Exploring the potential application of alternative nuclei in NMR based metabolomics.
Nuclear magnetic resonance (NMR) is widely used in metabolomics but it focusses on 1H over other NMR-active nuclei. To evaluate the potential of alternative NMR-sensitive nuclei to generate useful metabolomic data. Proton, carbon, phosphorus, and nitrogen-based NMR metabolomics was undertaken on extracts from mint and European honey bee tissue. Carbon NMR provided useful information but required larger sample sizes. Phosphorus produced overlapping peaks in one dimensional (1D) analysis but showed potential in 2D experiments. 15N NMR was found to not be sensitive enough for general metabolomic work. Alternative NMR active nuclei are useful for metabolomics.


Nano Polymorphism-Enabled Redox Electrodes for Rechargeable Batteries.
Nano polymorphism (NPM), as an emerging research area in the field of energy storage, and rechargeable batteries, have attracted much attention recently. In this review, the recent progress on the composition and formation of polymorphs, and the evolution processes of different redox electrodes in rechargeable metal-ion, metal-air, and metal-sulfur batteries are highlighted. First, NPM and its significance for rechargeable batteries are discussed. Subsequently, the current NPM modulation strategies of different types of representative electrodes for their corresponding rechargeable battery applications are summarized. The goal is to demonstrate how NPM could tune the intrinsic material properties, and hence, improve their electrochemical activities for each battery type. It is expected that the analysis of polymorphism and electrochemical properties of materials could help identify some "processing-structure-properties" relationships for material design and performance enhancement. Lastly, the current research challenges and potential research directions are discussed to offer guidance and perspectives for future research on NPM engineering.


EDXRF and the relative presence of K, Ca, Fe and as in amyloidogenic tissues.
Trace and minor elements play crucial roles in a variety of biological processes, including amyloid fibrils formation. Mechanisms include activation or inhibition of enzymatic reactions, competition between elements and metal proteins for binding positions, also changes to the permeability of cellular membranes. These may influence carcinogenic processes, with trace and minor element concentrations in normal and amyloid tissues potentially aiding in cancer diagnosis and etiology. With the analytical capability of the spectroscopic technique X-ray fluorescence (XRF), this can be used to detect and quantify the presence of elements in amyloid characterization, two of the trace elements known to be associated with amyloid fibrils. In present work, involving samples from a total of 22 subjects, samples of normal and amyloid-containing tissues of heart, kidney, thyroid, and other tissue organs were obtained, analyzed via energy-dispersive X-ray fluorescence (EDXRF). The elemental distribution of potassium (K), calcium (Ca), arsenic (As), and iron (Fe) was examined in both normal and amyloidogenic tissues using perpetual thin slices. In amyloidogenic tissues the levels of K, Ca, and Fe were found to be less than in corresponding normal tissues. Moreover, the presence of As was only observed in amyloidogenic samples; in a few cases in which there was an absence of As, amyloid samples were found to contain Fe. Analysis of arsenic in amyloid plaques has previously been difficult, often producing contradictory results. Using the present EDXRF facility we could distinguish between amyloidogenic and normal samples, with potential correlations in respect of the presence or concentration of specific elements.


Frequency comb-to-comb stabilization over a 1.3-km free-space atmospheric optical link.
Stabilizing a frequency comb to an ultra-stable optical frequency reference requires a multitude of optoelectronic peripherals that have to operate under strict ambient control. Meanwhile, the frequency comb-to-comb stabilization aims to synchronize a slave comb to a well-established master comb with a substantial saving in required equipment and efforts. Here, we report an utmost case of frequency comb-to-comb stabilization made through a 1.3 km free-space optical (FSO) link by coherent transfer of two separate comb lines along with a feedback suppression control of atmospheric phase noise. The FSO link offers a transfer stability of 1.7 × 10-15 at 0.1 s averaging, while transporting the master comb's stability of 1.2 × 10-15 at 1.0 s over the entire spectrum of the slave comb. Our remote comb-to-comb stabilization is intended to expedite diverse long-distance ground-to-ground or ground-to-satellite applications; as demonstrated here for broadband molecular spectroscopy over a 6 THz bandwidth as well as ultra-stable microwaves generation with phase noise of -80 dBc Hz-1 at 1 Hz.


First record and new species of the Oriental leafhopper genus Trifida Thapa Sohi (Hemiptera: Cicadellidae: Typhlocybinae) from China.
The Oriental leafhopper genus Trifida Thapa Sohi, 1986 and T. quadripunctata are recorded from China for the first time. Three new species, T. eleganta, T. robusta and T. elongata spp. nov., are described and illustrated. A check-list and key to all species of Trifida are provided.


Evaluation of anti-HBV drug resistant mutations among patients with acute symptomatic hepatitis B in the United States.
Reported HBV drug resistance mutations among previously untreated patients with chronic hepatitis B are variable. Whether resistant HBV strains are transmitted in the acute setting is uncertain. We sought to document the presence of antiviral resistance (AVR) mutations in patients with acute HBV (AHB) infection. AHB infection was defined by HBsAg/IgM anti-HBc positivity, ALT>10X ULN and compatible clinical history. The TRUGENE HBV kit was used to perform genotyping and direct sequencing of the viral polymerase. INNO-LiPA HBV DRv2 and DRv3 were used to detect AVR mutations. Clonal sequencing was conducted on selected specimens. Twenty-three patients were evaluated (mean age, 43 years; 54% male; 39% African American, 39% Caucasian, 13% Hispanic and 4% Asian). The mean peak ALT was 1554.2IU/L and mean peak total serum bilirubin was 12 mg/dl. The HBV DNA median viral load (N = 15) was 5.14 log(10)IU/ml. Nineteen patients were genotype A, and 1 each were genotype C, D, E and G. HBV drug resistance mutations were not detected by direct sequencing or INNO-LiPA. Clonal sequencing was conducted on 192 clones isolated from three patients and showed rtA181T, rtM250V and rtS202G mutations at an overall frequency of 1.54%, 1.39%, and 1.67% respectively. We detected adefovir/lamivudine and entecavir relevant mutations in a minor population (<2%) of viral clones by clonal sequencing only. The clinical significance of these mutations is uncertain and may represent small populations of quasi-species vs. transmission of drug resistant strains.


Radical cystectomy for BCG failure: has the timing improved in recent years?
• To analyse if there is a trend in recent years towards performing radical cystectomy (RC) before muscle invasion or extravesical spread after failure of bacille Calmette-Guérin (BCG) for high grade Ta/T1 bladder cancer. Although BCG is indicated for prophylaxis after endoscopic tumour resection there is still a risk of progression. • A retrospective analysis of our RC database (1992-2008) was performed to identify patients who underwent RC after receiving BCG. • Relevant clinical and pathological data for the patients with clinical stage Ta, T1 and/or Tis at initial transurethral resection of bladder tumour were analysed. • Pathological stage and survival for patients undergoing RC from 2003 to 2007 (group 2) were compared with those for patients operated between 1992 and 2002 (group 1). • A total of 152 patients were included (75 in group 2 and 77 in group 1). Both groups were similar in T-stage before BCG initiation, number of BCG cycles received and time interval to RC. • There was no change in the proportion of patients undergoing RC with ≥ pT2 bladder cancer in recent years (P= 0.5). • Fifty-two percent of group 2 and 43% of group 1 had ≥ pT2 BC. The 5-year survival was similar. • Despite concerns about delay in performing RC for patients failing one or more courses of BCG we have not observed a trend towards a lower pathological stage for patients undergoing RC after BCG. • A high proportion of patients have muscle-invasive bladder cancer; more than 10% have lymph node metastasis.


Introducing a novel human mtDNA mutation into the Paracoccus denitrificans COX I gene explains functional deficits in a patient.
We identified a novel mutation (S142F) in the human mtDNA CO I gene in a patient with a clinical phenotype resembling mitochondrial cardioencephalomyopathy. To substantiate pathogenicity, we modeled the identified mutation in the homologous gene in Paracoccus denitrificans and analyzed the biochemical consequences. We observed a deleterious effect on enzyme activity, with a lack of heme a3. Taking advantage of the extensive structural homology between the bacterial enzyme and the mammalian core complex, we conclude that the novel S142F mutation is disease-related. This approach can be used in other cases to support the pathogenicity of novel variants in the mitochondrial genome.


Acetaldehyde, methanol, and ethanol analysis by headspace gas chromatography.
This report describes a headspace procedure suitable for the gas chromatographic assay of acetaldehyde, methanol, ethanol and various other volatile substances in biological samples. Carbopack B coated with 5% Carbowax 20-M is compared to Carbopack C coated with 0.2% Carbowax 1500. Assay range, linearity and precision are reported for the Carbopack B material.


Age-related changes of human serum Sirtuin6 in adults.
Aging is a natural life process and with an aging population, age-related diseases (e.g. type 2 diabetes mellitus (T2DM), atherosclerosis-based cardiovascular diseases) are the primary mortality cause in older adults. Telomerase is often used as an aging biomarker. Detection and characterization of novel biomarkers can help in a more specific and sensitive identification of a person's aging status. Also, this could help in age-related diseases early prevent, ultimately prolonging the population's life span. Sirtuin 6 (Sirt6) - a member of the Sirtuins NAD+-dependent histone deacetylases family - is mainly intracellularly expressed, and is reported to be involved in the regulation of aging and aging-related diseases. Whether serum Sirt6 is correlated with aging and could be used as an aging biomarker is unknown. In the present study, we aimed to investigate the age-related Sirt6 changes in the serum of human adults. Participants were divided into three groups according to age: 20-30 years (Young); 45-55 years (Middle-aged); and ≥ 70 years (Old). The Sirt6 and telomerase serum concentrations were determined by ELISA. The Sirt6 and human telomerase reverse transcriptase (hTERT) expression in vessels from amputated human lower limbs were analyzed using real-time quantitative PCR (RT-qPCR) and immunohistochemical staining. The relationships between variables were evaluated by Pearson correlation analysis. The Sirt6 and telomerase serum levels reduced with an increase in age. A similar tendency was observed for Sirt6 and hTERT in the vessel. Serum levels of Sirt6 were higher in females compared with males. Pearson's regression analysis revealed that the Sirt6 serum level positively correlated with telomerase (r = 0.5743) and both were significantly negatively correlated with age (r = - 0.5830 and r = - 0.5993, respectively). We reported a negative correlation between serum Sirt6 concentration and aging in human beings. Therefore, the Sirt6 serum level is a potential sex-specific aging marker.


