Effects of Antihypertensive Deprescribing Strategies on Blood Pressure, Adverse Events, and Orthostatic Symptoms in Older Adults: Results From TONE.
The Trial of Nonpharmacologic Interventions in the Elderly (TONE) demonstrated the efficacy of weight loss and sodium reduction to reduce hypertension medication use in older adults. However, the longer-term effects of drug withdrawal (DW) on blood pressure (BP), adverse events, and orthostatic symptoms were not reported. TONE enrolled adults, ages 60-80 years, receiving treatment with a single antihypertensive and systolic BP (SBP)/diastolic BP <145/<85 mm Hg. Participants were randomized to weight loss, sodium reduction, both, or neither (usual care) and followed up to 36 months; ~3 months postrandomization, the antihypertensive was withdrawn and only restored if needed for uncontrolled hypertension. BP and orthostatic symptoms (lightheadedness, feeling faint, imbalance) were assessed at randomization and throughout the study. Two physicians independently adjudicated adverse events, masked to intervention, classifying symptomatic (lightheadedness, dizziness, vertigo), or clinical events (fall, fracture, syncope). Among the 975 participants (mean age 66 years, 48% women, 24% black), mean (±SD) BP was 128 ± 9/71 ± 7 mm Hg. Independent of assignment, DW increased SBP by 4.59 mm Hg (95% confidence interval [CI]: 3.89, 5.28) compared with baseline. There were 113 adverse events (84 symptomatic, 29 clinical), primarily during DW. Compared with usual care, combined weight loss and sodium reduction mitigated the effects of DW on BP (β = -4.33 mm Hg; 95% CI: -6.48, -2.17) and reduced orthostatic symptoms long term (odds ratio = 0.62; 95% CI: 0.41, 0.92), without affecting adverse events (hazard ratio = 1.81; 95% CI: 0.90, 3.65). In contrast, sodium reduction alone increased risk of adverse events (hazard ratio = 1.75; 95% CI: 1.04, 2.95), mainly during DW. In older adults, antihypertensive DW may increase risk of symptomatic adverse events, highlighting the need for caution in withdrawing their antihypertensive medications. Trial Number NCT00000535.


Impact of metformin treatment and swimming exercise on visfatin levels in high-fat-induced obesity rats.
Visfatin is a recently discovered adipocytokine that contributes to glucose and obesity-related conditions. Until now, its responses to the insulin-sensitizing agent metformin and to exercise are largely unknown. We aim to investigate the impact of metformin treatment and/or swimming exercise on serum visfatin and visfatin levels in subcutaneous adipose tissue (SAT), peri-renal adipose tissue (PAT) and skeletal muscle (SM) of high-fat-induced obesity rats. Sprague-Dawley rats were fed a normal diet or a high-fat diet for 16 weeks to develop obesity model. The high-fat-induced obesity model rats were then randomized to metformin (MET), swimming exercise (SWI), or adjunctive therapy of metformin and swimming exercise (MAS), besides high-fat obesity control group and a normal control group, all with 10 rats per group. Zoometric and glycemic parameters, lipid profile, and serum visfatin levels were assessed at baseline and after 6 weeks of therapy. Visfatin levels in SAT, PAT and SM were determined by Western Blot. Metformin and swimming exercise improved lipid profile, and increased insulin sensitivity and body weight reduction were observed. Both metformin and swimming exercise down-regulated visfatin levels in SAT and PAT, while the adjunctive therapy conferred greater benefits, but no changes of visfatin levels were observed in SM. Our results indicate that visfatin down-regulation in SAT and PAT may be one of the mechanisms by which metformin and swimming exercise inhibit obesity.


Could JC virus be linked to chronic idiopathic intestinal pseudo-obstruction?
JC virus is a member of the Polyomavirus family, infects humans worldwide, and 90% of the population carry antibodies to the virus by adult life. The initial infection is asymptomatic, but it may become persistent. JC virus DNA is frequently present in the upper and lower gastrointestinal tracts of healthy adults. Chronic idiopathic intestinal pseudo-obstruction, one of the most severe gastrointestinal motility disorders, is a condition characterized by a clinical picture mimicking small bowel occlusion with related symptoms and signs in the absence of demonstrable mechanical obstruction. Because of the known neuropathic capability of this virus, and its frequent presence in the gut, it has been proposed that JCV might be detectable in tissues of patients with chronic idiopathic intestinal pseudo-obstruction, and possibly be involved in the pathogenesis of this disease, because the virus may actively infect the enteroglial cells of the myenteric plexuses of the patients with chronic idiopathic intestinal pseudo-obstruction. We report two cases of upper idiopathic intestinal pseudo-obstruction associated with JCV infection.


Identification of new CRF51_01B in Singapore using full genome analysis of three HIV type 1 isolates.
A recent HIV-1 molecular epidemiology survey in Singapore identified a novel CRF01_AE/B recombinant form, which accounted for 13 (11.9%) of 109 patient samples. Peripheral blood mononuclear cell DNA from three of these 13 patients was used to generate near full-length sequences to characterize the novel CRF01_AE/B recombinant form. The three isolates had a recombinant structure composed of CRF01_AE and subtype B, and shared identical breakpoints. As the three patients were not epidemiologically linked, this recombinant form has been designated CRF51_01B. Identification of the novel recombinant forms indicates ongoing active HIV-1 transmission in Singapore.


Image Analysis Techniques for In Vivo Quantification of Cerebrospinal Fluid Flow.
Over the last decade, there has been a tremendously increased interest in understanding the neurophysiology of cerebrospinal fluid (CSF) flow, which plays a crucial role in clearing metabolic waste from the brain. This growing interest was largely initiated by two significant discoveries: the glymphatic system (a pathway for solute exchange between interstitial fluid deep within the brain and the CSF surrounding the brain) and meningeal lymphatic vessels (lymphatic vessels in the layer of tissue surrounding the brain that drain CSF). These two CSF systems work in unison, and their disruption has been implicated in several neurological disorders including Alzheimer's disease, stoke, and traumatic brain injury. Here, we present experimental techniques for in vivo quantification of CSF flow via direct imaging of fluorescent microspheres injected into the CSF. We discuss detailed image processing methods, including registration and masking of stagnant particles, to improve the quality of measurements. We provide guidance for quantifying CSF flow through particle tracking and offer tips for optimizing the process. Additionally, we describe techniques for measuring changes in arterial diameter, which is an hypothesized CSF pumping mechanism. Finally, we outline how these same techniques can be applied to cervical lymphatic vessels, which collect fluid downstream from meningeal lymphatic vessels. We anticipate that these fluid mechanical techniques will prove valuable for future quantitative studies aimed at understanding mechanisms of CSF transport and disruption, as well as for other complex biophysical systems.


SpaRTA Tracking Across Occlusions via Partitioning of 3D Clouds of Points.
Any 3D tracking algorithm has to deal with occlusions: multiple targets get so close to each other that the loss of their identities becomes likely; hence, potentially affecting the very quality of the data with interrupted trajectories and identity switches. Here, we present a novel tracking method that addresses the problem of occlusions within large groups of featureless objects by means of three steps: i) it represents each target as a cloud of points in 3D; ii) once a 3D cluster corresponding to an occlusion occurs, it defines a partitioning problem by introducing a cost function that uses both attractive and repulsive spatio-temporal proximity links; and iii) it minimizes the cost function through a semi-definite optimization technique specifically designed to cope with the presence of multi-minima landscapes. The algorithm is designed to work on 3D data regardless of the experimental method used: multicamera systems, lidars, radars, and RGB-D systems. By performing tests on public data-sets, we show that the new algorithm produces a significant improvement over the state-of-the-art tracking methods, both by reducing the number of identity switches and by increasing the accuracy of the estimated positions of the targets in real space.


Significance and relevance of serum preS1 antigen detection in wild-type and variant hepatitis B virus (HBV) infections.
These studies assessed whether the serum expression of preS1 antigen could be a useful HBV marker for monitoring the progress of antiviral therapy in the treatment of chronic active hepatitis B (CAH-B) virus infections. Our findings indicate that: 1) the rearrangements we observed in the preS region of mutated HBV DNA molecules during chronic infection did not effect the preS1 sequence (21-47) critical for HBV infectivity; 2) the persistence or even the rebound of preS1 antigen expression during follow-up in responders to antiviral therapy may indicate virus persistence, suggesting the possibility of relapse through wild-type HBV or the emergence of HBV variants following the immunoelimination phase.


Pharmacokinetic-hemodynamic studies of disopyramide.
The hemodynamic effects and pharmacokinetics of two doses of disopyramide (DP) given as a two-stage intravenous load and maintenance infusion were studied in anesthetized dogs. One group (n = 4) received 4 mg/kg for 30 min and 1 mg/kg/h for 30 min (low-dose group). The high-dose group (n = 4) received 8 mg/kg for 30 min and 4 mg/kg/h for 30 min. In the low-dose group, there was a fall in cardiac output which reached statistical significance at 300 min [from 3.4 +/- 0.4 (SD) to 2.7 +/- 0.7 L/min; p less than 0.05, analysis of variance (ANOVA)]. In the high-dose group, there also was a fall in cardiac output (from 4.6 +/- 1.4 to 3.0 +/- 0.4 L/min; p less than 0.01, ANOVA), and this was associated with a rise in total peripheral resistance (from 39 +/- 11 to 58 +/- 9 units; p less than 0.01). Peak total venous DP concentrations were 3.0 +/- 0.2 and 7.5 +/- 1.0 micrograms/ml for the low- and high-dose groups, respectively, and were achieved at the end of the load infusion. The free fraction of DP was not dependent on total venous DP concentration and approximated 0.66. Elimination half-life, clearance, and apparent volume of distribution were 3.91 +/- 0.53 h, 0.39 +/- 0.02 L/kg/h, and 2.22 +/- 0.32 L/kg, respectively, for the low-dose group and 3.67 +/- 0.91 h, 0.36 +/- 0.06 L/kg/h, and 1.84 +/- 0.29 L/kg, respectively, for the high-dose group. There were no significant differences between these measurements for low- versus high-dose groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Quantitative proteomics indicate a strong correlation of mitotic phospho-/dephosphorylation with non-structured regions of substrates.
Protein phosphorylation plays a critical role in the regulation and progression of mitosis. >40,000 phosphorylated residues and the associated kinases have been identified to date via proteomic analyses. Although some of these phosphosites are associated with regulation of either protein-protein interactions or the catalytic activity of the substrate protein, the roles of most mitotic phosphosites remain unclear. In this study, we examined structural properties of mitotic phosphosites and neighboring residues to understand the role of heavy phosphorylation in non-structured domains. Quantitative mass spectrometry analysis of mitosis-arrested and non-arrested HeLa cells revealed >4100 and > 2200 residues either significantly phosphorylated or dephosphorylated, respectively, at mitotic entry. The calculated disorder scores of amino acid sequences of neighboring individual phosphosites revealed that >70% of dephosphorylated phosphosites exist in disordered regions, whereas 50% of phosphorylated sites exist in non-structured domains. A clear inverse correlation was observed between probability of phosphorylation in non-structured domain and increment of phosphorylation in mitosis. These results indicate that at entry to mitosis, a significant number of phosphate groups are removed from non-structured domains and transferred to more-structured domains. Gene ontology term analysis revealed that mitosis-related proteins are heavily phosphorylated, whereas RNA-related proteins are both dephosphorylated and phosphorylated, suggesting that heavy phosphorylation/dephosphorylation in non-structured domains of RNA-binding proteins plays a role in dynamic rearrangement of RNA-containing organelles, as well as other intracellular environments.


