dNA: a simple dBASE program for medical studies.
The dNA program is an entirely self-contained package consisting of dBASE programs and files, that can be used by an analyst with some dBASE experience to integrate multiple dBASE files into a simple, coherent system. Only minimal training is required for a naive user to operate the resulting system. The source file for creating a system also serves as the system documentation. Consistency and validity checks can be built in, and system modifications are quite simple.


Should emergency surgical intervention be performed for an octogenarian with type A acute aortic dissection?
The number of octogenarians undergoing emergency surgery is increasing and may negate the impact of the beneficial advances. The aim of this study was to review octogenarians with type A acute aortic dissection and assess the prognosis. Fifty-eight patients with acute aortic dissection, whose average age was 83.2 years, were divided into 2 groups: Group I comprised 30 patients who underwent emergency surgery, and group II comprised 28 patients who were treated conservatively. We compared the 2 groups in terms of mortality and morbidity. In group I, postoperative hospital mortality was 13.3% (4 patients). In group II, 17 patients (60.7%) died in the hospital. In group I, although emergency aortic replacement was successfully completed, 5 patients became bedridden after surgery and 2 patients died of pneumonia or stroke in the early stages of institutional care. Thirteen patients in group I died of malignancies, abdominal aortic rupture, traffic accident, heart failure, or late-stage senility in later phase. There was no difference in actuarial survivals at 5 years, which were 48.5% in group I and 35.4% in group II. Emergency surgery for octogenarians with acute aortic dissection showed acceptable mortality. However, families had to take responsibility for patients who experienced unconsciousness, had dementia, or became bedridden. It is important to have consensus between the family and surgeons about emergency surgical treatment for octogenarians.


Slow inward current in aggregates of neonatal rat heart cells and its contribution to the steady state current-voltage relationship.
In voltage clamped neonatal rat heart cells a transient current is observed during depolarizing potential steps, which was identified as slow inward current (Isi) by its range of activation, by its reversal potential of approximately +50 mV and by its sensitivity to D600 or low external Ca2+. This Isi activates too fast to be detected by the present methods, which implies that activation is completed within milliseconds. The time constant of inactivation was weakly potential dependent and less than 30 ms between -40 mV and +20 mV. The f infinity curve of Isi had a sigmoidal shape with 90% and 10% values near -50 mV and -10 mV respectively, half maximum was at -25 mV. From double pulse experiments an estimate was obtained of the potential dependence and amplitude of steady state Isi. A maximum was expected around -30 mV. Steady state Isi appears to be present indeed in steady state current voltage relations, as the relative minimum at -30 mV in such relations is abolished by 5 X 10(-7) g/ml D600. Currents tails during hyperpolarizing steps from prepulse potentials near 0 mV are potential dependent in a way expected when Isi contributes to these current tails by a decrease in inactivation. Moreover, the current tails are diminished by D600 or Co2+. Consequences of steady state Isi are discussed.


Metabolic alterations elicited by Cd and Zn toxicity in Zea mays with the association of Claroideoglomus claroideum.
The concentrations of cadmium (Cd) and zinc (Zn) in arable lands exceed the maximum permissible levels due to the excessive use of phosphorus fertilizers and fungicides by farmers. The increasing issues related to the application of agrochemicals have lead to the demand for the implementation of sustainable agricultural approaches. Association of arbuscular mycorrhizae with crop plants is an appropriate strategy due to the potential of these microorganisms to augment the metals tolerance of plants through the immobilization of Cd and Zn in an eco-friendly manner. In the present study, 45 d old Zea mays (var. CoHM6) plants inoculated with AM fungi (Claroideoglomus claroideum) were exposed to 1.95 g Zn Kg-1 soil and 0.45 g Cd Kg-1 soil. The major objective of this study was to determine the metabolic alterations in the leaves and roots of mycorrhizal and non-mycorrhizal plants exposed to CdCl2 and ZnSO4. Both non AM and AM plants exhibited alterations in the quantity of primary and secondary metabolites on exposure to Zn and Cd toxicity. Moreover, Zn and Cd-induced accumulation of γ-sitosterol reduced the quantity of neophytadiene (a well-known terpenoid) and aided the production of 3-β-acetoxystigmasta-4,6,22-triene in maize leaves. Mycorrhization and heavy metal toxicity induced significant metabolic changes in the roots by producing 4,22-stigmastadiene-3-one, eicosane, 9,19-cyclolanost-24-en-3-ol, pentacosane, oxalic acid, heptadecyl hexyl ester, l-norvaline, and n-(2-methoxyethoxycarbonyl). In addition, the metal-induced variations in leaf and root lignin composition were characterized with the aid of the FTIR technique. Mycorrhization improved the tolerance of maize plants to Cd and Zn toxicity by stabilizing these metal ions in the soil and/or limiting their uptake into the plants, thus ensuring normal metabolic functions of their roots and shoots.