Neural Wiskott-Aldrich syndrome protein is required for accurate chromosome congression and segregation.
The accurate distribution and segregation of replicated chromosomes through mitosis is crucial for cellular viability and development of organisms. Kinetochores are responsible for the proper congression and segregation of chromosomes. Here, we show that neural Wiskott-Aldrich syndrome protein (N-WASP) localizes to and forms a complex with kinetochores in mitotic cells. Depletion of NWASP by RNA interference causes chromosome misalignment, prolonged mitosis, and abnormal chromosomal segregation, which is associated with decreased proliferation of N-WASP-deficient cells. N-WASP-deficient cells display defects in the kinetochores recruitment of inner and outer kinetochore components, CENP-A, CENP-E, and Mad2. Live-cell imaging analysis of GFP-α-tubulin revealed that depletion of N-WASP impairs microtubule attachment to chromosomes in mitotic cells. All these results indicate that N-WASP plays a role in efficient assembly of kinetochores and attachment of microtubules to chromosomes, which is essential for accurate chromosome congression and segregation.


Hepatic subcellular distribution of manganese in manganese and manganese-bilirubin induced cholestasis.
Administration of non-cholestatic doses of manganese (Mn2+) followed by injection of bilirubin (BR) results in a severe reduction in rat bile flow. Male Sprague-Dawley rats were given various doses of Mn2+ (2, 4.5, 8, and 18 mg/kg, i.v.) and killed 0.25, 1, 3, or 5 hr later. 54Mn2+ was used to evaluate Mn2+ content (micrograms/g protein) in different liver fractions: homogenate, mitochondria, microsomes, cytoplasm, nuclei-membrane fraction and liver cell plasma membrane fractions, one containing bile canalicular complexes (LCPM-BCM), the other containing sinusoidal membranes (LCPM-PM). In LCPM-BCM and LCPM-PM, two time-related patterns of Mn2+ content were observed. With non-cholestatic doses (2, 4.5, and 8 mg/kg), Mn2+ content decreased with time and rarely exceeded 50 micrograms/g protein. With 18 mg/kg (a cholestatic dose), Mn2+ content increased with time and reached values over 100 micrograms/g protein (3-5 hr), reflecting possible modification in membrane structure. BR caused a marked increase in Mn2+ content (at a dose of 4.5 mg Mn2+/kg) in LCPM-BCM (240%), approaching values seen with 18 mg Mn2+/kg, whereas in LCPM-PM it was less striking (50%). These and other results obtained with various treatments (cholestatic and non-cholestatic) suggest than Mn2+ concentration in bile canalicular membranes is a critical factor in both forms of cholestasis, and that BR can facilitate Mn2+ incorporation in the bile canalicular membrane.


Awareness on hematological malignancies among college students.
Cancers of blood arise when the abnormal blood cells undergo uncontrolled growth which outpaces the natural production of normal blood cells, interfering with the cells' normal functions. Leukemia, lymphoma, and myeloma are the three types of blood cancers. The aim of our study is to assess and create awareness of hematological malignancies among college students. A questionnaire was prepared using Google Forms based on the awareness of the Hematological malignancies disinfection methods among dental students in Chennai. It was then circulated among a certain set of participants using an online Google Form link. The participants were asked about their knowledge level regarding hematological malignancies and a majority (68.97%) were aware of the same, whereas 27.59% were not aware and the rest (3.45%) were not sure. When asked about how dental care detects various hematological malignancies, 10.34% of the participants replied as "patient speaks about any abnormality," 75.86% replied as "oral manifestations," and 13.79% replied as "dentists cannot detect hematological malignancies." From the above results and discussion, we can come to the conclusion that most of the dental students who participated in the survey are aware of hematological malignancies and its various types.


Setting legislative norms for environmental lead exposure: results of an epidemiological survey in the east of Belgium.
Blood lead concentrations (Pb-B, microgram/100 ml) was measured in children and adults, both sexes, living in and around Liège (control group, n = 859) and in the urban center of Verviers (exposed group, n = 568) where houses with lead piping are supplied with corrosive drinking water. In control children, the mean Pb-B increases with age; in control adults the levels are higher than for children, but are independent of age (ranges: males 19.1 - 21.1; females 12.9 - 16.9). In exposed children aged 5-14 years, the mean Pb-B is higher than in young exposed adults: these children constitute thus a high risk group. In the exposed adults, the mean Pb-B rises also with age (ranges: male 24.2 - 33.5; females 19.4 - 32.3). Our epidemiological survey shows that the safety margin of the present EEC figures is acceptable for children exposed to the low and usual urban Pb concentrations.


New insights into the responses of soil microorganisms to polycyclic aromatic hydrocarbon stress by combining enzyme activity and sequencing analysis with metabolomics.
Polycyclic aromatic hydrocarbons (PAHs), some of the most widespread organic contaminants, are highly toxic to soil microorganisms. Whether long-term polluted soils can still respond to the fresh input of pollutants is unknown. In this study, the soil enzyme activity, soil microbial community structure and function and microbial metabolism pathways were examined to systematically investigate the responses of soil microorganisms to fresh PAH stress. Microbial activity as determined by soil dehydrogenase and urease activity was inhibited upon microbe exposure to PAH stress. In addition, the soil microbial community and function were obviously shifted under PAH stress. Both microbial diversity and richness were decreased by PAH stress. Rhizobacter, Sphingobium, Mycobacterium, Massilia, Bacillus and Pseudarthrobacter were significantly affected by PAH stress and can be considered important indicators of PAH contamination in agricultural soils. Moreover, the majority of microbial metabolic function predicted to respond to PAH stress were affected adversely. Finally, soil metabolomics further revealed specific inhibition of soil metabolism pathways associated with fatty acids, carbohydrates and amino acids. Therefore, the soil metabolic composition distinctively changed, reflecting a change in the soil metabolism. In summary, fresh contaminant introduction into long-term polluted soils inhibited microbial activity and metabolism, which might profoundly affect the whole soil quality.


G-cell population in antral mucosa of the dog.
The gastrin-cell (G-cell) population in the pyloric antrum of 8 dogs was studied quantitatively by immunofluorescence. The G-cell population was dense in the pyloric antrum and very few cells were seen in the antrocorporal junction. The estimated total number of G cells was (1.66 +/- 0.12) X 10(7) in the pyloric antrum and the greatest number of G cells per unit mucosal surface area was along the greater curvature of the pyloric antrum. Except along the greater curvature, G cells per unit musocal volume were significantly greater in number (P less than 0.05) in the proximal antrum adjacent to the antrocorporal junction that in any other regions distal to it. Differences in mucosal thickness were considered as a causative factor for these differences.


Systemic sclerosis.
Systemic sclerosis affects the connective tissue of various organs. It is characterized by alteration of the microvasculature with a dense inflammatory cellular infiltrate, followed by massive deposition of collagen. This review discusses diagnostic criteria, clinical subsets, survival data, clinical evaluation, epidemiology, pathogenesis, immunobiology, genetics, and therapy for systemic sclerosis in adults. Because the diagnosis of systemic sclerosis is most dependent on its cutaneous involvement, knowledge of this is essential in the evaluation and management of patients with this disorder.


A case of posterior HIP dislocation with intertrochanteric fracture: Beware of the sharp calcar spike.
Posterior dislocation of hip is commonly associated with acetabular lip fractures. Involvement of neck, trochanter or intertrochanteric region is uncommon. Very few cases of posterior hip dislocation with ipsilateral intertrochanteric fracture in the absence of head or acetabular fracture have been reported in the literature. We report such a case in a 19yr male treated with open reduction and internal fixation with sliding hip screw with good functional and radiological outcome at 1 year. Being an extremely rare form of injury, such an injury pattern does not exist in present classification systems. There is a need to revise the existing classification systems and formulate a protocol for the management of the same. Such fractures may also be associated with a sharp calcar spike of the proximal fragment impinging femoral vessels and branches. Attempt at closed reduction without adequate anatomical orientation of the spike can lead to hazardous vascular consequences.


Rationale and design of DUAL study: Doxycycline to Upgrade response in light chain (AL) amyloidosis (DUAL): A phase 2 pilot study of a two-pronged approach of prolonged doxycycline with plasma cell-directed therapy in the treatment of AL amyloidosis.
Light chain (AL) amyloidosis is a plasma cell neoplasm associated with insoluble fibril deposition from clonal immunoglobulin chains systemically. The disease is associated with high early mortality and morbidity owing to advanced organ deposition as well as lack of proven de-fibrillogenic therapies. Pre-clinical and retrospective clinical data suggests that doxycycline has benefit in AL amyloidosis. The ongoing DUAL study is a single center, open label, phase 2 study in which patients with AL amyloidosis who are undergoing clone-directed therapy for the underlying neoplasm with oral doxycycline given for 1 year to test the hypothesis that prolonged doxycycline use will be safe, feasible, and lead to reduced early mortality in systemic AL amyloidosis and hasten organ amyloid response. Clinical follow up visits will occur at monthly intervals for systemic AL patients and at 3 monthly intervals for localized AL patients. Blood tests will be collected during these time points for hematologic response assessment. Organ testing will be conducted at 3 monthly intervals and radiologic testing will be conducted at 6 monthly intervals. Research blood samples will be collected at baseline, 6 and 12 months. Other correlative studies include matrix metalloproteinases (MMP), tissue inhibitor of metalloproteinases (TIMP) testing and patient-reported outcomes.


Autogenous rib graft-hydroxylapatite augmentation of the severely atrophic mandible: preliminary report.
Traditional transoral rib grafts were combined with particulate hydroxylapatite (HA) for augmentation in four patients who had advanced alveolar atrophy or cortical resection of the mandible. Follow-up evaluation for up to 18 months revealed restoration of mandibular morphology, with good prosthetic function and insignificant resorption. No infection or graft loss was observed, in spite of wound dehiscence in two of the four patients, possibly due to the placement of the HA lateral and superior to the rib grafts.