4-Anilinopyrimido[4',5':4,5]selenolo(2,3-b)quinoline and 4-piperazino pyrimido[4',5':4,5]selenolo(2,3-b)quinoline: new DNA intercalating chromophores with antiproliferative activity.
We have used circular dichroism, hydrodynamic methods, absorbance, and fluorescence titration to study the interaction of 4-anilinopyrimido[4',5':4,5] selenolo (2,3-b)quinoline (APSQ) and 4-piperazinopyrimido[4',5':4,5] selenolo(2,3-b)quinoline (PPSQ) with DNA. The association constants of APSQ and PPSQ were of the order of 10(4)M(-1). The fluorescence properties at ionic strength 0.01M are best fit by the neighbor exclusion model, with K=0.58-9.2 x 10(4)M(-1) and an exclusion parameter of 0.9-6.4 bp. Binding to the GC-rich DNA of Micrococcus lysodeikticus was stronger than the binding to calf thymus DNA, suggest that drug binds preferentially to G+C pairs at low r. CD spectra indicate that stacking of these compounds with DNA induces a strong helicity in the usually disordered structure of this double strand. Viscosity experiments show with sonicated calf thymus DNA with PPSQ an twice increase in slope (m) as that with APSQ. PPSQ increases the T(m) for calf thymus DNA melting by approximately 10 degrees C as binding approaches saturation, with biphasic melting. The cytotoxicities of these compounds on leukemia HL-60, K-562, B16F10 melanoma and Colo-205 are quite similar and inhibition (IC(50)) was in the range of 0.39-9.80 microM. The anticancer efficacy against B16F10 melanoma has provided evidence of major anticancer activity for PPSQ. Single or multiple intraperitonial (i.p.) doses of drug proved high level activity against the subcutaneous (s.c.) grafted B16 melanoma, significantly increase in life span (ILS 139% and 170%). The aim of this study was to analyze the physiochemical properties of these compounds in an attempt to understand its superior biological activity.


Morphometric studies on the appendicular bony skeleton of the ostriches (Struthio Camelus).
Morphometric study of the bony elements of the appendicular skeleton in the ostrich was fully described and identified. The appendicular skeleton included the bones of the pectoral girdle, the wing, the pelvic girdle and the pelvic limb. The shoulder girdle of the ostrich included the scapula and coracoid bones. The scapula appeared as a flattened spoon-like structure. The coracoid bone appeared quadrilateral in outline. The mean length of the scapula and coracoid (sternal wing) were 15.00 ± 0.23 and 10.00 ± 0.17 cm, respectively. The wing included the humerus, ulna, radius, radial carpal bone, ulnar carpal bone, carpometacarpus and phalanges of three digits. The mean length of the humerus, radius, and ulna were 33.00 ± 0.46, 10.50 ± 0.40 and 11.50 ± 0.29 cm respectively. The carpometacarpus was formed by the fusion of the distal row of carpal bones and three metacarpal bones. Digits of the wing were three in number; the alular, major and minor digits. Os coxae comprised the ilium, ischium and pubis. Their mean lengths were 36.00 ± 0.82 cm, 32.00 ± 0.20 and 55.00 ± 0.2.9 cm, respectively. The femur was a stout short bone, that appeared shorter than the tibiotarsus. The mean length of the femur, tibiotarsus, and tarsometatarsus were 30.00 ± 0.23, 52.00 ± 0.50 and 46.00 ± 0.28 cm. Tibiotarsus was the longest bone in the pelvic limb. The fibula was a long bone (44.00 ± 0.41 cm) lying along the lateral surface of the tibiotarsus. The tarsometatarsus was a strong long bone formed by the fusion of the metatarsal (II, III, IV) and the distal row of tarsal bones. It was worth mentioning that metatarsal II was externally absent in adults. In the appendicular skeleton of ostrich, there were special characteristic features that were detected in our study; the clavicle was absent, the coracoid bone was composed of a sternal wing and scapular wing, the ulna was slightly longer in length than the radius. The coupled patellae i.e., the proximal and distal patella were observed; and the ostrich pedal digits were only two; viz., the third (III) and fourth (IV) digits.


4-Hydroxytamoxifen-stimulated processing of cyclin E is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells.
Over-expression of cleaved cyclin E in breast tumors is closely associated with tumor progression and resistance to antiestrogens. 17β-Estradiol (E2) has been recently shown to induce cyclin E processing in breast cancer cells. Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of tamoxifen on the generation of cleaved cyclin E and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). 4-Hydroxytamoxifen (OHT, tamoxifen's active form) failed to prevent E2-induced proteolysis of cyclin E and migration, but rather triggered cyclin E cleavage coincident with augmented migration. OHT-induced cyclin E truncation also occurred in SK-BR-3 cells that express GPR30 and lack ERα, but not in MDA-MB-231 cells that express neither GPR30 nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of cyclin E and enhanced migration. Furthermore, OHT-stimulated cleavage of cyclin E and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30. In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of cyclin E, suggesting involvement of EGFR signaling. Collectively, our data indicate that OHT contributes to the production of proteolyzed cyclin E via GPR30 with augmented migration in MCF-7 cells.


Metabolomics and psychological features in fibromyalgia and electromagnetic sensitivity.
Fibromyalgia (FM) as Fibromyalgia and Electromagnetic Sensitivity (IEI-EMF) are a chronic and systemic syndrome. The main symptom is represented by strong and widespread pain in the musculoskeletal system. The exact causes that lead to the development of FM and IEI-EMF are still unknown. Interestingly, the proximity to electrical and electromagnetic devices seems to trigger and/or amplify the symptoms. We investigated the blood plasma metabolome in IEI-EMF and healthy subjects using 1H NMR spectroscopy coupled with multivariate statistical analysis. All the individuals were subjected to tests for the evaluation of psychological and physical features. No significant differences between IEI-EMF and controls relative to personality aspects, Locus of Control, and anxiety were found. Multivariate statistical analysis on the metabolites identified by NMR analysis allowed the identification of a distinct metabolic profile between IEI-EMF and healthy subjects. IEI-EMF were characterized by higher levels of glycine and pyroglutamate, and lower levels of 2-hydroxyisocaproate, choline, glutamine, and isoleucine compared to healthy subjects. These metabolites are involved in several metabolic pathways mainly related to oxidative stress defense, pain mechanisms, and muscle metabolism. The results here obtained highlight possible physiopathological mechanisms in IEI-EMF patients to be better defined.


Low-affinity state beta1-adrenoceptor-induced vasodilation in SHR.
Low-affinity state beta1-adrenoceptor (beta1-AR) was functionally expressed in some blood vessels and was different from beta1, beta2 and beta3-AR. In rat aorta, low-affinity state beta1-AR activation produced an endothelium-independent relaxation which was impaired in spontaneously hypertensive rats (SHRs). In the present work, we investigated whether renin-angiotensin system was involved in this alteration by evaluating the effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor or losartan, an AT1 angiotensin receptor antagonist. Cumulative concentration-response curves to low-affinity state beta1-AR agonists (CGP 12177, cyanopindolol or alprenolol) and to NS 1619, a large conductance Ca2+-activated K+ channels (BK) agonist were performed in denuded aortic rings isolated from control or treated Wistar Kyoto (WKY) rats or SHRs in different experimental conditions. The low-affinity state beta1-AR-mediated aortic vasodilation was impaired in 5 and 12 weeks old SHRs when compared to age-matched WKY. Twelve days enalapril (5 mg/kg/day) or losartan (15 mg/kg/day) treatments reduced systolic blood pressure (SBP) only in 12 weeks old SHRs whereas no significant change was observed in other groups. These treatments improved low-affinity state beta1-AR effect only in SHRs groups. In 12 weeks old WKY rats, CGP 12177-induced relaxation was insensitive to glibenclamide, a K(ATP)+ channel blocker, but was reduced by TEA or iberiotoxin, two large conductance Ca2+-activated K+ channel (BK) blockers. The impairment of NS 1619-induced vasodilation in both 5 and 12 weeks old SHRs was restored by enalapril or losartan. These results suggested that improvement of the low-affinity state beta1-AR-mediated vasodilation in 5 and 12 weeks old SHRs could be attributed to enhanced BK channels-induced hyperpolarization in SHRs independently of lowering of SBP.


Preservation versus replacement of the aortic root for acute type A aortic dissection.
To determine the impact of aortic root preservation versus aortic root replacement (ARR) after acute type A aortic dissection (ATAAD) repair. In this observational study of consecutive aortic surgeries between 2007 and 2021, patients with ATAAD were identified via a prospectively maintained institutional database and were stratified by root preservation versus ARR (including valve-sparing and complete ARR). Kaplan-Meier survival estimation and multivariable Cox regression analysis were performed. Among the 601 patients underwent aortic arch reconstruction for ATAAD, 370 (61.6%) underwent root preservation and the other 231 (38.4%) underwent ARR, with a median follow-up of 6.3 years (interquartile range, 3.8-9.6 years). Cardiopulmonary bypass and ischemic times were longer in the ARR group, but intraoperative variables were otherwise similar between the groups, including cannulation strategy and extent of distal repair. There were no between-group differences in postoperative outcomes, including operative mortality, stroke, mechanical ventilation time, renal failure, reexploration for bleeding, and total length of stay. At a 1-year follow-up, the incidence of aortic regurgitation (moderate or greater) was similar in the 2 groups. On multivariable Cox regression, ARR was not associated with improved long-term survival compared with root preservation (hazard ratio, 1.13; 95% confidence interval, 0.82-1.56; P = .44). Late reinterventions on the aortic root or valve were similar in the 2 groups and was 2.0% for the overall cohort. These findings suggest that aortic root preservation may achieve similar midterm outcomes as ARR after ATAAD repair.