Effect of prey size on attack components of the functional response by Notonecta undulata.
The number of encounters per prey, the proportion of encounters resulting in attacks, and the proportion of attacks that were successful were observed while fourth-instar Notonecta undulata nymphs preyed on smaller N. undulata nymphs. While encounters per prey and proportion of encounters resulting in attacks increased with prey size, the proportion of attacks that were successful decreased. The increase in encounter rate per prey was due in part to an increase in the predator's reactive distance to prey as prey size increased. While none of the attack parameters varied significantly with prey density, logarithmic regression of the number of encounters per unit search time on prey density suggested that prey density tends to have a positive effect on encounters per first-instar prey but a negative effect on encounters per second-instar prey. A functional response model is presented that incorporates components of the predator's attack rate as exponential functions of prey density and allows for effects of the time the predator may spend evaluating prey encountered but not attacked and time spent attacking prey not captured. Estimates of the attack parameters derived from the experimental data are used in the model to generate functional response curves for fourth-instar N. undulata preying on first- or second-instar conspecifics. The predicted curve for second-instar prey is typical type II but the curve for firstinstar prey is slightly positively density dependent at low prey densities, i.e., type III.


Models of Replicator Proliferation Involving Differential Replicator Subunit Stability.
Several models for the origin of life involve molecules that are capable of self-replication, such as self-replicating polymers composed of RNA or DNA or amino acids. Here we consider a hypothetical replicator (AB) composed of two subunits, A and B. Programs written in Python and C programming languages were used to model AB replicator abundance as a function of cycles of replication (iterations), under specified hypothetical conditions. Two non-exclusive models describe how a reduced stability for B relative to A can have an advantage for replicator activity and/or evolution by generating free A subunits. In model 1, free A subunits associate with AB replicators to create AAB replicators with greater activity. In simulations, reduced stability of B was beneficial when the replication activity of AAB was greater than two times the replication activity of AB. In model 2, the free A subunit is inactive for some number of iterations before it re-creates the B subunit. A re-creates the B subunit with an equal chance of creating B or B', where B' is a mutant that increases AB' replicator activity relative to AB. In simulations, at moderate number of iterations (< 15), a shorter survival time for B is beneficial when the stability of B is greater than the inactive time of A. The results are consistent with the hypothesis that reduced stability for a replicator subunit can be advantageous under appropriate conditions.


A novel 68Ga-labeled cyclic peptide molecular probe based on the computer-aided design for noninvasive imaging of PD-L1 expression in tumors.
Programmed death-ligand 1 (PD-L1) serves as a crucial biomarker for guiding the screening of cancer patients and the stratification of immunotherapy. However, due to the high heterogeneity of tumors, the current gold standard for detecting PD-L1 expression (immunohistochemistry) fails to comprehensively evaluate the overall PD-L1 expression levels in the body. Fortunately, the use of PD-L1 targeted radiotracers enables quantitative, real-time, and noninvasive assessment of PD-L1 expression levels and dynamics in tumors. Notably, analyzing the binding mode between the precursor and the target protein to find linker binding sites that do not affect the activity of the target molecule can greatly enhance the successful development of molecular probes. This study introduced a groundbreaking cyclic peptide molecular probe called 68Ga-DOTA-PG1. It was derived from the BMS-71 cyclic peptide and was specifically designed to evaluate the expression of PD-L1 in tumors. The radiolabeling yield of 68Ga-DOTA-PG1 surpassed 97% while maintaining a radiochemical purity of over 99%. In vitro experiments demonstrated the effective targeting of PD-L1 in tumor cells by 68Ga-DOTA-PG1, with significantly higher cellular uptake observed in A375-hPD-L1 cells (PD-L1 + ) compared to A375 cells (PD-L1-). Biodistribution and PET imaging studies consistently showed specific accumulation of 68Ga-DOTA-PG1 in A375-hPD-L1 tumors, with a maximum uptake of 11.06 ± 1.70% ID/g at 2 h, significantly higher than the tumor uptake in A375 cells (1.70 ± 0.17% ID/g). These results strongly indicated that 68Ga-DOTA-PG1 held great promise as a PET radiotracer for imaging PD-L1-positive tumors.


RTP801 immunoreactivity in retinal ganglion cells and its down-regulation in cultured cells protect them from light and cobalt chloride.
RTP801, a stress-related protein, is activated by adverse environmental conditions and inhibits the activity of mammalian target of rapamycin (mTOR) in promoting oxidative stress-dependent cell death. RTP801 exists both in the mammalian retina and the lens of the eye. Here, we observed RTP801 immunoreactivity in some retinal ganglion cells. Intravitreal injection of cobalt chloride (CoCl2) to mimick hypoxia influenced retinal GFAP (glial fibrillary acidic protein) and heme oxygenase-1 (HO-1) levels, but did not affect RTP801 immunoreactivity or mRNA content relative to GAPDH. However, RTP801 mRNA was elevated when compared with Brn3a mRNA, suggesting that RTP801 is activated in stressed Brn3a retinal ganglion cells. In cultures of RGC-5 cells, RTP801 immunoreactivity was located in the cytoplasm and partly present in the mitochondria. An insult of blue light or CoCl2 increased RTP801 expression, which was accompanied by cell death. However, in cultures where RTP801 mRNA was down-regulated, the negative influence of blue light and CoCl2 was blunted. Rapamycin nullified the CoCl2-induced up-regulation of RTP801 and attenuated cell death. Moreover, rapamycin was non-toxic to RGC-5 cells, even at a high concentration (10μM). The protective effect of rapamycin on RGC-5 cells caused by the inhibition of RTP801 suggests that rapamycin might attenuate retinal ganglion cell death in situ, as in glaucoma.


