frequencies and duty cycles. In addition, we develop a 2nd order model that identifies the source of the penalty to be the regulation of the Calvin cycle - present at all frequencies but compensated at high frequencies by slow kinetics of RuBisCO.


Experiences of Norwegian child and school health nurses with the "Starting Right™" child health assessment innovation: a qualitative interview study.
Although child health services are well established in Norway, the use of information technology for the systematic collection of evidence-based child- and proxy-reported health measures may be beneficial in the early identification of child development problems. The Norwegian "Starting Right™" health service innovation consists of parent- and child-reported online structured health assessments tools, including practical routines for child and school health assessments. The aim of this study was to explore the experiences of child and school health nurses with the Starting Right innovation. We used a qualitative design and conducted three focus group interviews with 18 child and school health nurses from three child health centres one year after the implementation of the innovation. The experiences of professionals with the Starting Right innovation were captured by three themes: (1) the digital innovation could be used to obtain a good overview of a child's health and development; (2) interpreting the questionnaires was a challenge; and (3) implementing the new digital innovation was time-consuming. Overall, the child and school health nurses experienced that the Starting Right innovation was useful for providing a comprehensive overview of child development and health. The challenges related to interpreting the parents' scores and follow-up of children, as well as providing the questionnaires in relevant foreign languages, should be addressed to allow all children and families to be reached.


Inactivation of bovine thrombin by water-soluble carbodiimides: the essential carboxyl group has a pKa of 5.51.
Bovine thrombin is rapidly and completely (greater than 99%) inactivated by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in a pseudo-first-order process. A plot of the pseudo-first-order rate constant for inactivation by 20 mM EDC at different pH values from pH 4.0 to 7.7 at 25 degrees C shows that inactivation is critically dependent on the protonated form of an acidic side chain with a pKa of 5.51. Significant protection against inactivation is provided by the competitive inhibitor dansyl-L-arginine N-(3-ethyl-1,5-pentanediyl)amide, suggesting that the essential carboxyl group may be involved in substrate binding. 1-Ethyl-3-(4-azonia-4,4-dimethylpentyl)carbodiimide (EAC) inactivates thrombin much more rapidly than EDC under the same conditions.