Mapping of a Regulatory Site of the Escherichia coli ADP-Glucose Pyrophosphorylase.
The enzyme ADP-glucose pyrophosphorylase (ADP-Glc PPase) controls the biosynthesis of glycogen in bacteria and starch in plants. It is regulated by various activators in different organisms according to their metabolic characteristics. In Escherichia coli, the major allosteric activator is fructose 1,6-bisphosphate (FBP). Other potent activator analogs include 1,6-hexanediol bisphosphate (HBP) and pyridoxal 5'-phosphate (PLP). Recently, a crystal structure with FBP bound was reported (PDB ID: 5L6S). However, it is possible that the FBP site found is not directly responsible for the activation of the enzyme. We hypothesized FBP activates by binding one of its phosphate groups to another site ("P1") in which a sulfate molecule was observed. In the E. coli enzyme, Arg40, Arg52, and Arg386 are part of this "P1" pocket and tightly complex this sulfate, which is also present in the crystal structures of ADP-Glc PPases from Agrobacterium tumefaciens and Solanum tuberosum. To test this hypothesis, we modeled alternative binding conformations of FBP, HBP, and PLP into "P1." In addition, we performed a scanning mutagenesis of Arg residues near potential phosphate binding sites ("P1," "P2," "P3"). We found that Arg40 and Arg52 are essential for FBP and PLP binding and activation. In addition, mutation of Arg386 to Ala decreased the apparent affinity for the activators more than 35-fold. We propose that the activator binds at this "P1" pocket, as well as "P2." Arg40 and Arg52 are highly conserved residues and they may be a common feature to complex the phosphate moiety of different sugar phosphate activators in the ADP-Glc PPase family.


Importance of a patient dosimetry and clinical follow-up program in the detection of radiodermatitis after long percutaneous coronary interventions.
Complex percutaneous interventions often require high radiation doses likely to produce skin radiation injuries. We assessed the methodology used to select patients with potential skin injuries in cardiac procedures and in need of clinical follow-up. We evaluated peak skin dose and clinical follow-up in a case of radiodermatitis produced during a total occlusion recanalization. This prospective study followed CIRSE and ACC/AHA/SCAI recommendations for patient radiation dose management in interventional procedures carried out in a university hospital with a workload of 4200 interventional cardiac procedures per year. Patient dose reports were automatically transferred to a central database. Patients exceeding trigger levels for air kerma area product (500 Gy cm(2)) and cumulative skin dose (5 Gy) were counseled and underwent follow-up for early detection of skin injuries, with dermatologic support. The Ethical Committee and the Quality Assurance and Radiation Safety Committee approved the program. During 2010, a total of 13 patients (3.0/1,000 that year) received dose values exceeding trigger levels in the cardiovascular institute. Only one patient, who had undergone two consecutive procedures resulting in 970 Gy cm(2) and 13.0 Gy as cumulative skin dose, showed signs of serious radiodermatitis that resolved in 3.7 months. The remaining patients did not manifest skin lesions during follow-up, and whenever patient examination was not feasible as part of the follow-up, neither patients nor families reported any skin injuries. Peak skin dose calculation and close clinical follow-up were feasible and appropriate, with a moderate additional workload for the staff and satisfaction for the patient.


Agricultural medicine core course: building capacity for health and safety professionals.
In 1987 the University of Iowa began training health care professionals to care for farmers' occupational health needs. The training enables health professionals from various disciplines to function in the anticipation, diagnosis, treatment, and prevention of occupational illnesses and injuries in the farm community. A grant from National Institute for Occupational Safety and Health (NIOSH) entitled "Building Capacity for Health and Safety Professionals" allowed for the expansion of this training to other states. This paper describes the challenges, successes, and lessons learned from dissemination of Agricultural Medicine Core Course.


The exponential Diophantine equation 2 x + b y = c z.
Let b and c be fixed coprime odd positive integers with min{b, c} > 1. In this paper, a classification of all positive integer solutions (x, y, z) of the equation 2 (x) + b (y) = c (z) is given. Further, by an elementary approach, we prove that if c = b + 2, then the equation has only the positive integer solution (x, y, z) = (1,1, 1), except for (b, x, y, z) = (89,13,1, 2) and (2 (r) - 1, r + 2,2, 2), where r is a positive integer with r ≥ 2.


Nitric oxide metabolite levels in preterm labor.
To investigate the role of nitric oxide metabolites as markers of infection in subjects with preterm labor or preterm premature rupture of membranes (PTPROM). PTPROM means that there was spontaneous rupture of fetal membrane before the onset of labor and gestational age was <37 weeks. This occurs because of imbalance between matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase. The cause of this imbalance that leads to degradation of collagen causing PTPROM is infection. The bactericidal, fungicidal, viricidal and tumoricidal activities of macrophages are determined in part by elaboration of nitric oxide, hence nitric oxide levels have been found to be increased in infections. During an 18-month period 50 women with preterm labor or PTPROM and 50 controls were enrolled prospectively. Blood and urine samples were obtained for analysis of nitric oxide metabolites. Patients with known causes of preterm labor were excluded. The nitric oxide metabolites, which included both nitrite levels and citrulline levels were significantly higher both in blood as well as urine in patients with preterm labor and PTPROM compared to controls. Serum nitrite levels in subjects with preterm labor were 376.5 +/- 345 nmol/L while in subjects with PTPROM they were 295.7 +/- 161.1 nmol/L and in controls the levels were 62.7 +/- 33.9 nmol/L. Serum citrulline levels in subjects with preterm labor were 5293.8 +/- 2916.7 nmol/L; in PTPROM they were 6536.6 +/- 609.91 nmol/L and in controls they were 949.8 +/- 67.1 nmol/L. On comparing patients with preterm labor, those in whom preterm labor could not be inhibited had statistically significant higher levels of nitrite in both serum and urine (482.9 +/- 387.7 nmol/L and 754.5 +/- 336.5 nmol/L, respectively) compared to patients in whom labor could be inhibited (172.2 +/- 61.9 nmol/L and 401.8 +/- 236.9 nmol/L, respectively). The citrulline levels were also higher among the group who delivered preterm for both serum and urine (5355.4 +/- 3229.7 nmol/L and 11 482.8 +/- 2541.4 nmol/L, respectively) compared to patients in whom labor could be inhibited (5260.2 +/- 2897.08 nmol/L and 10 651.4 +/- 1502.7 nmol/L, respectively) but this did not reach statistical significance. Higher nitric oxide metabolites in women with preterm labor are marker of subclinical infection.


Improving the Accuracy and Efficiency of Abnormal Cervical Squamous Cell Detection With Cytologist-in-the-Loop Artificial Intelligence.
Population-based cervical cytology screening techniques are demanding and laborious and have relatively poor diagnostic accuracy. In this study, we present a cytologist-in-the-loop artificial intelligence (CITL-AI) system to improve the accuracy and efficiency of abnormal cervical squamous cell detection in cervical cancer screening. The artificial intelligence (AI) system was developed using 8000 digitalized whole slide images, including 5713 negative and 2287 positive cases. External validation was performed using an independent, multicenter, real-world data set of 3514 women, who were screened for cervical cancer between 2021 and 2022. Each slide was assessed using the AI system, which generated risk scores. These scores were then used to optimize the triaging of true negative cases. The remaining slides were interpreted by cytologists who had varying degrees of experience and were categorized as either junior or senior specialists. Stand-alone AI had a sensitivity of 89.4% and a specificity of 66.4%. These data points were used to establish the lowest AI-based risk score (ie, 0.35) to optimize the triage configuration. A total of 1319 slides were triaged without missing any abnormal squamous cases. This also reduced the cytology workload by 37.5%. Reader analysis found CITL-AI had superior sensitivity and specificity compared with junior cytologists (81.6% vs 53.1% and 78.9% vs 66.2%, respectively; both with P < .001). For senior cytologists, CITL-AI specificity increased slightly from 89.9% to 91.5% (P = .029); however, sensitivity did not significantly increase (P = .450). Therefore, CITL-AI could reduce cytologists' workload by more than one-third while simultaneously improving diagnostic accuracy, especially compared with less experienced cytologists. This approach could improve the accuracy and efficiency of abnormal cervical squamous cell detection in cervical cancer screening programs worldwide.


Purification and properties of a nucleoside diphosphosugar: NAD+ 2-hexosyl oxidoreductase.
Penicillium charlesii contains a nucleoside diphosphosugar: NAD 2-hexosyl oxidoreductase that oxidizes UDPgalactose (UDP-Galp), ADPribose [1,2] and UDPglucose (UDP-Glc). Dithiothreitol, NAD and 0.25 M NaCl but not nucleoside diphosphates stabilize the enzyme activity. The enzyme was purified and separated on polyacrylamide disc gels by electrophoresis into one major and eight minor bands of protein. Oxidoreductase activity was located in the major and three of the minor bands of protein. Each of these proteins catalyze the oxidation of UDPGalp, ADPribose and UDP-Glc.


Synthesis of a disaccharide repeating unit of the O-antigen from Burkholderia ambifaria and its oligomers.
A disaccharide repeating unit of the O-antigen from Burkholderia ambifaria, 6-deoxy-β-d-Alt-(1 → 4)-α-d-Rha-O(CH2)3NH2 (1), and its dimer and trimer, 6-deoxy-β-d-Alt-(1 → 4)-α-d-Rha-(1 → 3)-6-deoxy-β-d-Alt-(1 → 4)-α-d-Rha-O(CH2)3NH2 (2) and 6-deoxy-β-d-Alt-(1 → 4)-α-d-Rha-(1 → 3)-6-deoxy-β-d-Alt-(1 → 4)-α-d-Rha-(1 → 3)-6-deoxy-β-d-Alt-(1 → 4)-α-d-Rha-O(CH2)3NH2 (3), were synthesized via a convergent strategy. The key disaccharyl thioglycoside 4 as a glycosyl donor was stereoselectively assembled by glycosylation of rhammnosyl acceptor 5 with 6-deoxy-altrosyl trichloroacetimidate donor 6b. The glycosidation of 4 with 3-azidopropanol followed by global deprotection afforded the target disaccharide 1. Further elongation of the carbohydrate chain of this glycosidation product with the disaccharyl donor 4 followed by global deprotection generated rapidly the dimeric tetrasaccharide 2 and the trimeric hexasaccharide 3 in a convergent [2 + 2] and [2 + 2 + 2] manner, respectively.


Exploring patient-provider interactions and the health system's responsiveness to street-connected children and youth in Kenya: a qualitative study.
In Kenya, street-connected children and youth (SCY) have poor health outcomes and die prematurely due to preventable causes. This suggests they are not accessing or receiving adequately responsive healthcare to prevent morbidity and mortality. We sought to gain insight into the health systems responsiveness to SCY in Kenya through an in-depth exploration of SCY's and healthcare provider's reflections on their interactions with each other. This qualitative study was conducted across 5 counties in western Kenya between May 2017 and September 2018 using multiple methods to explore and describe the public perceptions of, and proposed and existing responses to, the phenomenon of SCY in Kenya. The present analysis focuses on a subset of data from focus group discussions and in-depth interviews concerning the delivery of healthcare to SCY, interactions between SCY and providers, and SCY's experiences in the health system. We conducted a thematic analysis situated in a conceptual framework for health systems responsiveness. Through three themes, context, negative patient-provider interactions, and positive patient-provider interactions, we identified factors that shape health systems responsiveness to SCY in Kenya. Economic factors influenced and limited SCY's interactions with the health system and shaped their experiences of dignity, quality of basic amenities, choice of provider, and prompt attention. The stigmatization and discrimination of SCY, a sociological process shaped by the social-cultural context in Kenya, resulted in experiences of indignity and a lack of prompt attention when interacting with the health system. Patient-provider interactions were highly influenced by healthcare providers' adverse personal emotions and attitudes towards SCY, resulting in negative interactions and a lack of health systems responsiveness. This study suggests that the health system in Kenya is inadequately responsive to SCY. Increasing public health expenditures and expanding universal health coverage may begin to address economic factors, such as the inability to pay for care, which influence SCY's experiences of choice of provider, prompt attention, and dignity. The deeply embedded adverse emotional responses expressed by providers about SCY, associated with the socially constructed stigmatization of this population, need to be addressed to improve patient-provider interactions.