Infrared and Raman spectra and vibrational analyses calculated with Moeller-Plesset perturbation theory of second order of nitrosoethylene and its chloro-derivatives.
The conformational and structural stabilities of nitrosoethylene CH2=CH-N=O, chloronitrosoethylene CH2=CCl-N=O, and Dichloronitrosoethylene CCl2=CH-N=O were investigated by ab initio Moeller-Plesset perturbation theory of second order (MP2) calculations using the 6-311+G** basis set to include electron correlation. From the calculations all three were predicted to exist predominantly in the planar trans structure (C=C and N=O bonds are trans to each other) with high trans-cis rotational barriers of about 9 kcal mol(-1) as a result of pronounced conjugation between C=C and N=O bonds. The vibrational frequencies were computed for the three molecules, and also the d1 and d2 deuterated variants for the parent molecule at the MP2 level. Normal coordinate analyses were carried out and the potential energy distributions (PED), among the symmetry coordinates of the normal modes of the molecule were computed. Complete vibrational assignments were made on the basis of normal coordinate analyses for the molecules. The two chlorinated derivatives of nitrosoethylene were also investigated in the same way. As expected, we then find high Raman and infrared intensities in all modes that contain a high content of chlorine movements because vibrations of C-Cl bonds lead to large changes in polarizability, as well as to a large change in dipole moment. However, modes involving double bonds also have quite large intensities. An appreciable number of modes in these molecules are more or less pure symmetry coordinates.


Expression of vascular endothelial growth factor and its correlation with clinical symptoms and endoscopic findings in patients with chronic radiation proctitis.
The aim of this study was to assess the expression of vascular endothelial growth factor (VEGF) as a key proangiogenic factor and determine whether there is any correlation between its expression and clinical symptoms or endoscopic changes in patients with chronic radiation proctitis (ChRP). Fifty patients who had all undergone radiotherapy for prostate, cervical or uterine cancer were included in the study (37 women, 13 men). There was a control group of 20 patients (9 women, 11 men). The Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scoring system was used for grading the severity of the proctitis. Endoscopic scoring of late rectal mucosal damage was performed using Gilinsky's classification. Serum levels of VEGF were analysed by the enzyme-linked immunosorbent assay method. Most patients presented with Grade 1 symptoms. Endoscopic assessment showed that most patients had Grade 1 late rectal mucosal damage. The predominant endoscopic finding was the presence of telangiectasia. Assessment of VEGF correlation between the control group and the degrees of endoscopic changes showed statistically significant differences for all three degrees (P < 0.0001, P = 0.0251 and P = 0.0005, respectively). Due to the small numbers of patients with Grades 2 and 3 symptoms using the RTOG/EORTC scoring system, they were grouped with Grades 1 and 4 respectively forming two groups for statistical purposes. VEGF expression differed significantly between controls and group I and between controls and group II (P = 0.0001, P = 0.0009, respectively). A significant increase in VEGF expression was found to correlate with clinical symptoms and endoscopic rectal mucosa changes in patients with ChRP, suggesting that it may play an important role in pathological angiogenesis.


Long-term treatment with clarithromycin and carbocisteine improves lung function in chronic cough patients with chronic rhinosinusitis.
Chronic cough is a common complaint. Because the pathophysiology of chronic cough is complicated, the management of chronic cough is challenging. To the best of our knowledge, no previous study has examined the effect of macrolide antibiotics in chronic cough patients with chronic rhinosinusitis. The purpose of this study is to determine the changes in lung function for chronic cough patients with chronic rhinosinusitis who are treated by clarithromycin and carbocisteine. Thirty-two chronic cough patients with chronic rhinosinusitis were recruited. Patients using inhaled corticosteroids and/or a bronchodilator, asthmatic patients, and patients with abnormal findings on auscultation and/or chest X-ray examination were excluded from this study. The patients received low-dose clarithromycin treatment for 3 months. Both before and after the treatment, a computed tomography (CT) scan of the paranasal sinuses, lung function test, peripheral blood test, and sino-nasal outcome test (SNOT-20) were applied. Both the lung function and Lund-MacKay CT scores were improved by the long-duration therapy with macrolide antibiotics. The change in obstructive pulmonary function and the improvement of the CT score in each subject were significantly correlated. SNOT scores also improved after the treatment. The macrolide antibiotics treatment has beneficial effects on lung function in non-asthmatic chronic cough patients with normal chest X-ray findings. The improvement of chronic rhinosinusitis may have some role in the lung condition. Upper respiratory tract examination and treatment may be useful for the management of chronic cough.