Hepatic metastases in Hong Kong Chinese: evidence for an East-West difference in gastric cancer.
The incidence of hepatic metastases found at laparotomy for colorectal and gastric cancer amongst Hong Kong Chinese was found to be 16% and 5% respectively. These figures were compared to similar Western series, and the incidence of metastases from gastric cancer was significantly lower in the Chinese population. This geographical variation may have important implications for the interpretation of treatment results for gastric cancer in different parts of the world.


Bacteroides spp. and traditional fecal indicator bacteria in water quality assessment - An integrated approach for hydric resources management in urban centers.
As part of a sustainable water resources management, the Lisbon municipality identified groundwater and treated wastewater use increase as two opportunities for better and sustainable water use, with natural safeguard for public health as a priority. In this context, the aim of our research was to assess the suitability of the human-associated marker gene Bacteroides HF183 and the cattle feces-associated CowM2, in routine water quality monitoring as indicators for water use and reuse, providing a tool to more accurately assess public health risks. To this intent, Real-Time quantitative PCR was used for detection of human-associated marker gene Bacteroides HF183 and the bovine-associated CowM2, in a total of 67 samples - groundwater and wastewater at three different treatment stages of a Waste Water Treatment Plant, in Lisbon. HF183 marker gene was detected in treated and untreated wastewater samples, with significant concentration reductions from untreated (6,07 E+07 copies/mL) to secondary treated effluent (1,86 E+05 copies/mL) and a further decrease in tertiary treatment (5,74 E+04 copies/mL). In groundwater samples, this marker was also detected in concentrations ranging from 2,63 E+02 copies/mL to 2,24 E+03 copies/mL. CowM2 marker gene on the other hand was only detected in wastewater samples, with concentrations ranging from 2,47 E+02 copies/mL to 1,17 E+04 copies/mL. Our research indicates that the use of Bacteroides spp. in association with traditional fecal indicator bacteria (FIB) is advantageous for water managing entities in urban settings, such as Lisbon, were drainage system failures may occur. An integrated approach thus provides crucial and more adequate information towards mitigation and correction measures when fecal contamination is detected in environmental waters.


Molecular connectivity analyses of structure influencing chromatographic retention indexes.
The molecular connectivity indexes of various aliphatic alcohols, ketones, ethers, and esters were used to describe structural features influencing chromatographic retention indexes. Good correlations were obtained within chemical classes for a particular stationary phase.


Inpatient Choledocholithiasis Requiring ERCP and Cholecystectomy: Outcomes of a Combined Single Inpatient Procedure Versus Separate-Session Procedures.
Separate-session endoscopic retrograde cholangiography (ERCP) and laparoscopic cholecystectomy (LC) is the usual method for management of inpatient choledocholithiasis. Our goal was to compare single operative-session LC and ERCP to a multi-session approach for both the same hospitalization and within 30 days after; there is limited data comparing the three groups. A retrospective review on inpatients with choledocholithiasis that underwent ERCP and LC was performed. Single operative-session ERCP + LC (SOS group) and separate hospitalization ERCP + LC (DH group) were compared against the control cohort: separate-session ERCP + LC performed during the same hospitalization (SH group). Among the 214 cases, 37 (17%) had LC + ERCP performed under a single operative session (SOS), 130 (60.7%) cases had LC + ERCP performed in separate operative sessions during the same hospitalization (SH), and 47 (22%) cases had LC + ERCP performed in different hospitalizations, within 30 days (DH). There was no statistically significant difference in efficacy or adverse events. The SOS group had a statistically significant mean shorter length of hospital stay as compared to the SH and DH groups (5.46 vs 7.15 vs 9.38; p = 0.05 and 0.02). There was a statistically significant reduction in the total cost of care in the SOS group versus the SH group ($59,221 vs $75, 808; p = 0.007). The SOS approach is safe, efficacious, and cost-efficient when compared to separate operative sessions. This approach can be considered in situations where it is preferable for the patient to undergo a single session of anesthesia, without compromising technical success and safety.


Cellular transformation and the 'morphologic phenotype' of transformed cells.
Expression of the product of the transforming gene (src) of RNA tumour viruses promotes growth and usually alters the adhesion, appearance and surface properties of cultured fibroblasts. The latter group of properties termed the 'morphologic phenotype' of transformed cells is largely due to diminished cell-to-substratum adhesion. The role of cyclic AMP, cell surface protein (CSP), and other factors in producing the 'morphologic phenotype' are discussed. The effects of src expression bear a striking resemblance to the action of peptide hormones such as insulin on appropriate target cells.


Elicitation effects of oligosaccharides on the transcriptional level of bacitracin ABC transporter genes in Bacillus licheniformis.
Bacitracin ABC transporter comprises a self-resistance system in Bacillus licheniformis against its own product (bacitracin). Elicitation effects of carbohydrates on transcription level of bcrABC genes encoding bacitracin ABC transporter system were investigated through quantification by real-time PCR. Increases of 68% and 29% in bacitracin A yields after 36 h were achieved in cultures supplemented with oligoguluronate and oligoguluronate/mannan oligosaccharide combination. Cultures with combined elicitors showed 3, 2.6 and 3 transcriptional fold-changes in bcrA, bcrB and bcrC, respectively, compared to control. This could be due to a secondary effect caused by increased bacitracin A yield through elicitation.


Multiple and Recurrent Squamous Cell Carcinoma of the Oral Cavity After Graft-Versus-Host Disease.
Oral squamous cell carcinoma (OSCC) is one of the most common secondary solid tumors in patients who have undergone hematopoietic stem cell transplantation (HSCT). However, according to previous reports, multiple and recurrent OSCC is very rare. The presented case shows the susceptibility to the development of secondary malignancies, particularly oral cancer, of patients who present with chronic graft-versus-host disease after HSCT. OSCC after HSCT appears to be more invasive and has a tendency to recur, with a poor prognosis. Therefore, regular and thorough evaluations of the oral mucosa are recommended for all patients who undergo bone marrow transplantation and have chronic graft-versus-host disease.


Relationship between macrophage differentiation and the chemotactic activity toward damaged myoblast cells.
We investigated the effect of macrophage differentiation on the chemotactic activity to invade local damaged myoblasts using in vitro models of muscle injury. We found that: 1) the chemotactic activity of macrophages toward areas of damaged myoblasts might be induced more by live myoblasts than dead ones, 2) the chemotactic activity of macrophages is not due to velocity, but depends on the directionality toward damaged myoblast cells, and 3) macrophage differentiation strongly influence the chemotactic activity toward damaged myoblast cells through the expression of CCR2 and/or F-actin.


Gender differences in utilization of effective cardiovascular secondary prevention: a Cleveland clinic prevention database study.
Previous studies have suggested that women with cardiovascular disease may receive less aggressive care than men. Using a large cardiology database from a tertiary referral center, we sought to determine if treatment differences still persist in the current era. We analyzed data on 2462 patients who were referred for secondary prevention to the Preventive Cardiology Clinic at The Cleveland Clinic Foundation between 1997 and 2004. The primary objective was to evaluate use of effective secondary preventive therapies, by gender, as outlined in the ACC/AHA guidelines, such as antiplatelet therapy, beta-blockers, statins, and angiotensin-converting enzyme (ACE) inhibitors. Multivariate logistic regression analysis was performed to assess the independent effect of gender on all cause mortality. Women were older (62.2 +/- 11.1 vs. 59.4 +/- 11.0, p < 0.001) and more likely to be hypertensive (68.1% vs. 56.1%, p < 0.001) than men. Overall, women were more likely than men to have higher baseline C-reactive protein (CRP) (6.14 +/- 13.4 vs. 4.9 +/- 10.7, p < 0.001), low-density lipoprotein cholesterol (LDL-C) (135 +/- 66 vs. 116 +/- 46, p < 0.001), high-density lipoprotein cholesterol (HDL-C) (52 +/- 17 vs. 41 +/- 11, p < 0.001), and total cholesterol (238 +/- 98 vs. 202 +/- 65, p < 0.001). Women were less likely to be on antiplatelet therapy (76.6 % vs. 85.0%, p < 0.001) and statins or any lipid-lowering therapy (62.6% vs. 67.1%, p = 0.04) compared with men on presentation. Even in the current era, women with established cardiovascular disease continue to receive less aggressive care than men. They are less likely to be on aspirin and statin therapy. More aggressive efforts should be made to treat both men and women with standard secondary preventive efforts.


Positive influence of nifedipine on early-stage minipig shock lung.
Mechanical and biochemical lesions can be observed in shock lung. To investigate the influence of the calcium antagonist nifedipine on these lesions, we produced shock lung in male minipigs. Three groups (control, thrombin, and thrombin + nifedipine; n = 5) were formed. In the second and third group thrombin was administered intravenously (400 IU/kg body weight) over a period of 2 h. After that the animals received aminocaproic acid (100 mg/kg body weight/h) throughout the rest of the study. Nifedipine was administered in the third group at a dosage of 46 micrograms/kg body weight/h. During the investigation period coagulation and hemodynamic status were examined as well as blood gas levels. Then the isolated lungs were examined. Without nifedipine there was a significant decrease in arterial PO2, an increase in airway opening pressure (Pi), and a decrease in weight-specific end-inspiratory lung compliance (Ci). These changes were not observed under the influence of nifedipine, after which the results were similar to the control group. This demonstrates a positive influence of nifedipine on the acid-base status and the investigated lung mechanical parameters.


Comparative investigations to evaluate the use of organotypic cultures of transformed and native dermal and epidermal cells for permeation studies.
In a comparative study organotypic cultures of both transformed and native dermal and epidermal cells were used for permeation studies. In these organotypic cultures the dermal cells are incorporated into a contracted collagen gel, the epidermal cells are seeded on top of this gel and form a multilayered stratified epidermis when cultivated at the air-liquid interface. For permeation studies two different donor systems containing ibuprofen acid were used, Ibutop-Creme and Dolgit-Mikrogel. Studies using excised human stratum corneum showed differences in drug permeability for these two formulations which were also observed when the native organotypic cultures were used. In general, organotypic cultures show a higher permeability for topically applied drugs than excised human stratum corneum, the cultures consisting of transformed cells showed an increase in drug permeability for the Dolgit-Mikrogel compared with the native cultures which might be due to a higher sensitivity for the enhancer isopropanol in this formulation.


How much to worry about the FDA warning in the use of citalopram?
A number of studies have suggested that antidepressants such as selective serotonin reuptake inhibitors may increase a risk of developing harmful cardiac adverse event such as QT interval prolongation. In fact, the US Food and Drug Administration (FDA) consecutively gave safety warnings to healthcare professionals that the use of citalopram may be associated with QT interval prolongation in 2011 and 2012. Despite the fact that citalopram has been one of the most acceptable antidepressants worldwide, concerns on citalopram about cardiac safety issues have become apparent to clinicians after the FDA warning. However, a recent cohort study raises some practical questions about the FDA warnings on the use of citalopram and may also provide clinicians with a good guidance for prudent use of citalopram in clinical practice.