Using a peer mentorship approach improved the use of neonatal continuous positive airway pressure and related outcomes in Malawi.
This study evaluated whether peer mentorship was an effective and sustainable way of improving and maintaining knowledge and skills on neonatal continuous positive airway pressure (CPAP) in a low-resource setting with a high turnover of healthcare providers. The Malawi Ministry of Health recruited five nurses with considerable CPAP experience and provided them with mentorship training from July to August 2014. The mentors then provided 1-week on-site mentorship for 113 colleagues at 10 secondary and one tertiary hospital where gaps in neonatal CPAP use had been identified. CPAP competencies and outcomes were compared 3 months before and after each mentorship. In the 3 months before and after mentorship, the average CPAP competency score increased from 32 ± 4% to 97 ± 2%, while CPAP usage increased from 7% to 23% among eligible neonates. Survival following CPAP mentorship increased from 23% to 35%, but this was not significant due to the small sample size. Both mentees and mentors reported useful transfers of knowledge and skills when using CPAP. Mentorship effectively bridged the knowledge and skills gaps among health workers and increased CPAP use, competency scores and survival rates.


Severe Acute Respiratory Syndrome Type 2-Causing Coronavirus: Variants and Preventive Strategies.
COVID-19 vaccines have constituted a substantial scientific leap in countering severe acute respiratory syndrome type 2-causing coronavirus (SARS-CoV-2), and worldwide implementation of vaccination programs has significantly contributed to the global pandemic effort by saving many lives. However, the continuous evolution of the SARS-CoV-2 viral genome has resulted in different variants with a diverse range of mutations, some with enhanced virulence compared with previous lineages. Such variants are still a great concern as they have the potential to reduce vaccine efficacy and increase the viral transmission rate. This review summarizes the significant variants of SARS-CoV-2 encountered to date (December 2021) and discusses a spectrum of possible preventive strategies, with an emphasis on physical and materials science.


Indo-Asian experience of renal transplantation in Yorkshire: results of a 10-year survey.
There is a significant Indo-Asian community in Yorkshire. The rate of end-stage renal failure is disproportionately high in this ethnic group. There have not been any large studies of this ethnic minority's access to and outcome after cadaveric renal transplantation. Three local cohorts were studied: 846 adult patients (9.1% Asian) who started renal replacement therapy 1990-1994, 822 adult patients (11.4% Asian) registered on the transplant waiting list 1985-1994; and 608 adult patients (8.6% Asian) transplanted 1985-1994. At 1 year from the start of dialysis, 34% of Asian and 31% of non-Asian patients were registered onto the waiting list. After adjustment for age in a multifactorial model, Asian patients were less likely to be listed (relative risk, 0.68), although this did not reach statistical significance (P=0.06). There was a significant difference in graft rate between the groups: at 3 years 72% of non-Asians versus 55% of Asians had been transplanted from the waiting list (P<0.001). For those transplanted, HLA matching was superior for white patients: 34% versus 20% of pairings achieved a 000 mismatched or favorably matched graft (P<0.05). Transplant survival at 5 years was 71% in the non-Asian and 58% in the Asian patients (P=0.07). Asian cadaveric donation was identified in 2 of 608 transplants during a 10-year period. Asian patients gained access to the transplant waiting list at a similar rate to the non-Asian white majority. Because of difficulties with HLA matching, Asian patients were significantly disadvantaged in receiving a transplant once listed, and there was a trend towards reduced posttransplant survival. Cadaveric donation was uncommon from within the Asian community; the reasons for which are likely to be complex.


Synaptic reorganization in developing and adult nervous systems.
Evidence is accumulating that synapse reorganization already starts during development, soon after first synapses appear. Although remodeling continues throughout ontogenesis, there are apparently (critical) periods which are characterized by enhanced synaptic reorganization. In certain parts of the peripheral and central nervous system, synapses may undergo remodeling which leads to changes in their transmission efficiency or complete elimination of the synaptic junctions, even in adulthood. Synaptic reorganization includes progressive and regressive changes on branches of dendritic and/or axonal processes that accompany the formation and elimination of synapses. Three modes of elimination are presently known: Physiological cell death of synaptically connected neurons is involved, especially during certain developmental periods, during hormonally induced metamorphosis and in the olfactory bulb. Synaptic disconnection ("stripping") and lysosomal degradation predominantly of presynaptic elements occur under different conditions. In order to undergo plastic changes, neurons seem to respond to exogenous or intrinsic factors such as lesions (partial deafferentation and axotomy), long-lasting changes in neuronal activity (e.g. drug application and sensory deprivation), hormonal influences (e.g. sexual hormones) or learning conditions.


Shaping more resilient and just food systems: Lessons from the COVID-19 Pandemic.
The COVID-19 pandemic has highlighted weaknesses in global food systems, as well as opening windows of opportunity for innovation and transformation. While the nature and extent of this crisis is rare, extreme climatic events will increase in magnitude and frequency, threatening similar societal impacts. It is therefore critical to identify mechanisms for developing food systems that are resilient to such impacts. We examine impacts of the crisis on UK food systems and how these further entrenched social inequalities. We present data on the experiences and actions of producers, consumers, and community organisers. The data were collected by adapting ongoing research to include surveys, interviews and online workshops focused on the pandemic. Actors' responses to the pandemic foreshadow how enduring change to food systems can be achieved. We identify support required to enable these transformations and argue that it is vital that these opportunities are embedded in food justice principles which promote people-centred approaches to avoid exacerbating injustices prevalent pre-crisis. Learning from these experiences therefore provides insights for how to make food systems elsewhere more resilient and just.


Role of Yes-associated protein (YAP) in regulation of mesenchymal stem cell tenogenic differentiation.
The Yes-associated protein (YAP) transcription co-activator is recognized as a key mediator and has been implicated in the regulation of stem cell fate; however, the role of YAP in the tenogenic differentiation of mesenchymal stem cells (MSCs) is not well understood. In the present study, we characterized tenogenic differentiation of C3H10T1/2 cells induced by BMP-12 and evaluated the function of YAP in the regulation of the BMP-12-induced tenogenesis. We found that the tendon-related proteins Scleraxis, Tenascin C, and Tenomodulin were significantly increased after induction by 10 ng/ml BMP-12 for 48 h in C3H10T1/2 cells. In addition, the expression of YAP was significantly enhanced and transferred from the cytoplasm to the nucleus during tenogenic differentiation. In contrast, downregulation of YAP suppressed the cells' tenogenic differentiation, and the expression of YAP transferred from the nucleus to the cytoplasm. These results indicate that YAP is required for the expression of tenogenic markers in the tenocytic differentiation process of C3H10T1/2 cells. Collectively, we demonstrate that YAP transcription co-activator is a novel regulator in the process of BMP-12-induced MSCs tenogenesis and has a correlation with the other tenogenic regulators and markers. These results shed new light on the function of YAP in tendon healing and regeneration.


Spatial Variations of Soil Heavy Metal Potential Ecological Risks in Typical Moso Bamboo Forests of Southeast China.
Spatial patterns of soil heavy metal potential ecological risk are important for the scientific pollution management of bamboo forests. A total of 160 soil samples were collected from typical moso bamboo forests in the southeastern region of China. Ecological risk index and GIS-based kriging methodologies were applied to analyze spatial variations of analyzed metals and were compared to background levels in samples collected from Zhejiang Province. The results show that the exceeded background rate of the single-factor pollution index of Pb, Cd and Cu in all soil samples is greater than 50%, with the highest overbackground rate of Pb being 99.38%. The potential ecological risk of Hg, Pb and Cd reaches a stronger risk level, while other heavy metals such as As, Cu and Cr are associated with a slight risk level. Different spatial patterns across the whole study area indicate that the potential ecological risk in the northwest and southeast areas is high, but is relatively low in the north-central area.


Choroid Plexus Modulates Subventricular Zone Adult Neurogenesis and Olfaction Through Secretion of Small Extracellular Vesicles.
The choroid plexus (CP) in brain ventricles secrete cerebrospinal fluid (CSF) that bathes the adjacent subventricular zone (SVZ); the latter is the largest neurogenic region in adult brain harboring neural stem/progenitor cells (NSPCs) and supplies newborn neurons to the olfactory bulb (OB) for normal olfaction. We discovered the presence of a CP-SVZ regulatory (CSR) axis in which the CP, by secreting small extracellular vesicles (sEVs), regulated adult neurogenesis in the SVZ and maintained olfaction. The proposed CSR axis was supported by 1) differential neurogenesis outcomes in the OB when animals treated with intracerebroventricular (ICV) infusion of sEVs collected from the CP of normal or manganese (Mn)-poisoned mice, 2) progressively diminished SVZ adult neurogenesis in mice following CP-targeted knockdown of SMPD3 to suppress CP sEV secretion, and 3) compromised olfactory performance in these CP-SMPD3-knockdown mice. Collectively, our findings demonstrate the biological and physiological presence of this sEV-dependent CSR axis in adult brains. CP-secreted sEVs regulate adult neurogenesis in the SVZ.CP-secreted sEVs modulate newborn neurons in the OB.Suppression of sEV secretion from the CP deteriorates olfactory performance.


Ambient air pollution and respiratory disease.
To review the literature on ambient air pollution and respiratory disease, and to consider the criteria for defining causation. Medical and scientific journals indexed by Medline, conferences, proceedings and monographs. Two kinds of study were selected--(i) controlled clinical trials which have exposed normal or asthmatic subjects and/or patients with chronic obstructive airways disease to sulphur dioxide, nitrogen dioxide or ozone; and (ii) epidemiological studies which have investigated the chronic toxicity of these pollutants, acid aerosols and polycyclic aromatic hydrocarbons. Experimental studies were tabulated under the headings "Design", "Subjects", "Pollutant concentration", "Duration of exposure", "Outcome measures" and "Conclusions". Epidemiological studies were summarised and compared in an attempt to reconcile conflicting results. (The experimental and epidemiological evidence has been used by regulatory bodies to develop ambient air quality guidelines.) At the present state of knowledge, it is not possible to conclude that air pollution can cause respiratory disease de novo, but levels marginally above current guidelines certainly have adverse effects on individuals with pre-existing chronic lung disease.