Periodontal, Functional, and Esthetic Integration of Peri-Implant Soft Tissue: WHS Concept.
The long-term functional success of implant treatment depends on the stability of the crestal bone around the implant platform. The esthetic result is achieved by adequate quality and quantity of soft tissue in the peri-implant area. The soft tissue creates the buffer area that ensures the mechanical and biological protection of the underlying bone. Therefore, it is necessary to maintain in the long term, not only implant osseointegration, but also the integrity of the soft tissue around the sub- and suprastructures of the implant restoration. To create the protective soft tissue area, it is necessary to ensure 3 criteria. This treatment approach will be defined as TWS-soft tissue management: T for thickness, W for width, and S for stability. There are many ways to achieve the first 2 criteria, which are described in the literature. Achieving the third criterion of stability has become possible only recently because of the development of digital treatment planning, surgically guided, and prosthetic-assisted technology that uses a 1-time abutment and its implementation into the dental practice. The purpose of this article is to present with clinical cases a detailed description of each criterion.


Transcriptional regulation of de novo biosynthesis of cyanogenic glucosides throughout the life-cycle of the burnet moth Zygaena filipendulae (Lepidoptera).
The six-spotted burnet moth Zygaena filipendulae (Lepidoptera) utilize the two cyanogenic glucosides (CNglcs) linamarin and lotaustralin as deterrents against predators throughout the entire life cycle. CNglcs can be hydrolyzed and bioactivated by β-glucosidases, resulting in the release of toxic hydrogen cyanide. CNglcs are retained through metamorphosis, probably involved in mating communication, and transferred during mating from the male to the female as a nuptial gift. CNglcs can be biosynthesized de novo by Z. filipendulae larvae, but may also be sequestered from their food plant Lotus corniculatus (Fabaceae). These two strategies are tightly linked and adjusted according to the CNglc content and composition of the food plant in order to balance CNglc homeostasis in the larva. In this study, the amounts of CNglcs and transcript levels of the biosynthetic genes were monitored in all life-stages and tissues of Z. filipendulae. During pupation, transcription of the biosynthetic genes is turned off and the CNglc content slowly declines. In females but not males, transcription of the biosynthetic genes is re-activated at the end of pupation. Eggs and embryos do not biosynthesize CNglcs de novo, but are endowed with CNglcs following eclosion of the female. Similarly to larvae, de novo biosynthesis in female adults takes place in the integument from which CNglcs are then transported to other organs. This study demonstrates that Z. filipendulae has evolved the ability to adjust the production of CNglcs throughout its life-cycle for optimal utilization in defense and possibly other metabolic functions, while at the same time avoiding intoxication.


Frailty state transitions and associated factors in South Australian older adults.
Frailty is a state of decreased physiological reserve and vulnerability to stressors. Understanding the characteristics of those most at risk of worsening, or likely to improve their frailty status, are key elements in addressing this condition. The present study measured frailty state transitions and factors associated with improvement or worsening frailty status in the North West Adelaide Health Study. Frailty was measured using the frailty phenotype (FP) and a 34-item frailty index (FI) for 696 community-dwelling participants aged ≥65 years, with repeated measures at 4.5-year follow up. Improvement in frailty state was common for both tools (FP 15.5%; FI 7.9%). The majority remained stable (FP 44.4%; FI 52.6%), and many transitioned to a worse level of frailty (FP 40.1%; FI 39.5%). For both measures, multimorbidity was associated with worsening frailty among non-frail participants. Among pre-frail participants, normal waist circumference was associated with improvement, whereas older age was associated with worsening of frailty status. Among frail individuals, younger age was associated with improvement, and male sex and older age were associated with worsening frailty status. Frailty is a dynamic process where improvement is possible. Multimorbidity, obesity, age and sex were associated with frailty transitions for both tools. Geriatr Gerontol Int 2018; 18: 1549-1555.


Feasibility of conducting a randomized, placebo-controlled study assessing whether omega-3 fatty acids prevent gout flares when starting urate-lowering treatment.
The aim was to test the feasibility of a randomized controlled trial exploring whether omega-3 fatty acid supplementation limits gout flares during treat-to-target urate-lowering treatment (T2T-ULT). Adults with at least one gout flare in the past 12 months and serum urate (SU) ≥360 μmol/l were recruited from general practices (primary method) and randomly assigned 1:1 to receive omega-3 fatty acid supplementation (4 g/day) or placebo for 28 weeks. At week 5, participants began T2T-ULT. The primary outcome was drop-out rate. Secondary outcomes were recruitment rate, outcome data completeness, the number, severity and duration of gout flares between weeks 5 and 28, and study drug compliance. Ninety-five per cent of randomized participants (n = 60) completed all study visits. The primary method recruitment rate was 2.2%. Fifty and 42 participants achieved SU < 360 and 300 μmol/l (6 and 5 mg/dl), respectively. The number of gout flares [median (interquartile range): active 1 (0-2) and placebo 1 (0-2)], flare duration [mean (s.d.): active 7.00 (4.52) days and placebo 7.06 (8.14) days] and time to first flare [hazard ratio (95% CI) 0.97 (0.50, 1.86)] were comparable between both arms. Study drug compliance was high and comparable in both arms [median (interquartile range) returned capsule count: active 57 (26-100) and placebo 58 (27-154)]; red blood cell omega-3 fatty acid index increased twofold in the active arm and remained unchanged in the control arm. The study demonstrated feasibility and provided useful metrics for conducting a community-based gout flare prophylaxis trial. ISRCTN; https://www.isrctn.com/; ISRCTN79392964.