Anti-inflammatory active polyacetylenes from Bidens campylotheca.
The n-hexane extract of Bidens campylotheca Schultz Bip. ssp campylotheca (Compositae) showed significant in vitro inhibition of cyclooxygenase (CO) and 5-lipoxygenase (5-LO). Five polyacetylenes, heptadeca-2E,8E,10E,16-tetraene-4,6-diyne (1), heptadeca-2E,8Z,10E,16-tetraene-4,6-diyne (2), heptadeca-2E,8E,16-triene-4,6-diyne-10-ol (3), safynol (5) and, as a new compound, safynol-2-O-isobutyrate (4) could be isolated and their structures elucidated mainly by UV, MS, NMR, and COSY-NMR. The isolated compounds exhibited a significant inhibitory effect on cyclooxygenase and 5-lipoxygenase.


Jehovah's witness head and neck free flap reconstruction patient outcomes.
Jehovah's Witnesses are members of a Christian religious denomination that rejects the transfusion of whole blood and component blood products. Given new transfusion-free strategies, Jehovah's Witness patients are undergoing free flap reconstructions with increased regularity. However, outcome data remains limited. With this study, we sought to examine post-operative outcomes in Jehovah's Witness patients undergoing free flap reconstruction of the head and neck, compare their outcomes to non-Jehovah's Witness patients, and enumerate strategies to enhance the safety of transfusion-free surgery. A retrospective chart review was carried out on 10 patients who identified as Jehovah's Witness and 63 patients who did not. Demographic information, pre-operative laboratory values, peri-operative resuscitative interventions, and peri-operative outcome measures were compiled. Descriptive data analysis, Mann-Whitney, Chi-square tests, and multivariate analysis were used. Jehovah's Witness patients were significantly older than non-Jehovah's Witness patients (p = 0.03) and had significantly higher ASA scores (p = 0.009). Head and neck cancer was the primary surgical indication in both groups (p = 0.71). Jehovah's witness patients have significantly less intraoperative blood loss (p = 0.011) and lower post-operative hemoglobin (p = 0.002) compared to non-Jehovah's Witness patients. While Jehovah's Witness patients had significantly higher rates of severe anemia (p = 0.014), there was no significant difference between the two groups in other post-operative complications and readmission rates even in a multivariate analysis accounting for age and ASA score. Free flap microvascular reconstruction can be reliably performed on Jehovah's Witness head and neck patients without an increased risk of complication. Policies such as the use of non-blood volume expanders, albumin, Epogen, perioperative iron supplementation, cell saver and acute normovolemic hemodilution are key to ensuring good outcomes.


Erectile Dysfunction is Predictive of Endothelial Dysfunction in a Well Visit Population.
The relationship between erectile dysfunction and endothelial dysfunction has been described and is associated with adverse cardiac events. Endothelial dysfunction is believed to precede erectile dysfunction. Our objective was to characterize the prevalence of subjective erectile dysfunction, endothelial dysfunction and commonly related comorbidities in a population of men undergoing wellness screening. A total of 205 men presented for wellness screening. They underwent testing for endothelial dysfunction via peripheral arterial tonometry and completed a health screening questionnaire. Reactive hyperemia index scores were generated by peripheral arterial tonometry testing. A reactive hyperemia index score of 1.67 or less defined endothelial dysfunction. The Student t-test and Fisher exact test were performed for continuous and categorical variables, respectively. The association of endothelial dysfunction, erectile dysfunction and various comorbidities was calculated using univariate and multivariable analyses. Of 205 men 47 reported subjective erectile dysfunction. Median age was 44 years old. The mean reactive hyperemia index in patients with erectile dysfunction was significantly lower than in patients without erectile dysfunction (1.63 vs 1.87, p = 0.001). Endothelial dysfunction was more common in men with than without erectile dysfunction (55% vs 36%, p = 0.027). Multivariable analysis revealed that men with erectile dysfunction and obesity were twofold more likely to have concomitant endothelial dysfunction (OR 2.45, 95% CI 1.13-4.24, p = 0.02 and OR 2.08, 95% CI 1.16-3.75, p = 0.01, respectively). Among middle-aged men presenting for wellness screening erectile dysfunction and obesity independently predicted endothelial dysfunction, a known risk factor for long-term adverse cardiac events.


Post-approval trials of new medicines: widening use or deepening knowledge? Analysis of 10 years of etanercept.
To investigate the main aims of the post-approval randomized controlled trials (RCTs) on etanercept and the extent to which they were designed to gain more comparative information. A search of the literature (Medline, Embase), trial registries (Clinical Trials.gov, Controlled Trials.com), and market authorization reports from the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) was carried out to identify all RCTs. A comparison of trial data identified unpublished trials and multiple publications relating to the same study. All RCTs completed and/or published after initial market approval was regarded as post-approval. Up until 2008, we found 84 post-approval trials, 11 (13%) trials on approved extensions of indication, another 30 (36%) trials on the approved indications, and 43 (51%) trials on indications not (yet) approved. Nearly half of the studies on indications not yet approved were initiated and funded by independent sponsors. After the initial approval of etanercept, six head-to-head trials were conducted on the approved indications. Overall, the main objectives of post-approval trials with etanercept were found to confirm efficacy and safety in new indications, and to gather additional information for optimal use on the approved indications. Post-approval RCTs on etanercept focus more on studies searching for new indications than on deepening knowledge about use. Ten years after the market entry of etanercept, one of the reasonable demands of clinical practice, for more comparative information, still remains unanswered.


Alkaline-thermal hydrolysate of waste activated sludge as a co-metabolic substrate enhances biodegradation of refractory dye reactive black 5.
Aromatic azo dyes possess inherent resistance and are known to be carcinogenic, posing a significant threat to human and ecosystems. Enhancing the biodegradation of azo dyes usually requires the presence of co-metabolic substrates to optimize the process. In addressing the issue of excessive waste activated sludge (WAS) generation, this study explored the potential of utilizing alkaline-thermal hydrolysate of WAS as a co-metabolic substrate to boost the degradation of reactive black 5 (RB5) dyes. The acclimated microbial consortium, when supplemented with the WAS hydrolysate obtained at a hydrolysis temperature of 30 °C, achieved an impressive RB5 decolorization efficiency of 90.3% (pH = 7, 35 °C) with a corresponding COD removal efficiency of 45.0%. The addition of WAS hydrolysate as a co-substrate conferred the consortium with a remarkable tolerance to high dye concentration (1500 mg/L RB5) and salinity levels (4-5%), surpassing the performance of conventional co-metabolic sugars in RB5 degradation. 3D-EEM analysis revealed that protein-like substances rich in tyrosine and tryptophan, present in the WAS hydrolysate, played a crucial role in promoting RB5 biodegradation. Furthermore, the microbial consortium community exhibited an enrichment of dye-degrading species, including Acidovorax, Bordetella, Kerstersia, and Brevundimonas, which dominated the community. Notably, functional genes associated with dye degradation and intermediates were also enriched during the RB5 decolorization and biodegradation process. These findings present a practical strategy for the simultaneous treatment of dye-containing wastewater and recycling of WAS.


Validation of portable electronic equipment (Accutrend® Plus) to determine glucose, total cholesterol, and triglycerides in rats (Rattus) and dogs (Canis lupus familiaris).
This study aimed to validate the analytical precision of the Accutrend® Plus portable electronic equipment (PE) to determine glucose (GLU), total cholesterol (TC), and triglycerides (TG) in rats and dogs using the conventional laboratory method (CM) as a reference. To determine the analytical accuracy of the Accutrend® Plus in the measurement of GLU, CT, and TG. The EP-9-A2 guide (Clinical and Laboratory Standards Institute), Bland-Altman graphical analysis, and Lin's correlation coefficient of concordance (CCC) were implemented. The average differences (p > 0.05) between PE and CM for GLU, TC, and TG were 2.21, 1.20, and 0.72 mg·dl-1, respectively, in rats and 1.06, 4.30, and 2.41 mg·dl-1, respectively, in dogs (p > 0.05). Both methods showed a linear relationship with Pearson's correlation coefficients > 0.96 and R 2 > 0.97 for the three biochemical indicators evaluated in both species. The GLU, TC, and TG values obtained by the PE were substantial, as evident from Lin's CCC > 0.96. The PE Accutrend® Plus is potent for monitoring GLU, TC, and TG in rats and dogs because of its precision and ability to facilitate measurement by reducing stress in animals during sampling.


Efficacy of radiotherapy for malignant gliomas in elderly patients.
Age above 65 years is a strong negative prognostic factor for survival in patients with malignant gliomas (MG) treated with radiotherapy (RT) and its value has been questioned. We analyzed the effect of RT on the survival of elderly patients with malignant gliomas. We examined 85 consecutive elderly patients with a histological diagnosis of MG. Age ranged from 65 to 81 years (median 70 years). Glioblastoma multiforme (GBM) was diagnosed in 64 patients (75.3%). Surgical treatment included needle biopsy in 32 patients (37.6%). Median postoperative Karnofsky Performance Status (KPS) was 60 (range: 30-100). Survival probability was estimated using Kaplan-Meier method and compared with the log-rank test. Crude and adjusted hazard ratios (HR) were calculated using Cox's regression models. Median survival time for all patients was 18.1 weeks. In multivariate analysis, RT was the only independent prognostic variable for survival (HR: 9.1 [95% CI: 4.5-18.7]). Forty-two patients did not start RT mostly due to low KPS (<50). The median survival of the 43 patients who started RT was 45 weeks. In these patients, Cox multivariate analysis indicated that age was independently associated with prolonged survival (HR: 2.85 [95% CI 1.31-6.19]). Median survival of patients age 70 years and younger was 55 weeks compared with 34 weeks for patients older than 70 years. The overall survival for elderly patients with MG is poor. RT seems to improve survival in patients up to 70 years, but in older patients treated with RT the survival is significantly shorter.