Surface-Based Spatial Pyramid Matching of Cortical Regions for Analysis of Cognitive Performance.
We propose a method to analyze the relationship between the shape of functional regions of the cortex and cognitive measures, such as reading ability and vocabulary knowledge. Functional regions on the cortical surface can vary not only in size and shape but also in topology and position relative to neighboring regions. Standard diffeomorphism-based shape analysis tools do not work well here because diffeomorphisms are unable to capture these topological differences, which include region splitting and merging across subjects. State-of-the-art cortical surface shape analyses compute derived regional properties (scalars), such as regional volume, cortical thickness, curvature, and gyrification index. However, these methods cannot compare the full extent of topological or shape differences in cortical regions. We propose icosahedral spatial pyramid matching (ISPM) of region borders computed on the surface of a sphere to capture this variation in regional topology, position, and shape. We then analyze how this variation corresponds to measures of cognitive performance. We compare our method to other approaches and find that it is indeed informative to consider aspects of shape beyond the standard approaches. Analysis is performed using a subset of 27 test/retest subjects from the Human Connectome Project in order to understand both the effectiveness and reproducibility of this method.


Precise Installation of Diazo-Tagged Side-Chains on Proteins to Enable In Vitro and In-Cell Site-Specific Labeling.
The chemistry of diazo compounds has generated a huge breadth of applications in the field of organic synthesis. Their versatility combined with their tunable reactivity, stability, and chemoselectivity makes diazo compounds desirable reagents for chemical biologists. Here, we describe a method for the precise installation of diazo handles on proteins and antibodies in a mild and specific approach. Subsequent 1,3-cycloaddition reactions with strained alkynes enable both bioimaging through an in-cell "click" reaction and probing of the cysteine proteome in cell lysates. The selectivity and efficiency of these processes makes these suitable reagents for chemical biology studies.


Effects of phenytoin on field bursts of rat hippocampal slices in low-calcium solutions.
Recurring bursts of population spikes, a simple model of epileptiform activity, can be produced by exposing slices of rat hippocampus to saline containing 0.2 mM [Ca2+] and 4.0 mM [Mg2+], at which concentration chemical synaptic activity is blocked. Phenytoin at 7.3-73 microM shortened the duration of these bursts. At 73 microM the bursts were slowed and often eliminated. This model appears to be more sensitive to the action of phenytoin than the penicillin model of epileptiform bursting.


Primary Mutational Landscape Linked with Pre-Docetaxel Lactate Dehydrogenase Levels Predicts Docetaxel Response in Metastatic Castrate-Resistant Prostate Cancer.
Docetaxel chemotherapy is a standard of care for metastatic castrate-resistant prostate cancer (mCRPC): 40-50% of patients achieve a biochemical response. However, there is a lack of response predictive biomarkers. To assess lactate dehydrogenase (LDH) as a docetaxel response biomarker in mCRPC and to examine the association of LDH with genomic alterations in primary diagnostic biopsies. Clinical and associated primary tumour-targeted next-generation sequencing data from matched training (n=150) and test (n=120) cohorts of progressive mCRPC patients receiving docetaxel therapy were analysed. Data were correlated with large-scale prostate cancer genomic datasets. Prostate-specific antigen (PSA) response, radiographic response, biochemical progression-free survival (PFS), overall survival (OS), genomic analysis of primary biopsies, and genomic datasets (Memorial Sloan Kettering Cancer Center [MSKCC] and SU2C/PCF). Serum LDH ≥450U/l is a reliable prognostic biomarker (area under the curve: 0.757 [standard deviation 0.054, 95% confidence interval [CI] 0.650-0.864, p<0.001]) in progressive mCRPC, predicting PFS at 3 mo. Patients with LDH ≥450U/l were poorer PSA responders, with shorter PFS (213 vs 372 d, hazard ratio [HR] 1.876, 95% CI 1.289-2.7300) and OS (362 vs 563 d, HR 1.630, 95% CI 1.127-2.357). High LDH is an independent surrogate marker for survival following docetaxel and predicts a poor radiological response (p=0.043). Of the 14 patients with LDH ≥450U/l available for next-generation sequencing, nine (64.3%) were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2, Fanconi anaemia gene) in their primary biopsy. Cross correlation with MSKCC and SU2C/PCF databases revealed a positive correlation between LDHA, PARP1 (r=0.667, p<0.01), and other DNA repair genes. Genomic abnormalities of LDHA and DNA repair in primary biopsies link to high pretreatment LDH and poor response to docetaxel in mCRPC. The presence of mutations of the lactate dehydrogenase and DNA repair pathways are associated with aggressive prostate cancer and poor response to chemotherapy later in the disease.


Cyclic changes in the ovary of the rainbow trout, Salmo gairdneri, with special reference to sites of steroidogenesis.
In the maturation cycle of ovaries of cultured rainbow trout, three periods can be distinguished: (1) a period of ovulation and previtellogenesis (January-May), (2) a period of exogenous vitellogenesis (May-November/December), and (3) a period of maturation of oocytes (November/December-January). Enzyme cytochemical and electron microscopical data indicate that stroma cells (i.e., interstitial cells and special theca cells) and granulosa cells represent sources of steroids. Steroidogenesis in stroma cells is found throughout the annual cycle, reaching a peak activity in January and February. Weak steroidogenic activity is observed in the granulosa cells of exogenous vitellogenic follicles and young postovulatory follicles. Possible functions of steroids secreted by stroma cells and granulosa cells are discussed.


End-to-end anastomosis by enclosure between a prosthesis and a vessel with a significant difference in diameter.
A technique is described that allows an end-to-end anastomosis between a vascular prosthesis and a vessel that is much smaller in diameter. This procedure involves enclosing the prosthesis and the vessel while keeping the vascular axis straight without any kinking. In addition, this technique makes little demand on the extensibility of the natural tissue in order to adapt to the prosthesis, which is inextensible.


Neutrophil phagocytosis following inoculation of Salmonella choleraesuis into swine.
Neutrophils are an important mediator of host defence, especially in early stages of infection. A major function of neutrophils is the uptake and killing of invading microbes. Little is known about the effect of neutrophil activity on the pathogenesis and development of the carrier state in swine following infection with Salmonella choleraesuis. A human whole-blood microassay using flow cytometry was modified to measure the effect of S. choleraesuis infection in vivo on the rate of ingestion, or rate of uptake, of homologous bacteria by porcine neutrophils. Pigs were inoculated intranasally with 5-8 x 10(8) CFU S. choleraesuis and blood was collected in heparinized tubes at -5, 0, 1, 2, 3 and 4 days post inoculation (PI). Heat-killed S. choleraesuis were labelled with fluorescein isothiocyanate and incubated for various times with diluted whole blood. Red blood cells were lysed, external non-phagocytized bacteria were quenched with a commercially available lysing solution, and fluorescence from internalized bacteria labelled with fluorescein isothiocyanate was detected by flow cytometry. The rate of uptake by neutrophils did not increase until 2 days PI and then remained elevated to 4 days PI. The minimal uptake of S. choleraesuis early after exposure to these organisms may provide an opportunity for the pathogen to colonize and/or replicate to levels that facilitate establishment of a carrier state or clinical infection in swine.


The short-chain fatty acid butyrate accelerates vascular calcification via regulation of histone deacetylases and NF-κB signaling.
Recent studies have shown that short-chain fatty acids (SCFAs), primarily acetate, propionate and butyrate, play a crucial role in the pathogenesis of cardiovascular disease. Whether SCFAs regulate vascular calcification, a common pathological change in cardiovascular tissues, remains unclear. This study aimed to investigate the potential role of SCFAs in vascular calcification. Using cellular and animal models of vascular calcification, we showed that butyrate significantly enhanced high phosphate (Pi)-induced calcification and osteogenic transition of vascular smooth muscle cells (VSMC) in vitro, whereas acetate and propionate had no effects. Subsequent studies confirmed that butyrate significantly promoted high Pi-induced aortic ring calcification ex vivo and high dose vitamin D3 (vD3)-induced mouse vascular calcification in vivo. Mechanistically, butyrate significantly inhibited histone deacetylase (HDAC) expression in VSMCs, and a pan HDAC inhibitor Trichostatin A showed similar inductive effects on calcification and osteogenic transition of VSMCs to butyrate. In addition, the SCFA sensing receptors Gpr41 and Gpr109a were primarily expressed by VSMCs, and butyrate induced the rapid activation of NF-κB, Wnt and Akt signaling in VSMCs. Intriguingly, the NF-κB inhibitor SC75741 significantly attenuated butyrate-induced calcification and the osteogenic gene Msx2 expression in VSMCs. We showed that knockdown of Gpr41 but not Gpr109a attenuated butyrate-induced VSMC calcification. This study reveals that butyrate accelerates vascular calcification via its dual effects on HDAC inhibition and NF-κB activation. Our data provide novel insights into the role of microbe-host interaction in vascular calcification, and may have implications for the development of potential therapy for vascular calcification.


Long non-coding RNA HEIH: a novel tumor activator in multiple cancers.
The last decade has witnessed the altered expression levels of long non-coding RNA HEIH in different types of cancer. More than half of the HEIH studies in cancer have been published within the last two years. To our knowledge, this is the first review to discuss very recent developments and insights into HEIH contribution to carcinogenesis. The functional role, molecular mechanism, and clinical significance of HEIH in human cancers are described in detail. The expression of HEIH is elevated in a broad spectrum of cancers, and its disorder contributes to cell proliferation, migration, invasion, and drug resistance of cancer cells through different underlying mechanisms. In addition, the high expression of HEIH is significantly associated with advanced tumor stage, tumor size and decreased overall survival, suggesting HEIH may function as a prognostic biomarker and potential therapeutic target for human cancers.