The role of the kidney in the maintenance of water balance.
This chapter shows how the mammalian kidney is able to regulate the excretion of water independently from that of solutes. For this function, which derives from several evolutionary steps among vertebrates, it takes advantage of the diluting ability of the thick ascending limb to produce osmotic energy which is then used to concentrate solutes in the urine. This concentration is permitted by a highly sophisticated architecture of nephrons and vessels in the renal medulla, combined with special permeability characteristics of the different nephron segments and specific hormonal regulation. Two different types of loops of Henle and several well-insulated vascular compartments contribute to this process. The major nitrogenous waste product, urea, is concentrated by an indirect process involving a transfer of osmotic energy from the outer to the inner medulla. As known for several decades, concentrating function is primarily regulated by the effect of antidiuretic hormone (ADH) on water permeability of the collecting duct. However, as discovered more recently, it is also largely dependent upon the effect of the same hormone on urea permeability in the terminal collecting duct. In addition, recent investigations have revealed a much more complex hormonal regulation of the concentrating process than previously thought. ADH itself acts on many other structures in the kidney, and many other hormones and mediators, the secretion of which is not thought to be influenced by the water status, do affect urine concentration either directly or by their interaction with ADH. Rodents display a wide spectrum of morphological and functional renal adaptations improving water conservation. Their study has brought a better understanding of the significant steps and anatomical structures that contribute to the concentrating process. Finally, it is also apparent that the capacity to concentrate urine is influenced in individual animals of a given species by the availability of water, by specific feeding patterns, and by the protein content of the diet.


Synthesis and antioxidant properties of novel N-methyl-1,3,4-thiadiazol-2-amine and 4-methyl-2H-1,2,4-triazole-3(4H)-thione derivatives of benzimidazole class.
Some novel 1-methyl-4-(2-(2-substitutedphenyl-1H-benzimidazol-1-yl)acetyl)thiosemicarbazides (16a-20a), 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl]-N-methyl-1,3,4-thiadiazol-2-amines (17b-20b), and 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl-4-methyl-2H-1,2,4-triazole-3(4H)-thiones (16c-20c) were synthesized and tested for antioxidant properties by using various in vitro systems. Compounds 16a-20a were found to be a good scavenger of DPPH radical (IC(50), 26 microM; IC(50), 30 microM; IC(50), 43 microM; IC(50), 55 microM; IC(50), 74 microM, respectively) when compared to BHT (IC(50), 54 microM). Noteworthy results could not be found on superoxide radical. Compound 19b, which is the most active derivative inhibited slightly lipid peroxidation (28%) at 10(-3)M concentration. Compound 17c inhibited the microsomal ethoxyresorufin O-deethylase (EROD) activity with an IC(50)=4.5 x 10(-4)M which is similarly better than the specific inhibitor caffeine IC(50)=5.2 x 10(-4)M.


San copolymer membranes with ion exchangers for Cu(II) removal from synthetic wastewater by electrodialysis.
Heterogeneous membranes were obtained by using styrene-acrylonitrile copolymer (SAN) blends with low content of ion-exchanger particles (5wt.%). The membranes obtained by phase inversion were used for the removal of copper ions from synthetic wastewater solutions by electrodialytic separation. The electrodialysis was conducted in a three cell unit, without electrolyte recirculation. The process, under potentiostatic or galvanostatic control, was followed by pH and conductivity measurements in the solution. The electrodialytic performance, evaluated in terms of extraction removal degree (rd) of copper ions, was better under potentiostatic control then by the galvanostatic one and the highest (over 70%) was attained at 8V. The membrane efficiency at small ion-exchanger load was explained by the migration of resin particles toward the pores surface during the phase inversion. The prepared membranes were characterized by various techniques i.e. optical microscopy, Fourier transform infrared spectroscopy, scanning electron microscopy, thermogravimetric analysis and differential thermal analysis and contact angle measurements.


The moderating role of depression in the association between hypertension during pregnancy and birth outcomes.
Investigate how hypertension during pregnancy (HDP) and depression during pregnancy (DDP) independently and jointly affect infant birth outcomes. This population-based, retrospective cohort study included a sample of 68,052 women who participated in PRAMS 2016-2018 survey. Poisson regression was used for adjusted relative risks (aRRs). Compared to women without HDP and DDP, aRRs for PTB and LBW among women with both HDP and DDP are 2.04 (95% CI 1.73, 2.42) and 2.84 (95% CI 2.27, 3.56), respectively, albeit lower than the expected joint effect of risk. DDP may modify the association between HDP and PTB, LBW.