ESR1 hotspot mutations in endometrial stromal sarcoma with high-grade transformation and endocrine treatment.
High-grade endometrial stromal sarcomas (HGESSs) are more aggressive and have higher rates of resistance to endocrine therapy than low-grade endometrial stromal sarcomas (LGESSs). The pathogenesis of hormonal resistance in these lesions has yet to be defined. Here we sought to histologically and genetically characterize 3 LGESSs and their recurrences that underwent histologic high-grade transformation following endocrine therapy. For this, DNA from primary tumors and select subsequent recurrences were subject to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutation analyses were performed using validated bioinformatics methods. In addition, RNA from each case was evaluated for the presence of gene fusions using targeted RNA-sequencing. All patients initially presented with LGESS, developed HGESS recurrences, and received at least 2 lines of hormonal suppressive therapy. Gene fusions classically described as associated with LGESS were identified in all 3 cases, including JAZF1-PHF1, EPC1-PHF1 and JAZF1-SUZ12 fusions for Cases 1, 2 and 3, respectively. Targeted sequencing analysis revealed that none of the primary LGESS, however the HGESS recurrences of Cases 1 and 3, and the LGESS and HGESS recurrences of Case 2 post endocrine treatment harbored ESR1 p.Y537S hotspot mutations. These ESR1 ligand-binding domain mutations have been found as a mechanism of acquired endocrine resistance in breast cancer. Also, a reduction in estrogen receptor (ER) expression was observed in recurrences. Our findings suggest that the ESR1 p.Y537S hotspot mutation in LGESS with histologic high-grade transformation may be associated with endocrine resistance in these lesions. Furthermore, our data suggest that genetic analyses may be performed in recurrent LGESS following hormonal therapy, development of high-grade morphology, and/or altered/diminished ER expression.


Redescription of Chloromyxum ellipticum Li & Nie, 1973 (Myxosporea: Chloromyxidae) infecting the gall bladder of grass carp Ctenopharyngodon idellus Valenciennes, 1844, supplemented by morphological and molecular characteristics.
The traditional taxonomy of the genus Chloromyxum Mingazzini, 1890 has been intensively challenged to be paraphyletic by recent ribosomal DNA (rDNA)-based phylogenetic analysis. Undersampling to get rich sequence data to infer more scientific phylogenetic relationships makes scientists conservatively assign all non-marine elasmobranch-infecting species as Chloromyxum sensu lato. Although complex ridge pattern on the spore surface observed by scanning electron microscopy was thought to be critical for the identification of Chloromyxum species, insufficient data also prevent this ultrastructural data to be a valid taxonomic feature for this genus. It is especial for Chloromyxum species to be reported in China. Molecular and ultrastructural characteristics are yet available for all 22 Chloromyxum species recorded in China. During the investigation of the diversity of coelozoic fish myxosporeans, Chloromyxum ellipticum Li & Nie, 1973 was found to highly infect the gall bladder of Ctenopharyngodon idellus Valenciennes, 1844 in Poyang Lake watershed of Jiangxi province, Eastern China. Here, we redescribed it by the currently recommended holistic approach of combining morphological, ultrastructural, and molecular characteristics. Mature spores were found floating free in the gall bladder, but no plasmodium observed. Spores are typical freshwater teleost-infecting Chloromyxum species, spherical or subspherical in lateral view, measuring 7.7 ± 0.08 μm (6.9-9.1) in length, 6.3 ± 0.09 μm (5.6-7.6) in width, and 5.8 ± 0.20 μm (5.2-6.3) in thickness. Four pyriform polar capsules, located at the anterior end of the spores, were equal in size, 3.3 ± 0.06 μm (2.2-4.1) long and 2.1 ± 0.03 μm (1.7-2.5) wide. Polar filaments coiled with four to five turns. Two equal spore valves are symmetrical, with 10-16 surface extrasutural ridges per valve, aligned along the longitudinal axis. The obtained partial 18S rDNA of C. ellipticum did not match any sequences available in GenBank. Phylogenetic analysis showed that C. ellipticum clustered firstly with Chloromyxum legeri with robust nodal support and grouped then with urinary system of freshwater teleost-infecting Chloromyxum clade, rather than other gall bladder of freshwater teleost-infecting clade.


RNA virus-encoded microRNAs: biogenesis, functions and perspectives on application.
MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression at the posttranscriptional level and play a crucial role in development and many diseases. The discovery of miRNAs has greatly expanded our understanding of the intricate scenario of genome-wide regulation. Over the last two decades, hundreds of virus-encoded miRNAs have been identified, most of which are from DNA viruses. Although the number of reported RNA virus-derived miRNAs is increasing, current knowledge of their roles in physiological and pathological processes has remained lacking. In this review, we discuss the biogenesis and biological functions of RNA virus- encoded miRNAs and their proposed roles in virus-host interactions and further underscore their potential value in the diagnosis and treatment of viral diseases.


Lateralization of kinesthetically guided spatial perception.
The present study measured unimanual kinesthetic discrimination for the right and left thumb angular position of male and female right handers without left handed relatives. Each subject's discrimination threshold and constant error were obtained by the Method of Constant Stimuli. Subjects either made an active movement in assessing the standard thumb angle or were passive while the angle was set by the experimenter. Subjects either reported their decision orally or made a non-verbal movement. A difference was found between the thumbs in the direction of more sensitive kinesthetic discrimination by the left thumb (right hemisphere). The left thumb was found to have smaller discrimination threshold of angular position by about 20% over the right thumb. Sex, passive movement mode, and verbal response were not related to the lateralization effect.


HIRA-dependent boundaries between H3 variants shape early replication in mammals.
The lack of a consensus DNA sequence defining replication origins in mammals has led researchers to consider chromatin as a means to specify these regions. However, to date, there is no mechanistic understanding of how this could be achieved and maintained given that nucleosome disruption occurs with each fork passage and with transcription. Here, by genome-wide mapping of the de novo deposition of the histone variants H3.1 and H3.3 in human cells during S phase, we identified how their dual deposition mode ensures a stable marking with H3.3 flanked on both sides by H3.1. These H3.1/H3.3 boundaries correspond to the initiation zones of early origins. Loss of the H3.3 chaperone HIRA leads to the concomitant disruption of H3.1/H3.3 boundaries and initiation zones. We propose that the HIRA-dependent deposition of H3.3 preserves H3.1/H3.3 boundaries by protecting them from H3.1 invasion linked to fork progression, contributing to a chromatin-based definition of early replication zones.


Renal function after long-term low-dose cyclosporin for psoriasis.
Two groups of patients receiving cyclosporin A (CyA) for psoriasis had their renal function assessed by measurement of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). The first group comprised 13 patients who had taken low dose (average 3 mg/kg per day) CyA for an average period of 2.5 years. Seven of the 13 had a normal GFR of 108 (77-121) ml/min (median; range). In the other six patients the GFR was low at 63 (50-77) ml/min and CyA was discontinued for periods ranging from 3 to 17 weeks. The GFR rose in all six patients, to 79 (60-91) ml/min; this change was significant (P less than 0.05). The six patients restarted CyA because their psoriasis recurred and after a mean interval of 15 weeks the GFR had fallen in all six to 63 (46-80) ml/min (P less than 0.05) and the ERPF decreased from 339 (231-414) ml/min to 244 (177-321) ml/min (P less than 0.05). In the second group of 11 patients measurements were made prior to starting CyA and after taking CyA for a mean of 9 weeks. The GFR fell in eight out of 11 subjects, the GFR for the 11 patients being 117 (72-128) ml/min before taking CyA and 97 (51-122) ml/min after CyA (P less than 0.02). The ERPF was measured in nine of the 11 patients and fell in seven of the nine. The ERPF for the nine patients before CyA was 490 (296-642) ml/min and for the 11 patients after CyA was 410 (195-543) ml/min (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Localization of chromatographically characterized oxytocin and arginine-vasopressin to sensory neurones in the rat.
Following treatment with colchicine 50-60% of all neurones in rat trigeminal and L5 spinal ganglia showed oxytocin (OXT)- and arginine-vasopressin (AVP)-like immunoreactivity. Further, OXT and AVP, together with their associated neurophysins, could be isolated from trigeminal ganglia by reversed-phase high-performance liquid chromatography followed by radioimmunoassay.


ABCA2 as a therapeutic target in cancer and nervous system disorders.
Overexpression of ATP-binding cassette (ABC) transporters is a major adaptive advantage used by tumor cells to evade the accumulation of cytotoxic agents. ABCA2, a transporter highly expressed in the cells of the nervous and haematopoetic systems, is associated with lipid transport and drug resistance in cancer cells, including tumor stem cells. Recently, a single nucleotide polymorphism (SNP) in Abca2 was linked to early onset Alzheimer's disease (AD). The characterization of two independent knockout mouse models has shed light on putative in vivo functions of this transporter in the development and maintenance of myelin membrane lipids in the CNS. The objective of this review is to guide the reader through the existing scope of literature on the ABCA2 transporter, focusing on its potential as a future target in human pathologies, specifically cancer and neurological disease. An NCBI PubMed literature search was conducted to address the growing body of ABCA2 literature that, at the time of publication, included 39 reports. From these, we focused on papers that provided insight into the functional importance of this transporter in tumor stem cells, cancer, drug resistance, Alzheimer's disease and myelination. These studies have implicated ABCA2 as a therapeutic target in modulating the drug resistance phenotype prevalent in human cancers and in the treatment of neuropathies, including Alzheimer's disease and myelin-related disorders.


Semi-automatic analysis of microscopic images of the human cerebral cortex using the grey level index.
A new semi-automatic method is introduced which makes possible the quantitative examination of cresyl-fast-violet stained sections of the cerebral cortex. These sections are divided into measuring fields of 20 X 20 microns in a well-defined area. A scanning procedure then automatically determines the grey level index of every single field. The image of the histological section can be compared with the grey level index data matrix by means of a plotted image, the density of the plotted points of which is proportional to the measured grey level index. By overlaying this plotted image with the original section, the boundaries of the laminae can be fixed in the data matrix. The grey level index profiles--the grey level data plot as a function of the cortical depth--after smoothing and standardization are typical of special cortical areas. The mean thickness and the mean portion of the grey level index profile of the different laminae of the striate area are compared with data from other publications.


Ureteropelvic junction obstruction and calyceal diverticulum in a child with Turner syndrome and horseshoe kidney.
Laparoscopic dismembered pyeloplasty for ureteropelvic junction (UPJ) obstruction is considered to be a routine procedure in many pediatric surgical centers. UPJ obstruction is known to be associated with horseshoe kidney and several reports on successful laparoscopic repair in such cases exist. The case of a 9-month-old girl with Turner syndrome is reported. A horseshoe kidney with grade 4 hydronephrosis on the left side was diagnosed by ultrasound during the neonatal period. MAG3 diuretic renography and dynamic magnetic resonance imaging nephrography revealed a differential renal function of 31% and 69% on the left and right side, respectively. No drainage from the left renal pelvis could be demonstrated. Laparoscopy showed a combined UPJ obstruction and a calyceal diverticulum with a narrow infundibulum of the upper pole calices on the left side of the horseshoe kidney. Laparoscopic dismembered pyeloplasty and an additional infundibulopelvic anastomosis was performed. No intraoperative complications occurred. The immediate postoperative course was uneventful. Unobstructed drainage and stable differential renal function on the left side could be demonstrated on MAG3 diuretic renography 6 weeks postoperatively. In conclusion, laparoscopic repair of complex malformations of the upper urinary tract is feasible and leads to good functional outcome in selected cases.