Documentation and validation of climate change perception of an ethnic community of the western Himalaya.
The high-altitude regions of Himalaya are among the best indicators of climate change yet noticeable for the lack of climate monitoring stations. However, they support ethnic communities whose livelihood activities are climate driven. Consequently, these communities are keen observers of the same and documenting their perception on changing climate is now an important area of global research. Therefore, the present study was conducted with the prime objective of documenting the climate change perception of Bhangalis-a resident community of western Himalaya, and analyzing variation in their perceptions in relation to age and gender. For this, respondent surveys (household, n = 430; individual interviews, n = 240) were carried out and the collected data were subjected to statistical analyses. The study also validated the perception of Bhangalis using the available weather data (1974-2017) through the Mann-Kendall test. The results reveal that Bhangalis perceived 11 indicators of changing climate, of which decrease in snowfall was the most prominent (reported by ~ 97% of the respondents). The perceptions varied between the two genders with males having significantly higher proportion of responses for all the 11 indicators. Similarly, differences in perception among the age groups were also observed, elderly people reported higher proportion of climate change indicators as compared to respondents of lower age. Notably, patterns of temperature and rainfall perceptions by the Bhangalis agreed with the trends of meteorological data. This highlights the importance of the study in documenting knowledge of ethnic communities especially from areas that lack monitoring stations. It argues for involving them in climate change programs.


[Treatment of extremely obese adolescents and young adults at the Insula Obesity Center in Bischofswiesen].
The Insula Obesity Center has been treating extremely obese adolescents and young adults since 1992. Various programs ranging from 2-9 months' duration are offered. The mean BMI at admission has been increasing continuously and is presently 41.5 kg/m(2) with occasional extremes over 80 kg/m(2). Obesity comorbidities are common. A mean weight reduction of 1.3 kg/week is achieved during a mean duration of treatment of 4.7 months. Follow-up in residential support groups is offered for up to 2 years for selected patients with special challenges such as lack of family support.


Release of [hydroxyproline3]-kinins by tissue kallikreins of pig, rat and man.
To determine the susceptibility of kininogens containing the recently described [Hyp3]-bradykinin moiety to cleavage by tissue kallikreins, we have studied the release of [Hyp3]-kinins from heat inactivated human plasma by purified tissue kallikreins. Kallikreins from man and pig were employed and compared with purified rat urinary kallikrein which is known to have a different cleavage specificity. Kinins released were separated by a modified reversed phase HPLC method and quantitated by bioassay and radioimmunoassay. Human urinary kallikrein and hog tissue kallikreins released 85-90% of the total kinins as Lys-bradykinin and 10-15% as [Hyp3]-Lys-bradykinin. In contrast, rat urinary kallikrein released 77% as bradykinin, 22% as [Hyp3]-bradykinin and negligible amounts of [Hyp3]-Lys-bradykinin from the identical substrate source indicating that rat tissue kallikreins prefer the Lys-Arg-bond within both unhydroxylated and hydroxylated kininogens. Therefore, hydroxylation of human kininogens apparently does not affect their ability to serve as substrates for tissue kallikreins with different cleavage specificities.


[Studies on the botanical origins of herba epimedii from a Sichuan market].
12 species and one new species of Herba Epimedii from Sichuan were investigated and identified by taxonomical study, and a key to these identified species is presented. About 30 samples deriving from 8 species of this genus were identified by pharmacognostical study.


Spondylodiscitis: A Retrospective Analysis of Clinical, Etiological, and Radiological Diagnosis.
Spondylodiscitis is an uncommon disease, and due to its indolent nature, it is often a late diagnosis. Great stress is put on the etiologic diagnosis, but blood cultures do not always yield positive results. Magnetic resonance imaging (MRI), despite being the diagnostic method of choice, is not always available. Our aim was to characterize the clinical presentation and to identify and check the efficacy of the etiologic and radiological methods of diagnosis of spondylodiscitis used at our hospital. A retrospective study was conducted in which spontaneous spondylodiscitis cases were identified. The clinical presentation and the results of etiologic and radiological methods of diagnosis were analyzed. Over a period of 5 years, 34 patients fulfilled the inclusion criteria of the study. Regarding days of complaints, we identified a median of 9.5 days (1-547 days), with back pain being the predominant symptom. Fever was present in half the patients. Blood cultures were positive in 16 patients (48.5%). Nineteen patients underwent a computed tomography (CT)-guided biopsy (positive in 7 patients [36.8%]), and 10 patients underwent a surgical biopsy (positive in half of them). Overall, 27 patients (79.4%) had an etiologic diagnosis. The diagnostic work-up consisted mostly of an initial CT scan followed by a confirmatory MRI. Of note, in 5 patients the CT scan did not reveal changes that were later confirmed by MRI. A total of 29 patients (85.3%) underwent an MRI, with 28 being diagnostic. Spondylodiscitis remain a difficult diagnosis. Blood cultures should always be obtained before antibiotic administration and a CT-guided or surgical biopsy should be done if needed. Our results confirm the importance of MRI as the imaging modality of choice and highlight the possibility of false-negative CT scans and the inability of CT to allow for a definitive diagnosis.


The efficacy of traditional Chinese medicine in the treatment of the COVID-19 pandemic in Henan Province: a retrospective study.
Since 2020, novel coronavirus disease (COVID-19) has posed serious threats to health systems and led to tremendous economic decline worldwide. Traditional Chinese medicine (TCM) is considered a promising treatment strategy for COVID-19 in China and is increasingly recognized as a key participant in the battle against COVID-19. Clinicians also need accurate evidence regarding the effectiveness of TCM treatments for COVID-19. We retrospectively analyzed patients diagnosed with COVID-19 by collected from the electronic medical records of the hospitals in Henan Province from January 19, 2020, to March 2, 2020. Demographic characteristics, clinical data, frequency analysis of Chinese patent medicines (CPMs), Chinese medicine injections (CMIs), evaluation of baseline symptom scores, nucleic acid negative conversion, length of hospitalization, and mortality rates were studied. Between 15 January 2020 and 2 March 2020, 131 hospitals with 1245 patients were included. Survey response Chinese herbal decoction, CPMs, and CMIs combined with conventional Western medicine (CWM) used for the treatment of COVID-19. The top 8 CPMs were Lianhua Qingwen capsules, Shuanghuanglian oral liquid, Pudilan Xiaoyan oral liquid, Banlangen granules, Lanqin oral liquid, compound licorice tablets, Bailing capsules, montmorillonite powder. The most frequently used CMIs were Xuebijing, Tanreqing, Reduning, Xiyanping and Yanhuning. TCM combined with CWM improved the patients' symptom scores for fever, cough, chest tightness, shortness of breath, and fatigue. Nucleic acid negative conversion occurred at11.55 ± 5.91 d and the average length of hospitalization was 14.92 ± 6.15 d. The mortality rate was approximately 1.76%, which is a reduction in patient mortality. TCM combined with CWM improved clinical symptoms and reduced hospitalization and mortality rates.


Intraoperative lower extremity reflex muscle activity as an adjunct to conventional somatosensory-evoked potentials and descending neurogenic monitoring in idiopathic scoliosis.
Lower extremity polysynaptic reflexes and descending neurogenic motor and ascending somatosensory activity were recorded. Two cases are presented to illustrate the intraoperative use of lower extremity reflex recordings for detecting compromise of spinal cord function. Lower extremity reflex processing can be used to measure integrated spinal cord activity, whereas descending neurogenic and ascending somatosensory potentials measure only long tract function. Eight channels of lower extremity polysynaptic reflex activity were recorded simultaneously after unilateral lower extremity mixed nerve stimulation. Sequential descending neurogenic and ascending somatosensory activity was recorded simultaneously with reflex recordings. In these two patients with idiopathic scoliosis, intraoperative reflexes changed before descending neurogenic and before ascending somatosensory activity changed. High-amplitude synchronous persistent reflex activity correlated with a postoperative neurologic deficit. Low-amplitude asynchronous transient reflex activity was not associated with a postoperative neurologic deficit. Intraoperative lower extremity reflex changes are more sensitive to spinal cord compromise than are changes in long tract function. Lower extremity polysynaptic reflexes monitor the integrated activity of the spinal cord that is responsible for the control of complex motor behavior.


Clinicopathologic correlates of solitary fibrous tumors.
Solitary fibrous tumors (SFTs) are rare fibrous neoplasms. Since their initial description as arising from the pleura, SFTs have been reported at a wide range of anatomic sites. To the authors's knowledge, there are no large series reporting both thoracic and extrathoracic SFTs nor are there any large series that analyze clinicopathologic correlates of tumor behavior. Institutional soft tissue tumor and pathology databases were reviewed to identify patients. Pathologic material was reviewed by an experienced soft tissue pathologist and scored for the presence of a histologically malignant component. Clinical information was obtained from medical records and phone calls to patients. Statistical analysis was performed using the Student t test, Pearson chi-square test, and log-rank test. Seventy-nine patients with SFTs treated at a single institution over an 18-year period were identified. These tumors arose in a wide range of anatomic sites. Thoracic and extrathoracic SFTs had similar clinical and pathologic features, although extrathoracic tumors were more likely to be symptomatic on diagnosis. Seventy-five patients underwent surgical excision of a SFT at our institution. Overall, SFTs had a low rate of local recurrence and metastasis after surgical treatment. Extrathoracic SFTs had an increased risk of local recurrence that was small but statistically significant. There was no difference in metastasis-free survival between thoracic and extrathoracic SFTs. Positive surgical margins and the presence of a histologically malignant component were factors predicting worse local recurrence-free survival. Positive surgical margins, tumor size greater than 10 cm, and the presence of a malignant component predicted worse metastasis-free survival. Solitary fibrous tumors are rare tumors that occur at all anatomic sites. Most SFT patients fare well after surgical treatment. Closer surveillance is warranted for those tumors that are larger than 10 cm or with the presence of a histologically malignant component.


Dynamic cardiomyoplasty: clinical follow-up at 12 years.
The purpose of this study is to evaluate the long-term outcome of dynamic cardiomyoplasty. This surgical technique was conceived to assist the failing heart. The many proposed mechanisms of action of cardiomyoplasty are: (1) systolic assist; (2) limitation of ventricular dilation; (3) reduction of ventricular wall stress (sparing effect); (4) ventricular remodeling with an active girdling effect; (5) angiogenesis; and (6) a neurohumoral effect. We investigated 95 patients in our hospital undergoing this procedure due to severe chronic heart failure, refractory to optimal medical treatment. Patients had a mean age of 51 +/- 12 years. The etiology of heart failure was ischemic 55%, idiopathic 34%, ventricular tumor 6%, and other 5%. The mean follow-up was 44 months. The mean New York Heart Association (NYHA) functional class improved postoperatively from 3.2 to 1.8. Average radioisotopic left ventricular (LV) ejection fraction increased from 17 +/- 5 to 27 +/- 4% (P < 0.05). Stroke volume index increased from 32 +/- 7 to 43 +/- 8 ml/beat per m2 (P < 0.05). The heart size remained stable over the long term. Following cardiomyoplasty, the number of hospitalizations due to congestive heart failure was reduced to 0.4 hospitalizations/patient per year (preoperative: 2.5, P < 0.05). Computed tomography scans showed at long term a preserved latissimus dorsi muscle structure in 84% of patients. Survival probability at 7 years is 54%. Six patients underwent heart transplant after cardiomyoplasty (mean delay: 25 months), due to the natural evolution of their underlying heart disease. There were no specific technical difficulties. Clinically, this procedure reverses heart failure, improves functional class and ameliorates quality of life. The latissimus dorsi muscle histological structure is maintained at long-term, when postoperative electrostimulation is performed, avoiding excessive stimulation. Cardiomyoplasty may delay or prevent the progression of heart failure and the indication of cardiac transplantation.