High-grade prostate cancer and biochemical recurrence after radical prostatectomy among men using 5α-reductase inhibitors and alpha-blockers.
Two clinical trials have shown that users of 5α-reductase inhibitors finasteride and dutasteride (5-ARIs) have reduced overall prostate cancer risk, while the proportion of high-grade tumors is increased. We studied tumor characteristics, risk of biochemical recurrence and mortality after radical prostatectomy in 5-ARI and alpha-blocker users. The study cohort consisted of 1,315 men who underwent radical prostatectomy at the Tampere University Hospital during 1995-2009. Biochemical relapse was defined as serum PSA ≥ 0.2 ng/ml after the operation. Information on mortality and medication purchases was obtained from national registries. Cox proportional regression was used to analyze hazard ratios (HRs) and 95% confidence intervals (95% CI) of biochemical relapse and death. The proportion of high-grade (Gleason 7-10) tumors was significantly elevated among men who had used 5-ARIs for 4 years or longer compared to the non-users (83.3% vs. 53.3%, respectively). Survival curves for biochemical relapse-free survival differed between long-term and short-term 5-ARI users, but the hazard ratio remained statistically non-significant. Risk of biochemical recurrence was elevated among alpha-blocker users (HR 1.68, 95% CI 1.37-2.06), but in sensitivity analyses this was evident only in men using alpha-blockers after prostatectomy. Mortality was not associated with medication usage. Long-term users of finasteride or dutasteride had more often high-grade prostate cancer. Our results suggest also worse progression-free survival. The association between risk of biochemical recurrence and post-operative alpha-blocker usage suggests that voiding or storage symptoms after prostatectomy may predict biochemical relapse.


Immunohistochemical differential diagnosis of granulocytic sarcomas and malignant lymphomas on formalin-fixed material.
A panel of monoclonal antibodies (anti-CD45 [common leukocyte antigen], Ki-B3, L26, MT1, UCHL1, anti-CD15 [X-hapten], anti-neutrophil granule protein elastase [NP57]), anti-lysozyme, and the naphthol-ASD-chloroacetate reaction were applied to two cases of granulocytic sarcoma (GS) for evaluation of their utility in differentiating GS from malignant lymphoma. Lysozyme and naphthol-ASD-chloroacetate esterase were found to be the most reliable markers for detection of the myeloid nature of the tumour cells. GS infiltrated solely the mucosa of the nasal cavity in one case, while in the other it involved both the nasal cavity and maxillary sinus with simultaneous eruptions on the skin of the trunk. In both cases, peripheral blood and bone marrow findings were inconspicuous at the time of diagnosis of GS.


Generalized morphea in a child with harlequin ichthyosis: a rare association.
Harlequin ichthyosis (HI) is a severe and rare hereditary congenital skin disorder characterized by excessive dryness, ectropion and eclabion. The association of ichthyosis with systemic sclerosis has been described in only three children. No patient with generalized morphea (GM) associated with harlequin ichthyosis was described. A 4-years and 6-months girl, diagnosed with harlequin ichthyosis based on diffuse cutaneous thickening, scaling, erythema, ectropion and eclabium since the first hours of birth was described. She was treated with acitretin (1.0mg/kg/day) and emollient cream. At 3 years and 9 months, she developed muscle contractures with pain on motion and limitation in elbows and knees, and diffuse sclerodermic plaques on the abdomen, back, suprapubic area and lower limbs. Skin biopsy showed rectified epidermis and mild hyperorthokeratosis, reticular dermis with perivascular and periadnexal infiltrates of lymphocytes and mononuclear cells, and reticular dermis and sweat gland sclerosis surrounded by a dense collagen tissue, compatible with scleroderma. The patient fulfilled the GM subtype criteria. Methotrexate and prednisone were introduced. At 4 years and 3 months, new scleroderma lesions occurred and azathioprine was associated with previous therapy, with no apparent changes after two months. A case of harlequin ichthyosis associated with a GM was reported. The treatment of these two conditions is a challenge and requires a multidisciplinary team.


Mitral valvuloplasty by inoue balloon under transthoracic echocardiographic guidance.
Mitral valvuloplasty traditionally performed under fluoroscopic guidance has emerged as an effective nonsurgical technique for the treatment of symptomatic patients with mitral stenosis. We undertook a study to evaluate the feasibility of performing valvuloplasty by the Inoue balloon solely under transthoracic echocardiographic (TTE) guidance with the backup of transesophaeal echocardiography (TEE) and fluoroscopy. Between September 2003 and July 2004, mitral valvuloplasty using the Inoue balloon was performed solely under TTE guidance in the catheterization laboratory with backup of fluoroscopy and TEE in 75 patients (52 female patients, including 18 who were pregnant, and 23 male patients) with symptomatic mitral stenosis (New York Heart Association class II-IV) with satisfactory TTE window and valve morphology suitable for valvuloplasty. The procedure was technically successful (no requirement of TEE or fluoroscopy) in 68 patients (89%). TEE was required for septal puncture in 3 patients whereas fluoroscopic assistance was required to complete the procedure in 4 patients. Procedural success after valvuloplasty (doubling of mitral valve area or mean gradient across mitral valve < 5 mm Hg in absence of complications like severe mitral regurgitation or tamponade) was achieved in 70 patients. There was an increase in mean mitral valve area as assessed echocardiographically from 0.84 +/- 0.16 cm2 to 1.7 +/- 0.27 cm2 with decrease in mean diastolic gradient from 27.2 +/- 8.4 mm Hg (18-36 mm Hg) to 5.2 +/- 4.1 mm Hg (3-14 mm Hg). The mean procedure time was 27.2 +/- 8.4 minutes (15-45 minutes). Mild mitral regurgitation appeared or increased in severity to moderate degree as assessed by color Doppler during the procedure in 11 patients (14.6%) but no patient developed severe mitral regurgitation. No patient had cardiac tamponade as puncture of the septum under TTE guidance prevents inadvertent puncture of the aorta, coronary sinus, inferior vena cava, and right atrial and left atrial wall that sometimes occurs during septal puncture under fluoroscopic guidance. Balloon mitral valvuloplasty under sole TTE guidance is safe and feasible in experienced hands.