Intranasal administration of a synthetic lipopeptide without adjuvant induces systemic immune responses.
Parenteral injection of a lipopeptide containing a human leucocyte antigen (HLA)-A*0201-restricted cytotoxic T-lymphocyte (CTL) epitope from the human cytomegalovirus (HCMV) immunodominant matrix protein pp65 efficiently induces systemic CTL responses in HLA-A*0201 transgenic mice. In this study, we demonstrate that intranasal (i.n.) administration of this lipopeptide, covalently linked to a universal T helper (Th) epitope (PADRE), also induces potent systemic CTL responses. Immune responses were substantially reduced when the unlipidated peptide analogue was used (P<0.01). The induced CTL were CD8+, major histocompatibility complex (MHC) class I-restricted and CMV specific. Moreover, i.n. administration of this lipidated peptide elicited both systemic and local mucosal CD4+ T-cell proliferative responses, as well as antigen-specific delayed type hypersensitivity (DTH) immune responses. In contrast, mice receiving the unlipidated peptide analogue developed substantially reduced Th or DTH responses (P<0.05). These results highlight the usefulness and potential of lipopeptides delivered via mucosal routes as painless, safe, and non-invasive vaccines.


Evaluation and management of the "new" lymphoma entities: mantle cell lymphoma, lymphoma of mucosa-associated lymphoid tissue, anaplastic large-cell lymphoma, and primary mediastinal B-cell lymphoma.
Non-Hodgkin's lymphomas (NHL) represent a major health problem worldwide, and incidence has been on the rise continuously for the last few decades. It is estimated that approximately 55,000 new cases of NHL will be diagnosed in the United States in 1998 and that slightly fewer than 25,000 patients will die of treatment failure or recurrent disease. The rising incidence of NHL is related not only to the acquired immunodeficiency syndrome epidemic but to also a steady increase in the number of cases diagnosed in older patients without immunosuppression. The new pathologic classification of NHL (revised European-American lymphoma classification, REAL) developed by the International Lymphoma Study Group (ILSG) is already resulting in more accurate disease-specific epidemiologic and clinical investigations. These studies have brought a new awareness of the existence and the relative prevalence of discrete NHL subtypes that appear to predominate among patients in different populations according to age, sex, geographic distribution, and predisposing conditions. This developing database has also the potential to result in the discovery of specific environmental causes, predisposing genetic factors, and therapeutic approaches. Some of the entities defined in the REAL classification, such as follicular lymphomas, diffuse B large-cell lymphomas, and T-cell lymphoblastic lymphomas, were already well described in the older classification systems (Kiel and Working Formulation). Others, such as mantle cell lymphoma, (MCL) anaplastic large-cell lymphoma (ALCL), lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), and primary mediastinal B-cell lymphoma (PMBCL) are relatively new members of the family, and accurate data on their clinicopathologic features and natural histories have only recently begun to emerge. This review presents in detail the most recent data on the clinical presentation of, diagnostic evaluation of, and treatment options for the most common of the new NHL entities: MCL, MALT lymphoma, CD30+ (Ki-1+) ALCL, and PMBCL. These four entities combined represent approximately 20% of all cases of NHL and exemplify well the broad clinicopathologic spectrum of NHL and the diagnostic and therapeutic challenges facing those who care for patients affected by these conditions.


Mechanistic insights into ultrasonic neurostimulation of disconnected neurons using single short pulses.
Ultrasonic neurostimulation is a potentially potent noninvasive therapy, whose mechanism has yet to be elucidated. We designed a system capable of applying ultrasound with minimal reflections to neuronal cultures. Synaptic transmission was pharmacologically controlled, eliminating network effects, enabling examination of single-cell processes. Short single pulses of low-intensity ultrasound were applied, and time-locked responses were examined using calcium imaging. Low-pressure (0.35 MPa) ultrasound directly stimulated ∼20% of pharmacologically disconnected neurons, regardless of membrane poration. Stimulation was resistant to the blockade of several purinergic receptor and mechanosensitive ion channel types. Stimulation was blocked, however, by suppression of action potentials. Surprisingly, even extremely short (4 μs) pulses were effective, stimulating ∼8% of the neurons. Lower-pressure pulses (0.35 MPa) were less effective than higher-pressure ones (0.65 MPa). Attrition effects dominated, with no indication of compromised viability. Our results detract from theories implicating cavitation, heating, non-transient membrane pores >1.5 nm, pre-synaptic release, or gradual effects. They implicate a post-synaptic mechanism upstream of the action potential, and narrow down the list of possible targets involved.


Density and strength distribution in the human subchondral bone plate of the patella.
The aim of this study was to map the strength distribution of the human patella and correlate it to the subchondral bone plate density obtained by means of computed tomographyosteoabsorptiometry (CT-OAM). Measurements were performed at 34 standardized points on each patella. The mineralization patterns of the subchondral bone plate of 20 patellae were displayed with the help of CT-OAM. False-coloured distribution patterns for our measurements were generated. The mechanical strength was determined at the same points by indentation testing. We showed that neither the density nor the mechanical strength is distributed homogeneously but exhibited regular, reproducible distribution patterns which mirror long-term stress distribution in articular surfaces. A direct correlation was found between both parameters in the subchondral bone plate. The correlation of density and mechanical strength makes CT-OAM a valuable tool to assess and monitor changes in the strength of the subchondral bone plate in vivo.


Machine learning and sensitivity analysis for predicting nasal drug delivery for targeted deposition.
Targeted nasal drug delivery can provide improved efficacy for drug formulations to be delivered at high efficacy rates. Some parameters that influence drug delivery have a dependency on the patient's technique of administration and the spray device itself. When the different parameters, each having a specific range of values are combined, the combinatory permutations for studying its effects on particle deposition become large. In this study, we combine six input spray parameters (the spray half-cone angle, the mean spray exit velocity, the breakup length from the nozzle exit, the diameter of the nozzle spray device, the particle size, and the sagittal angle of the spray) with a range of values to produce 384 combinations of spray characteristics. This was repeated for three inhalation flow rates of 20, 40, and 60 L/min. To reduce the computational costs of a full transient Large Eddy Simulation flow field, we create a time-averaged frozen field and perform the time integration of particle trajectories through the flow field to determine the particle deposition in four anatomical regions of the nasal cavity (anterior, middle, olfactory and posterior) for each of the 384 spray field. A sensitivity analysis determined the significance of each input variable on the deposition. It was found the particle size distribution significantly affected deposition in the olfactory and posterior regions, while the spray device insertion angle was significant for deposition in the anterior and middle regions. Five machine learning models were evaluated based on 384 cases and it was found that despite the small sample dataset the simulation data was sufficient to provide accurate machine-learning predictions.


Synthesis of novel 2,3-dihydro-1,4-dioxino[2,3-g]quinoline derivatives as potential antitumor agents.
New dioxinoquinolines (1-8) have been synthesized and their antiproliferative properties have been tested against several cell lines. The treatment of the 6-acetamido-2,3-dihydro-1,4-benzodioxine (10) with phosphorous oxychloride in the presence of DMF leads to a mixture of linear and angular tricyclic compounds. The key intermediates were modified and cyclized giving the corresponding dioxinoquinolines. In general, these compounds have a moderate citotoxycity.


The effect of delivered energy on defibrillation shock impedance.
The impedance of internal defibrillator shocks is an important determinant of defibrillation efficacy. To assess the effect of delivered energy on impedance, we studied 97 patients with 4 different lead systems. The lead systems evaluated were two epicardial patches, a hybrid system of a patch and right atrial coil, a dual coil transvenous lead and a transvenous lead with a subcutaneous patch. Impedances were measured for 6 shock energies between 0.1 and 30 J. Shock impedance increased at low energies for all lead systems (p < 0.001), although the rate of increase varied markedly between systems. The energy factor (FE), which is the ratio of impedances for the 0.1 and 10 J shocks, was least for the platinum transvenous lead (1.2 +/- 0.02) and greatest for the titanium hybrid lead (4.2 +/- 0.2). Reversing the polarity of the hybrid lead markedly attenuated the impedance rise. These findings indicate that there is at least a modest rise (20%) of shock impedance at very low delivered energies. The largest increases noted with titanium lead systems are primarily due to polarization. Titanium transvenous leads should be avoided when low energy shocks are utilized such as for the cardioversion of ventricular tachycardia or atrial fibrillation.


Interaction of arsenic species with tropical river aquatic humic substances enriched with aluminum and iron.
The mobility and bioavailability of arsenic (As) are strongly controlled by adsorption/precipitation processes involving metal oxides. However, the organic matter present in the environment, in combination with these oxides, can also play an important role in the cycle of arsenic. This work concerns the interaction between As and two samples of aquatic humic substances (AHS) from tropical rivers. The AHS were extracted as proposed by IHSS, and were characterized by (13)C NMR. The experiments were conducted with the AHS in natura and enriched with metal cations, with different concentrations of As, and complexation capacity was evaluated at three different pH levels (5.0, 7.0, and 9.0). The AHS samples showed similar chemical compositions. The results suggested that there was no interaction between As(III) and AHS in natura or enriched with Al. Low concentrations of As(V) were bound to AHS in natura. For As(III), the complexation capacity of the AHS enriched with Fe was approximately 48 μmol per g of C, while the values for As(V) were in the range 69-80 μmol per grams of C. Fluorescence spectra showed that changes in Eh affected the complexation reactions of As(V) species with AHS.


Well-differentiated papillary mesothelioma of the peritoneum: a borderline mesothelioma. Report of two cases and review of literature.
Well-differentiated papillary mesothelioma (WDPM) is considered to be a distinct subtype of peritoneal mesothelioma. Although the WDPM is usually qualified as benign, the natural history of this lesion has not been clearly established. This report relates to two WDPMs which were found incidentally. In a 51-year-old man the WDPM developed over a period of 5 years into a typically malignant diffuse mesothelioma. Thus, although the WDPM morphologically lacks signs of malignancy, it should be regarded as a borderline mesothelioma.


Sensory feedback modulates quipazine-induced stepping behavior in the newborn rat.
Research has shown that sensory feedback modulates locomotor behavior in intact as well as spinal adult animals. Here we examined if locomotor activity ("stepping") in newborn rats is influenced by cutaneous and proprioceptive feedback. One-day-old rats were treated with the serotonergic receptor agonist quipazine (3.0mg/kg) to induce air-stepping behavior or with saline (vehicle control). During stepping, a substrate/floor (elastic, stiff, or none) was placed beneath their limbs so that the feet could make plantar surface contact with a substrate. Pups treated with quipazine showed significantly more alternated fore- and hindlimb steps and plantar paw contact with the substrate, compared to pups treated with saline. Pups also made proportionately less contact with the stiff substrate versus the elastic substrate during stepping. Different types of movements made on the substrate (paw pushes, taps, swipes, and stances) were also characterized. These results indicate that sensory feedback modulates locomotor mechanisms and behavior in perinatal rats.