Multiscale connected chain topological modelling for microcalcification classification.
Computer-aided diagnosis (CAD) systems can be employed to help classify mammographic microcalcification clusters. In this paper, a novel method for the classification of the microcalcification clusters based on topology/connectivity has been introduced. The proposed method is distinct from existing techniques which concentrate on morphology and texture of microcalcifications and surrounding tissue. The proposed approach used multiscale morphological relationship of connectivity between microcalcifications where connected chains between nearest microcalcifications were generated at each scale. Subsequently, graph connectivity features at each scale were extracted to estimate the topological connectivity structure of microcalcification clusters for benign versus malignant classification. The proposed approach was evaluated using publicly available digitized datasets: MIAS and DDSM, in addition to the digital OPTIMAM dataset. The classification of features using KNN obtained a classification accuracy of 86.47±1.30%, 90.0±0.00%, 82.5±2.63%, 76.75±0.66% for the DDSM, MIAS-manual, MIAS-auto and OPTIMAM datasets respectively. The study showed that topological/connectivity modelling using a multiscale approach was appropriate for microcalcification cluster analysis and classification; topological connectivity and distribution can be linked to clinical understanding of microcalcification spatial distribution.


Functional connectivity of amygdala subregions predicts vulnerability to depression following the COVID-19 pandemic.
The amygdala is vital in processing psychological stress and predicting vulnerability or resilience to stress-related disorders. This study aimed to build the link between functional magnetic resonance imaging data obtained before the stress event and the subsequent stress-related depressive symptoms. Neuroimaging data obtained before the coronavirus disease 2019 pandemic from 39 patients with major depressive disorder (MDD) and 61 health controls (HCs) were used in this study. The participants were divided retrospectively into four groups in accordance with the severity of depressive symptoms during the pandemic: remitted patients, non-remitted patients, depressed HCs (HCd) and non-depressed HCs (HCnd). Seed-based resting-state functional connectivity (rsFC) analyses of the amygdala and its subregions, including the centromedial (CM), the basolateral and the superficial (SF), were performed. Vulnerability to depression was suggested by decreased rsFC between the left CM amygdala and the bilateral lingual gyrus in the HCd group compared with the HCnd group, and decreased rsFC of the left CM or right SF amygdala with the precuneus and the postcentral gyrus in the HCd group compared with patients with MDD. No evidence supported the rsFC of the amygdala or its subregions as a biomarker for the resilience of patients with MDD to stress under antidepressant treatment. Smaller sample size and no longitudinal neuroimaging data. Our findings suggested that the rsFC of amygdala subregions may represent a neurobiological marker of vulnerability to depression following stress.


Does the presence of general practitioners in emergency departments affect quality and safety in English NHS hospitals? A retrospective observational study.
Emergency departments (EDs) in NHS hospitals in England have faced considerable increases in demand over recent years. Most hospitals have developed general practitioner services in emergency departments (GPEDs) to treat non-emergency patients, aiming to relieve pressure on other staff and to improve ED efficiency and patient experience. We measured the impact of GPED services on patient flows, health outcomes and ED workload. Retrospective observational study. Differences in GPED service availability across EDs and time of day were used to identify the causal effect of GPED, as patients attending the ED at the same hour of the day are quasi-randomly assigned to treatment or control groups based on their local ED's service availability. Attendances to 40 EDs in English NHS hospitals from April 2018 to March 2019, 4 441 349 observations. Outcomes measured were volume of attendances, 'non-urgent' attendances, waiting times over 4 hours, patients leaving without being treated, unplanned reattendances within 7 days, inpatient admissions and 30-day mortality. We found a small, statistically significant reduction in unplanned reattendances within 7 days (OR 0.968, 95% CI 0.948 to 0.989), equivalent to 302 fewer reattendances per year for the average ED. The clinical impact of this was judged to be negligible. There was no detectable impact on any other outcome measure. We found no adverse effects on patient outcomes; neither did we find any evidence of the hypothesised benefits of placing GPs in emergency settings beyond a marginal reduction in reattendances that was not considered clinically significant.


[Spontaneous growth of suspended hamster embryonic cells transformed in vitro by methyl-7 benzo(a)anthracene].
A transformed and malignant cell line was obtained by treatment of secondary hamster embryo cells with 7-methyl benz(a)anthracene (10 mug/ml of medium). Later on these cells acquired the capacity to grow spontaneously in suspension and form "spheroids". The evolution of this cell line showed similarities between the carcinogenic process in vitro and in vivo.


Application of nematicide avermectin enriched antibiotic-resistant bacteria and antibiotic resistance genes in farmland soil.
The extensive use of antibiotics in medicine and agriculture has resulted in the accumulation of antibiotic-resistant microorganisms and antibiotic resistance genes (ARGs) in environments, which threaten human health and contaminate environment. Nematicide avermectin is widely applied to control root-knot nematodes. The effect of five-years application of avermectin on rhizosphere microbiome and resistome of sick tobacco plants in farmland were investigated in present study. The environmental risks of avermectin was assessed adequately. Metagenomic method was used to analyze antibiotic-resistant bacteria and antibiotic resistance genes in the avermectin-treated soil. The abundance and distribution of antibiotic-resistant bacteria and their antibiotic resistance genes were affected by avermectin application. The antibiotic resistant Proteobacteria occupied the highest percentage (36%) in rhizosphere soil and carried 530 ARGs. Opportunistic human pathogens carrying antibiotic resistance genes were enriched in the avermectin-treated soil. Avermectin application increased the counts of many types of antibiotic resistance genes. The relative abundances of genes adeF, BahA, fusH, ileS, and tlrB in the avermectin-treated soil were significantly greater than in the untreated control soil. Different resistance mechanisms were revealed in the avermectin-treated soil. The efflux of antibiotic (670 ARGs), inactivation of antibiotic (475 ARGs), and alteration of antibiotic target (267 ARGs) were the main resistance mechanisms. Rigid control the avermectin dose and use frequency and other pesticides can decrease soil antibiotic resistance genes and protect agricultural products' safety and public health. Overall, application of nematicide avermectin enriched antibiotic-resistant bacteria and antibiotic resistance genes in farmland soil, which should be on the alert for environment protection.


Very short answer questions: a viable alternative to multiple choice questions.
Multiple choice questions, used in medical school assessments for decades, have many drawbacks such as hard to construct, allow guessing, encourage test-wiseness, promote rote learning, provide no opportunity for examinees to express ideas, and do not provide information about strengths and weakness of candidates. Directly asked, directly answered questions like Very Short Answer Questions (VSAQ) are considered a better alternative with several advantages. This study aims to compare student performance in MCQ and VSAQ and obtain feedback. from the stakeholders. Conduct multiple true-false, one best answer, and VSAQ tests in two batches of medical students, compare their scores and psychometric indices of the tests and seek opinion from students and academics regarding these assessment methods. Multiple true-false and best answer test scores showed skewed results and low psychometric performance compared to better psychometrics and more balanced student performance in VSAQ tests. The stakeholders' opinions were significantly in favour of VSAQ. This study concludes that VSAQ is a viable alternative to multiple-choice question tests, and it is widely accepted by medical students and academics in the medical faculty.


Caution order for nurse who did not attempt CPR.
A nurse has admitted misconduct after failing to attempt to resuscitate a care home resident she believed was dead.


Post-traumatic stress disorder psychological interventions in sub-Saharan Africa: protocol for a systematic review of the literature.
Untreated post-traumatic stress disorder (PTSD) results in considerable morbidity and higher risk of mortality. However, little is being done to treat PTSD in sub-Saharan Africa (SSA) settings where rates of PTSD are likely to be elevated due to mass exposure of the population to traumatic events. This systematic review aims to summarise available evidence on the efficacy of psychological therapies for PTSD in SSA. A systematic search of the literature will be conducted in four electronic databases: PubMed, PsychInfo, EMBASE and Cochrane Register of Controlled Trials using keywords and synonyms related to 'PTSD', 'psychological therapies' and 'SSA'. Studies will be included if they were conducted in SSA and used a randomised controlled trial design. Two researchers will screen the studies for eligibility to be included, and data on intervention types, population, comorbidities, comparison group intervention and PTSD outcomes will be extracted from those included. Risk of bias will be assessed using Cochrane risk-of-bias tool for randomised trials (version 2). Narrative synthesis of data will be conducted and pooled effect estimates calculated. Ethical approval is not required as this is a protocol of a systematic review of available data. Findings will be disseminated to the scientific community through peer-reviewed publications and presentation at conferences. CRD42020181638.


Risk factors for mechanical ventilation in children with Guillain-Barré syndrome.
We assessed clinical predictors of mechanical ventilation in children with Guillain-Barré syndrome (GBS) to help identify patients who require mechanical ventilation. We retrospectively collected the clinical, laboratory, and electrophysiological data of 103 children with GBS. Patients were categorized into two groups based on the requirement for mechanical ventilation. Variables that were significantly different between the two groups in univariate analysis were analyzed by multivariate logistic regression models. Time from symptom onset to admission (P = .002), facial or bulbar weakness (P = .001), and axonal type (P = .005) were associated with mechanical ventilation in univariate analysis. In multivariate analysis, facial or bulbar weakness (odds ratio [OR], 7.936; P = .013) and axonal type (OR, 4.582; P = .022) were independent predictors for mechanical ventilation. Facial or bulbar weakness and axonal type were associated with increased risk for mechanical ventilation in children with GBS.