Therapeutic concerns when oral medications are administered nasogastrically.
Administering oral medications to patients with nasogastric tube (NGT) is a challenging patient-care issue. Inappropriate prescribing behaviour and incorrect procedure for extemporaneous preparation of oral suspensions given via NGT may result in significant harm to patients. There are many drugs which have not been tested regarding oral absorption profile and bioavailability derived from NGT dosing. Although several studies and case-reports have been reported, there is no up-to-date review of drug administration via NGT. The aim of this review is to increase awareness of rational drug administration via NGT and to encourage relevant research in this area. Full prescribing information from each currently available oral medication was reviewed for any data indicating that the medication could not be crushed or opened. Literature was identified by searching PubMed (1988 to Aug 2012). There is evidence to show that NGT dosing of some medications may bring both benefits (e.g. cost saving) and disadvantages (e.g. decrease in efficacy and/or safety). For medications with package inserts that warn that they should not be crushed or opened, alternatives are usually recommended. However, in some cases, there is evidence to support NGT dosing. Sometimes special procedures are required to avoid problems such as instability, interaction with enteral nutrition, adsorption, tube obstruction and low recovery when preparing extemporaneous oral suspensions. Physicians, pharmacists and nurses should know the procedures for drug administration by NGT, as well as the latest evidence on such administrations. There may not be bioequivalence between oral and nasogastric administrations. Care must be taken to avoid compromising the physicochemical, biopharmaceutical and pharmacological properties of drugs given by NGT to ensure their safety and efficacy.


NTR1 encodes a high affinity oligopeptide transporter in Arabidopsis.
Hterologous complementation of yeast mutants has enabled the isolation of genes encoding several families of amino acid transporters. Among them, NTR1 codes for a membrane protein with weak histidine transport activity. However, at the sequence level, NTR1 is related to rather non-specific oligopeptide transporters from a variety of species including Arabidopsis and to the Arabidopsis nitrate transporter CHL1. A yeast mutant deficient in oligopeptide transport was constructed allowing to show that NTR1 functions as a high affinity, low specificity peptide transporter. In siliques NTR1-expression is restricted to the embryo, implicating a role in the nourishment of the developing seed.


The involvement of dimethyl sulfoxide in a bacteriotoxic response of the Ames assay tester strains TA98 and TA100.
Dimethyl sulfoxide is a widely accepted and recommended solvent in which to dissolve compounds to be tested for mutagenicity via the Ames Salmonella/mammalian microsome assay. Using tester strains TA98 and TA100, we observed a bacteriotoxic response with various fractions isolated from beer when dissolved in DMSO but not when dissolved in water. Further characterization of the role of solvent in simple model systems consisting of butanol, DMSO and bacteria strongly suggests a chemical reaction occurs between dimethyl sulfoxide and specific chemical constituents of the test substance, nutrient broth, or the Ames bacterial strains. The result of such an interaction could be misinterpreted as a toxic response to the test substance when, in fact, the bacteriotoxicity could be due to another compound, chemically distinct from the test substance.


Comparative developmental toxicities of zebrafish towards structurally diverse per- and polyfluoroalkyl substances.
Structurally diverse per- and polyfluoroalkyl substances (PFASs) are increasingly detected in ecosystems and humans. Therefore, the clarification of their ecological and health risks is urgently required. In the present study, the toxicity of a series of PFASs, including PFOS, PFBS, Nafion BP1, Nafion BP2, F53B, OBS, PFOA, PFUnDA, PFO5DoDA, HFPO-TA was investigated. Similarities and differences in the developmental toxicity potentials were revealed. Our results demonstrated that PFUnDA exhibited the highest toxicity with the lowest EC50 value of 4.36 mg/L (for morphological abnormality); this was followed by F53B (5.58 mg/L), PFOS (6.15 mg/L), and OBS (10.65 mg/L). Positive correlations with volatility/solubility and chemotypes related to specific biological activity, including the bioconcentration factor (LogBCF), and negative correlations with lipid solubility and carbon chain component-related chemotypes, including the number of carbon and fluorine atoms, provided a reasonable explanation in the view of molecular structures. Furthermore, comparative transcriptome analysis provided molecular evidence for the relationship between PFASs exposure and malformations. Common differentially expressed genes (DEGs) involved in spine curve development, pericardial edema, and cell/organism growth-related pathways presented common targets, leading to toxic effects. Therefore, the present results provide novel insights into the potential environmental risks of structurally diverse PFASs and contribute to the selection of safer PFAS replacements.