[Surgical treatment of snapping triceps syndrome].
Treatment of a persistently painful snapping triceps and possibly snapping ulnar nerve. Snapping triceps. General surgical risks. Following the anterior transposition of the ulnar nerve (subcutaneously or submuscular), the snapping portion of the triceps tendon is transsected and reinforced, and transposition of the medial triceps margin into the central triceps portion is carried out. Cast for 5-7 days; for a total of 6 weeks functional exercise without maximum flexion and resistance exercise of the triceps. Weight loading after 3 months. In the case presented, complaints were absent after 3 months. Full load exercise, e.g., push-ups, was achieved 4 months after surgery. There was no recurrent snapping within the first year. The results of this case are in agreement with the 25 patients previously reported in the PubMed literature. Recurrence, gross restrictions of movement, and complications were not observed in patients who underwent surgery.


Detecting peroxiredoxin hyperoxidation by one-dimensional isoelectric focusing.
The activity of typical 2-cys peroxiredoxin (Prxs) can be regulated by hyperoxidation with a consequent loss of redox activity. Here we developed a simple assay to monitor the level of hyperoxidation of different typical 2-cys prxs simultaneously. This assay only requires standard equipment and can compare different samples on the same gel. It requires much less time than conventional 2D gels and gives more information than Western blotting with an antibody specific for hyperoxidized peroxiredoxin. This method could also be used to monitor protein modification with a charge difference such as phosphorylation.


Association between the distal tibiofibular syndesmosis morphology classification and ankle osteoarthritis: a retrospective study.
Syndesmosis injury is proposed to contribute to ankle stability and osteoarthritis (OA). However, whether distal tibiofibular syndesmosis structure is closely related to ankle OA is unclear. We hypothesized that different DTS morphology classifications would affect the biomechanics properties in ankle OA. The study aimed to determine the association between the distal tibiofibular syndesmosis (DTS) morphological classification and ankle OA. This is a retrospective study examining imaging data of 147 patients (87 males and 60 females) with ankle OA. Magnetic resonance imaging was used to access the DTS morphological classification, according to measuring various parameters. Joint space narrowing and osteophytes were measured using ankle weight-bearing radiography. The classification and parameters were analyzed to determine the relationship between the syndesmosis classification and the abnormality of ankle OA. Five morphological classifications of the DTS, including Chevron (19.6%), Widow's peak (16.2%), Flat (22.3%), Trapezoid (32.0%), and Crescent (19.6%), were shown. There were statistical differences between DTS classification and tibial angle surface angle (TAS) (P = .009) and talar tilt angle (TTA) (P = .014). The TAS (degree) of the Crescent (86.47 ± 3.21) was less than Chevron (88.75 ± 2.72) (P = .006), Widow's peak (89.26 ± 3.15) (P = .001), Flat (88.83 ± 3.62) (P = .003) and Trapezoid (88.11 ± 2.62) (P = .041), respectively. The TTA (degree) of Crescent (86.83 ± 5.30) was less than Chevron (89.28 ± 2.46) and Widow's peak (89.82 ± 3.41). The men were greater than women for TAS (P = .008) and angle (P = .003), which are consistent with osteophyte (P = .019) and the modified Kellgren-Lawrence grades (P = .041) between gender. DTS morphological classification might affect the biomechanics properties in TAS and TTA in ankle OA. In clinical practice, surgeons should pay attention to the effects of DTS on ankle OA. Level III, retrospective study.


Knowledge and attitudes of lower Michigan primary care physicians towards dietary interventions: A cross-sectional survey.
Dietary interventions are first-line therapies for the prevention and management of many chronic diseases, yet primary care physicians prescribe these interventions infrequently. This study investigates primary care physicians' current knowledge and opinions regarding the delivery of dietary interventions. This work aims to identify modifiable barriers to prescribing dietary interventions to prevent and treat diet-related diseases. We designed and fielded an anonymous, cross-sectional survey of faculty and resident physicians across the Internal Medicine, Family Medicine, and Pediatrics departments in three academic and community hospitals in lower Michigan. Data were collected between January 15 and April 15, 2019. Self-rated knowledge and attitudes were measured on a 5-point Likert scale. Objective scores were calculated for each question as percentage answered correctly among all respondents. Objective knowledge scores were compared based on participants' years in practice. Response rate was 23% (356 responses). The sample was 62.3% female and 75.3% non-Hispanic White, and 56.7% were age 40 or younger. Average objective knowledge score was 70.3% (±17.2) correct. Mean self-rated knowledge score was 2.51 (±0.96) on a scale of 1(Poor) - 5(Excellent). Overall agreement with a statement of importance of dietary interventions was 3.99 (±0.40) on a scale of 1 (strongly disagree) to 5 (strongly agree). A majority (91.7%) of respondents indicated they would like more opportunities to learn about the evidence supporting dietary interventions. Physicians desire to incorporate dietary interventions into their practice. Findings encourage the development of educational strategies to support dietary intervention use among primary care physicians.


Isolation of pancreatic trypsin inhibitor from bovine pituitary glands.
A trypsin inhibitor has been isolated from bovine pituitary extracts. From its amino acid composition, NH2-terminal residue, mobility in paper electrophoresis, and behavior in high-performance liquid chromatography and from the tryptic pattern of the performic acid-oxidized material, it appears that the inhibitor is identical to the Kunitz and Northrop pancreatic trypsin inhibitor.


Emergency general surgery in the geriatric patient.
Emergency general surgery in the elderly is a particular challenge to the surgeon in charge of their care. The aim was to review contemporary aspects of managing elderly patients needing emergency general surgery and possible alterations to their pathways of care. This was a narrative review based on a PubMed/MEDLINE literature search up until 15 September 2015 for publications relevant to emergency general surgery in the geriatric patient. The number of patients presenting as an emergency with a general surgical condition increases with age. Up to one-quarter of all emergency admissions to hospital may be for general surgical conditions. Elderly patients are a particular challenge owing to added co-morbidity, use of drugs and risk of poor outcome. Frailty is an important potential risk factor, but difficult to monitor or manage in the emergency setting. Risk scores are not available universally. Outcomes are usually severalfold worse than after elective surgery, in terms of both higher morbidity and increased mortality. A care bundle including early diagnosis, resuscitation and organ system monitoring may benefit the elderly in particular. Communication with the patient and relatives throughout the care pathway is essential, as indications for surgery, level of care and likely outcomes may evolve. Ethical issues should also be addressed at every step on the pathway of care. Emergency general surgery in the geriatric patient needs a tailored approach to improve outcomes and avoid futile care. Although some high-quality studies exist in related fields, the overall evidence base informing perioperative acute care for the elderly remains limited.


Auricularia auricula polysaccharides attenuate obesity in mice through gut commensal Papillibacter cinnamivorans.
Auricularia auricula is a well-known traditional edible and medical fungus with high nutritional and pharmacological values, as well as metabolic and immunoregulatory properties. Nondigestible fermentable polysaccharides are identified as primary bioactive constituents of Auricularia auricula extracts. However, the exact mechanisms underlying the effects of Auricularia auricula polysaccharides (AAP) on obesity and related metabolic endpoints, including the role of the gut microbiota, remain insufficiently understood. The effects of AAP on obesity were assessed within high-fat diet (HFD)-based mice through obesity trait analysis and metabolomic profiling. To determine the mechanistic role of the gut microbiota in observed anti-obesogenic effects AAP, faecal microbiota transplantation (FMT) and pseudo-germ-free mice model treated with antibiotics were also applied, together with 16S rRNA genomic-derived taxonomic profiling. High-fat diet (HFD) murine exposure to AAP thwarted weight gains, reduced fat depositing and enhanced glucose tolerance, together with upregulating thermogenesis proteomic biomarkers within adipose tissue. Serum metabolome indicated these effects were associated with changes in fatty acid metabolism. Intestine-dwelling microbial population assessments discovered that AAP selectively enhanced Papillibacter cinnamivorans, a commensal bacterium with reduced presence in HFD mice. Notably, HFD mice treated with oral formulations of P. cinnamivorans attenuated obesity, which was linked to decreased intestinal lipid transportation and hepatic thermogenesis. Mechanistically, it was demonstrated that P. cinnamivorans regulated intestinal lipids metabolism and liver thermogenesis by reducing the proinflammatory response and gut permeability in a JAK-STAT signaling-related manner. Datasets from the present study show that AAP thwarted dietary-driven obesity and metabolism-based disorders by regulating intestinal lipid transportation, a mechanism that is dependent on the gut commensal P. cinnamivorans. These results indicated AAP and P. cinnamivorans as newly identified pre- and probiotics that could serve as novel therapeutics against obesity.


Ommochrome pathway genes kynurenine 3-hydroxylase and cardinal participate in eye pigmentation in Plutella xylostella.
Eye pigmentation genes have been utilized as visible markers for constructing genetic control prototypes in several insect vectors of human disease. Here, orthologs of two ommochrome pathway genes, kynurenine 3-hydroxylase (kmo) and cardinal, were investigated in Plutella xylostella, a globally distributed, economically important pest of Brassica crops. Both somatic mosaic and germline mutations were efficiently created using the CRISPR/Cas9 system, and null mutant strains of Pxkmo and Pxcardinal were obtained. A frame-shift mutation in Pxkmo caused yellow compound eyes at adult stage while an in-frame mutation lacking two amino acids resulted in a hypomorphic red eye phenotypes. In contrast, Pxcardinal-deficient moths with a frame-shift mutation exhibited yellow eye pigmentation in newly emerged adults which turned to red as the adults aged. Additionally, differences were observed in the coloration of larval ocelli, brains and testes in Pxkmo and Pxcardinal yellow-eye mutant lines. Our work identifies the important roles of Pxkmo and Pxcardinal in P. xylostella eye pigmentation and provides tools for future genetic manipulation of this important crop pest.


Serum osteocalcin and other indices of bone formation: an 8-decade population study in healthy men and women.
In a study of 435 healthy men and women aged 17-97 yr, serum osteocalcin and alkaline phosphatase were measured together with 99TcMDP retention in women. In women, serum osteocalcin falls to a nadir at 35-39 yr, and the mean then rapidly rises 2-fold to a plateau from 50-75 yr. 99TcMDP retention falls to a minimum at 40-45 yr and then rises steadily with increasing age. Serum alkaline phosphatase rises in an indeterminate fashion from 20-25 yr onwards. Osteocalcin in men fell until age 60-70 yr and hardly changed thereafter, whereas serum alkaline phosphatase reached a minimum at age 30-40 yr and thereafter rose with age, as in women.