Efficient fluorescence-based localization technique for real-time tracking endophytes route in host-plants colonization.
Bacterial isolates that enhance plant growth and suppress plant pathogens growth are essential tools for reducing pesticide applications in plant production systems. The objectives of this study were to develop a reliable fluorescence-based technique for labeling bacterial isolates selected as biological control agents (BCAs) to allow their direct tracking in the host-plant interactions, understand the BCA localization within their host plants, and the route of plant colonization. Objectives were achieved by developing competent BCAs transformed with two plasmids, pBSU101 and pANIC-10A, containing reporter genes eGFP and pporRFP, respectively. Our results revealed that the plasmid-mediated transformation efficiencies of antibiotic-resistant competent BCAs identified as PSL, IMC8, and PS were up 84%. Fluorescent BCA-tagged reporter genes were associated with roots and hypocotyls but not with leaves or stems and were confirmed by fluoresence microscopy and PCR analyses in colonized Arabidopsis and sorghum. This fluorescence-based technique's high resolution and reproducibility make it a platform-independent system that allows tracking of BCAs spatially within plant tissues, enabling assessment of the movement and niches of BCAs within colonized plants. Steps for producing and transforming competent fluorescent BCAs, as well as the inoculation of plants with transformed BCAs, localization, and confirmation of fluorescent BCAs through fluorescence imaging and PCR, are provided in this manuscript. This study features host-plant interactions and subsequently biological and physiological mechanisms implicated in these interactions. The maximum time to complete all the steps of this protocol is approximately 3 months.


Acceptability and preliminary effectiveness of a single-arm 12-week digital behavioral health intervention in patients with knee osteoarthritis.
Digital health interventions may improve osteoarthritis (OA) management. This study evaluated the acceptability and preliminary effectiveness of a multimodal digital nutrition, exercise, and mindfulness intervention in adults with knee OA. Adults with advanced knee OA and an orthopaedic referral were invited to self-enroll in a pragmatic 12-week single-arm intervention. OA-focused nutrition and exercise resources were delivered weekly by email, and secondary components accessed on-demand (web-platform, webinars, and nutrition consultation). Acceptability was assessed by qualitative interview data and completion rates. Preliminary effectiveness on clinical outcomes was assessed by change in health-related quality of life, well-being, mindfulness, self-efficacy, and interest in total knee arthroplasty (TKA) between baseline and 12-weeks. N = 102 patients self-enrolled (73.5% female, age 64 ± 7 years, body mass index 32.9 ± 7.3 kg/m2); n = 53 completed the 12-week intervention (71.7% female, age 65 ± 7 years, body mass index 33.4 ± 6.3 kg/m2). Acceptability was demonstrated by positive perceptions of tailored intervention resources. In study completers, health-related quality of life components of pain and physical functioning domains improved at 12-weeks [change in SF36 4.4 (95%CI 0.2-8.6), p = 0.016, and 6.7 (95%CI 2.7-10.7), p < 0.001, respectively]. Self-efficacy for managing daily activities improved [change in PROMIS T-score 4.4 (95%CI 2.8-6.0), p < 0.001]. A 12-week digital multimodal intervention for knee OA was acceptable to patients and shows preliminary effectiveness in improving self-efficacy, aspects of quality of life, and decreasing interest in TKA. Digital behavioral interventions for knee OA may be an acceptable approach to improve patient outcomes and OA self-management while potentially reducing utilization of costly health system resources.


Coping with COVID-19: An Examination of the Role of (Non)Religiousness/(Non)Spirituality.
Psychological distress and coping strategies employed during collective trauma events may vary for theists and atheists, as well as others along the (non)religious spectrum. The present study explored these differences via data collected from a US-based sample during the COVID-19 pandemic. Statistical models suggested relationships between maladaptive coping and distress for all participants and potential differences in coping and, in turn, distress between participants high and low in institutional religiousness and individual spirituality. Additionally, all participants, though especially nonreligious participants, appeared less able to engage in adaptive emotion-focused coping strategies. Implications for future research are provided.


Pieter van Keep Memorial Lecture. Menopause--a modern perspective from a controversial history.
The major milestones in the history of menopause provide a fascinating background to understanding current attitudes and prognosticating future trends in the perception and management of this event through which all women will inevitably pass. 'Menopause' is a word of multiple meanings. Once the subject of taboo; now almost in danger of overexposure. Once neglected, now recognized by multiple groups as the entry to a 'market'. The result is a new level of confusion and even exploitation in the minds of the health profession and the public alike. A historical survey of issues relating to the menopause is therefore an ideal vehicle for providing information and perspective into this fascinating and extremely important component of women's health care. One milestone on my personal historical journey is labeled 'Pieter van Keep', a time and a place where we met, forged an instant and remarkable friendship and during the course of an extraordinary day conceptualized a menopause club, ultimately the International Menopause Society (I.M.S.), a journal to become Maturitas, and an idea for enhanced quality years for women by primary preventative health care, utilizing menopause as a positive entry point. Achievement of the dream of wide scale introduction of preventive health care services to a properly informed public is certain to be as successful in reducing morbidity to older women as was the introduction years ago of proper prenatal care in reducing death and disability related to childbirth. Where we were, where we are generally and the I.M.S. specifically, and where the I.M.S. should position itself in the future is the focus of this lecture, my personal 'swan song' to the I.M.S.


Sleep and waking in 5,7-DHT-lesioned or (-)-pindolol-pretreated rats after administration of buspirone, ipsapirone, or gepirone.
The effects of partial 5-HT1A receptor agonists buspirone (0.010-4.0 mg/kg), ipsapirone (0.010-6.0 mg/kg), and gepirone (0.025-4.0 mg/kg) on sleep and waking were studied in vehicle-treated and 5,7-dihydroxytryptamine (5,7-DHT)-injected rats. 5,7-DHT-treated animals showed a marked and significant serotonin and 5-HIAA depletion in the raphe regions of the pons and upper brain stem, cerebral cortex, hippocampus, and striatum. Subcutaneous administration of the partial agonists to both the vehicle-infused and the 5,7-DHT-treated animals significantly increased waking (W) and reduced light sleep (LS), slow-wave sleep (SWS), and REM sleep (REMS). Pretreatment with (-)pindolol (2.0 mg/kg) reversed the effects of buspirone and gepirone on W and non-REM sleep (LS + SWS) whereas REMS remained suppressed. (-)-Pindolol failed to reverse the effects of ipsapirone on sleep and W. The present results tend to indicate that increased W after acute administration of buspirone, ipsapirone, or gepirone depends upon the activation of postsynaptic 5-HT1A receptors. The well-known anxiolytic action observed after chronic administration of the azapirones seems to be related to mechanisms other that these involved in their stimulant effect.


Thioredoxin-interacting protein (TXNIP) as a target for Alzheimer's disease: flavonoids and phenols.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid plaques and tangles that have become the fifth leading cause of death worldwide. Previous studies have found that thioredoxin interacting protein (TXNIP) expression was increased during the development of AD neurons. TXNIP separates from the TXNIP-thioredoxin complex, and the TXNIP-NLRP3 complex assembles ASC and pro-caspase-1 to form the NLRP3 inflammasome, which triggers AD inflammation and apoptosis. CB-dock was used to explore whether 21 natural flavonoids and phenols target TXNIP based on references. Docking results showed that rutin, puerarin, baicalin, luteolin and quercetin are the most potent TXNIP inhibitors, and among them, rutin as the most effective flavonoid. And rosmarinic acid is the most potent TXNIP inhibitor of phenols. These phytochemicals could be helpful to find the lead compounds in designing and developing novel agents for Alzheimer's disease.


Targeting NADPH Oxidase and Integrin α5β1 to Inhibit Neutrophil Extracellular Traps-Mediated Metastasis in Colorectal Cancer.
Metastasis leads to a high mortality rate in colorectal cancer (CRC). Increased neutrophil extracellular traps (NETs) formation is one of the main causes of metastasis. However, the mechanism of NETs-mediated metastasis remains unclear and effective treatments are lacking. In this study, we found neutrophils from CRC patients have enhanced NETs formation capacity and increased NETs positively correlate with CRC progression. By quantitative proteomic analysis of clinical samples and cell lines, we found that decreased secreted protein acidic and rich in cysteine (SPARC) results in massive NETs formation and integrin α5β1 is the hub protein of NETs-tumor cell interaction. Mechanistically, SPARC regulates the activation of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) pathway by interacting with the receptor for activated C kinase 1 (RACK1). Over-activated NADPH oxidase generates more reactive oxygen species (ROS), leading to the release of NETs. Then, NETs upregulate the expression of integrin α5β1 in tumor cells, which enhances adhesion and activates the downstream signaling pathways to promote proliferation and migration. The combination of NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) and integrin α5β1 inhibitor ATN-161 (Ac-PHSCN-NH2) effectively suppresses tumor progression in vivo. Our work reveals the mechanistic link between NETs and tumor progression and suggests a combination therapy against NETs-mediated metastasis for CRC.


The active ingredients and mechanisms of Longchai Jiangxue Formula in treating PV, based on UPLC/Q-TOF-MS/MS, systematic pharmacology, and molecular biology validation.
Polycythemia vera (PV) is a refractory hematological disease that lack of effective therapy. Chinese traditional medicine Longchai Jiangxue formula (LCJX) has showed the powerful effects on PV. However, the active ingredients and mechanisms of this formula have not been elucidated. We explored the active ingredients and mechanisms of LCJX for treating PV. The chemical constituents of LCJX were qualitatively analyzed by UPLC/Q-TOF-MS/MS. On this basis, the TCMSP, ETCM, PubChem BioAssay and ChEMBL databases were searched to predict the potential targets of chemical components of LCJX. Then Genecards, GEO, DisGeNET, and OMIM databases were used to retrieve data of targets related to PV. Drug-disease-target network and protein-protein-interaction (PPI) network were built. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed. Finally, Molecular docking, CCK-8 assay, Annexin V-FITC/PI staining and western blot were processed so as to screen the active components related to PV and elucidate its mechanisms. A total of 84 compounds were identified from LCJX by UPLC/Q-TOF-MS/MS. After removed duplicate items, there were 143 targets linked to both disease and drugs. Crucial genes, such as MTOR, HIF1A, JAK2, VEGFA, STAT3, AKT1, TERT, MAPK1, were shown in PPI network. GO enrichment indicated that oxidative stress process, tyrosine kinase activity and phosphatase binding function, and cell membrane structure were in reference to LCJX against PV. KEGG enrichment showed that JAK-STAT signaling pathway and PI3K-Akt signaling pathway, were put in an important position of the treatment. Furthermore, Molecular docking, CCK-8 assay, Annexin V-FITC/PI staining and western blot technique proved the therapeutic effect of Saikosaponin A, main ingredient of LCJX. This study, combined with UPLC/Q-TOF-MS/MS, network pharmacology and molecular biology, provides a reference for the identification of effective components, screening of quality markers and analysis of its action mechanism of LCJX.