Healthcare system engagement and algorithm-identified cancer incidence following initiation of a new medication.
Implausibly high algorithm-identified cancer incidence within a new user study after medication initiation may result from increased healthcare utilization (HU) around initiation ("catch-up care") that increases diagnostic opportunity. Understanding the relationships between HU prior to and around initiation and subsequent cancer rates and timing is important to avoiding protopathic bias. We identified a cohort of 417 458 Medicare beneficiaries (2007-2014) aged ≥66 initiating an antihypertensive (AHT) after ≥180 days of non-use. Initiators were stratified into groups of 0, 1, 2-3, and ≥4 outpatient visits (OV) 60-360 days before initiation. We calculated algorithm-identified colorectal cancer (aiCRC) rates stratified by OVs and time since AHT initiation: (0-90, 91-180, 181-365, 366-730, and 731+ days). We summarized HU -360/+60 days around AHT initiation by aiCRC timing: (0-29, 30-89, 90-179, and ≥180 days). AiCRC incidence (311 per 100 000 overall) peaked in the first 0-90 days, was inversely associated with HU before initiation, and stabilized ≥180 days after AHT initiation. Catch-up care was greatest among persons with aiCRCs identified <30 days in follow-up. Catch-up care magnitude decreased as time to the aiCRC date increased, with aiCRCs identified ≥180 days after AHT initiation exhibiting similar HU compared with the full cohort. Lower HU before-and increased HU around AHT initiation-seem to drive excess short-term aiCRC incidence. Person-time and case accrual should only begin when incidence stabilizes. When comparison groups within a study differ by HU, outcome-detection bias may exist. Similar observations may exist in other settings when typical HU is delayed (e.g., cancer screening during SARS-CoV-2).


Serum bisphenol A analogues in women diagnosed with the polycystic ovary syndrome - is there an association?
Due to the endocrine disrupting effects of bisphenol A (BPA) several governmental authorities have banned its use and the manufacturers had to find alternative substances with similar chemical properties. This led to the increase in the use of so-called BPA analogues, which however also turn out to possess mild estrogenic and ani-androgenic properties and thus, may cause fertility problems and sex-hormone dependent endocrinopathies. The aim of this study was to evaluate the potential association between the exposure to BPA and its two analogues: BPS and BPF, with the diagnosis of the polycystic ovary syndrome (PCOS), which remains the most common female endocrinopathy. Serum concentrations of BPA, BPS and BPF were measured using high performance liquid chromatography method with tandem mass spectrometry (HPLC-MS/MS) among 199 women with PCOS and 158 control subjects. In women with PCOS serum BPS concentrations were significantly higher compared to the control subjects (geometric mean [95% CI]: 0.14 ng/mL [0.10; 1.17] vs. 0.08 ng/mL [0.06; 0.09], P = 0.023). Serum BPA and BPF concentrations did not differ between the studied groups. There was however a negative correlation between serum BPA and HOMA-IR (r = - 0.233, P = 0.001) and TST (r = - 0.203, P = 0.006) in women with PCOS. No correlations were found between the serum BPs and other metabolic parameters such as serum lipids, insulin, DHEA-S, androstenedione and FAI. When studying the association between serum BPA analogues and PCOS it turned out that women whose serum BPS concentrations were in the first tertile were more likely to be diagnosed with this endocrinopathy (OR [95% CI]: 1.21 [1.04; 3.46], P = 0.017). This association was also statistically significant when adjusted for age, education, BMI, smoking, income, and alcohol consumption (adjusted OR [95% CI]: 1.12 [1.03; 3.71], P = 0.029). These results point to the potential association between the exposure to BPS and the diagnosis of PCOS. The role of BPA is not clear and warrants further studies.


Unraveling the complexity of faba bean (Vicia faba L.) transcriptome to reveal cold-stress-responsive genes using long-read isoform sequencing technology.
Faba bean (Vicia faba L.), a globally important grain legume providing a stable source of dietary protein, was one of the earliest plant cytogenetic models. However, the lack of draft genome annotations and unclear structural information on mRNA transcripts have impeded its genetic improvement. To address this, we sequenced faba bean leaf transcriptome using the PacBio single-molecule long-read isoform sequencing platform. We identified 28,569 nonredundant unigenes, ranging from 108 to 9669 bp, with a total length of 94.5 Mb. Many unigenes (3597, 12.5%) had 2-20 isoforms, indicating a highly complex transcriptome. Approximately 96.5% of the unigenes matched sequences in public databases. The predicted proteins and transcription factors included NB-ARC, Myb_domain, C3H, bHLH, and heat shock proteins, implying that this genome has an abundance of stress resistance genes. To validate our results, we selected WCOR413-15785, DHN2-12403, DHN2-14197, DHN2-14797, COR15-14478, and HVA22-15 unigenes from the ICE-CBF-COR pathway to analyze their expression patterns in cold-treated samples via qRT-PCR. The expression of dehydrin-related genes was induced by cold stress. The assembled data provide the first insights into the deep sequencing of full-length RNA from faba bean at the single-molecule level. This study provides an important foundation to improve gene modeling and protein prediction.


Lung hypoplasia in rats with esophageal atresia and tracheo-esophageal fistula.
Survivors of esophageal atresia and tracheo-esophageal fistula (EA-TEF) often suffer chronic respiratory tract disease. EA-TEF results from abnormal emergence of the trachea from the foregut. This study in a rat model tests the hypothesis that primary lung maldevelopment might be a downstream consequence of this defect. The lung was hypoplastic in rats with EA-TEF although the histological pattern was normal. Maturation and arteriolar wall thickness were unchanged, but mesenchymal control of airway branching was weakened. This branching was deficient from embryonal day (E13) on in adriamycin-treated explants. In conclusion, the lungs were hypoplastic in rats with experimental EA-TEF due to defective embryonal airway branching. However, arteriolar wall and respiratory epithelial patterns remained normal. These findings suggest that similarly defective lung development might contribute to chronic respiratory disease in EA-TEF patients. Pregnant rats received either 1.75 mg/kg i.p. adriamycin or vehicle on E7, E8, and E9. Lungs were recovered at E15, E18, and E2. Lung weight/body weight ratio, total DNA and protein, radial alveolar count, arteriolar wall thickness, lung maturity, and mesenchymal control of airway branching were assessed. E13 lungs were cultured for 72 h and explant airway branching was measured daily. For comparisons, nonparametric tests (*P < 0.05) were used.


Exploring Nursing Undergraduates' Experiences with a Redesigned Blended Learning Course: A Descriptive Qualitative Study.
To explore the experience of nursing undergraduates with a blended course, that was redesigned using the Community of Inquiry framework. The Obstetrics and Gynaecology Nursing Course was redesigned using blended learning pedagogy, which starts from the creation of teaching presence, plays the intermediary role of social presence and aims at realizing cognitive presence. After the course completion, we conducted a qualitative descriptive study and collected data using focus group interviews and field notes. The findings comprised three main themes including role promotion, passive and selective learning and recommendations. Teachers and peers reportedly played the supervisors, facilitators and coordinators in learning promotion. Some students experienced difficulties in adapting to the blended learning environment due to passive learning habits, character flaws and academic pressure. However, a majority of them supported the application of the model.


Potential influence of fine aerosol chemistry on the optical properties in a semi-arid region.
The current understanding regarding the potential influence of aerosol chemistry on the optical properties does not satisfy accurate evaluation of aerosol radiative effects and precise determination of aerosol sources. We conducted a comprehensive study of the potential influence of aerosol chemistry on the optical properties in a semi-arid region based on various observations. Organic matter was the main contributor to the scattering coefficients followed by secondary inorganic aerosols in all seasons. We further related aerosol absorption to elemental carbon, organic matter, and mineral dust. Results showed that organic matter and mineral dust contributed to >40% of the aerosol absorption in the ultraviolet wavelengths. Therefore, it is necessary to consider the absorption of organic matter and mineral dust in addition to that of elemental carbon. We further investigated the potential influence of chemical composition, especially of organic matter and mineral dust on the optical parameters. Mineral dust contributed to higher absorption efficiency and lower scattering efficiency in winter. The absorption Ångström exponent (AAE) was mostly sensitive to organic matter and mineral dust in winter and spring, respectively; it was relatively high (i.e., 1.68) in winter and moderate (i.e., 1.42) in spring. Unlike in the other seasons, mineral dust contributed to higher mass absorption efficiency in winter. This work reveals the complexity of the relationship between aerosol chemistry and optical properties, and especially the influence of organic matter and mineral dust on aerosol absorption. The results are highly important regarding both regional air pollution and climate.


The history of the Golgi apparatus in neurones from its discovery in 1898 to electron microscopy.
We celebrate in 1998 the centenary of the discovery of the Golgi apparatus. Neurones have played a special role in the history of this cell organelle, primarily because the endocellular apparatus was discovered in nerve cells by Camillo Golgi when he was studying the cerebellum of an owl. In the following years, the apparatus of the nerve cell represented the prototype of this cell component which, however, was soon also detected in many other cell types. During the 1920s and 1930s the original idea of a Golgi endocellular "network" was refused and research was focused on the constituents and function of the organelle, using various tissues and techniques. However, the real existence of the apparatus was seriously questioned until the organelle was finally identified by electron microscopy in the mid-1950s. The studies performed on nerve cells during these decades is briefly reviewed here.


Dynamic changes in the metabolite profile and taste characteristics of Fu brick tea during the manufacturing process.
Fu brick tea is a typical post-fermentation tea known for its special flavor and health benefits. Liquid chromatography-mass spectrometry, and sensory evaluation with multivariate analysis were used to characterize the dynamic changes in metabolite profile and taste characteristics. Seventy-one compounds were identified as critical metabolites, catechins, flavonoids, phenolic acids, terpenoids and others. During the manufacturing process, these compounds exhibited sharp fluctuations in content, the intensities of astringency, bitterness, and sourness of the tea materials reduced greatly, but the mellow intensity increased sharply. Several catechins and phenolic acids were positively related to the 'astringent', 'bitter', and 'sour' tastes attributes. The fungal genera, Aspergillus, Candida, unclassified_o_Hypocreales, unclassified_o_Saccharomycetales and Wallemia and the bacterial genus, Klebsiella, were identified as core functional microorganisms linked to the metabolic variations during the process. Overall, these findings provided a more comprehensive understanding of the formation of the sensory characteristics in Fu brick tea during the manufacturing process.