Prevalence of Plasmodium falciparum haplotypes associated with resistance to sulfadoxine-pyrimethamine and amodiaquine before and after upscaling of seasonal malaria chemoprevention in seven African countries: a genomic surveillance study.
Seasonal malaria chemoprevention is used in 13 countries in the Sahel region of Africa to prevent malaria in children younger than 5 years. Resistance of Plasmodium falciparum to seasonal malaria chemoprevention drugs across the region is a potential threat to this intervention. Between December, 2015, and March, 2016, and between December, 2017, and March, 2018, immediately following the 2015 and 2017 malaria transmission seasons, community surveys were done among children younger than 5 years and individuals aged 10-30 years in districts implementing seasonal malaria chemoprevention with sulfadoxine-pyrimethamine and amodiaquine in Burkina Faso, Chad, Guinea, Mali, Nigeria, Niger and The Gambia. Dried blood samples were collected and tested for P falciparum DNA by PCR. Resistance-associated haplotypes of the P falciparum genes crt, mdr1, dhfr, and dhps were identified by quantitative PCR and sequencing of isolates from the collected samples, and survey-weighted prevalence and prevalence ratio between the first and second surveys were estimated for each variant. 5130 (17·5%) of 29 274 samples from 2016 and 2176 (7·6%) of 28 546 samples from 2018 were positive for P falciparum on quantitative PCR. Among children younger than 5 years, parasite carriage decreased from 2844 of 14 345 samples (19·8% [95% CI 19·2-20·5]) in 2016 to 801 of 14 019 samples (5·7% [5·3-6·1]) in 2018 (prevalence ratio 0·27 [95% CI 0·24-0·31], p<0·0001). Genotyping found no consistent evidence of increasing prevalence of amodiaquine resistance-associated variants of crt and mdr1 between 2016 and 2018. The dhfr haplotype IRN (consisting of 51Ile-59Arg-108Asn) was common at both survey timepoints, but the dhps haplotype ISGEAA (431Ile-436Ser-437Gly-540Glu-581Ala-613Ala), crucial for resistance to sulfadoxine-pyrimethamine, was always rare. Parasites carrying amodiaquine resistance-associated variants of both crt and mdr1 together with dhfr IRN and dhps ISGEAA occurred in 0·05% of isolates. The emerging dhps haplotype VAGKGS (431Val-436Ala-437Gly-540Lys-581Gly-613Ser) was present in four countries. In seven African countries, evidence of a significant reduction in parasite carriage among children receiving seasonal malaria chemoprevention was found 2 years after intervention scale-up. Combined resistance-associated haplotypes remained rare, and seasonal malaria chemoprevention with sulfadoxine-pyrimethamine and amodiaquine is expected to retain effectiveness. The threat of future erosion of effectiveness due to dhps variant haplotypes requires further monitoring. Unitaid.


[Vascular recanalization techniques: renal artery stenoses].
Decisive for the evaluation for radiological interventional therapy of renal artery stenosis, are the morphologic diagnostic by Duplex sonography, non-invasive cross-sectional angiography and digital subtraction angiography in addition to the anamnesis and clinical constellation. A standardized diagnostic algorithm and an evidence-based indication status contribute just as importantly to improvement of outcome as the implementation of uniform peri-interventional measures and a structured procedure for angiography, percutaneous transluminal renoangioplasty and follow-up. The aim of this article is to provide a practical introduction for the current radiological management of renal artery stenosis.


Dynamic PET images denoising using spectral graph wavelet transform.
Positron emission tomography (PET) is a non-invasive molecular imaging method for quantitative observation of physiological and biochemical changes in living organisms. The quality of the reconstructed PET image is limited by many different physical degradation factors. Various denoising methods including Gaussian filtering (GF) and non-local mean (NLM) filtering have been proposed to improve the image quality. However, image denoising usually blurs edges, of which high frequency components are filtered as noises. On the other hand, it is well-known that edges in a PET image are important to detection and recognition of a lesion. Denoising while preserving the edges of PET images remains an important yet challenging problem in PET image processing. In this paper, we propose a novel denoising method with good edge-preserving performance based on spectral graph wavelet transform (SGWT) for dynamic PET images denoising. We firstly generate a composite image from the entire time series, then perform SGWT on the PET images, and finally reconstruct the low graph frequency content to get the denoised dynamic PET images. Experimental results on simulation and in vivo data show that the proposed approach significantly outperforms the GF, NLM and graph filtering methods. Compared with deep learning-based method, the proposed method has the similar denoising performance, but it does not need lots of training data and has low computational complexity.


The correlation between vitamin B12 and folate levels and bone mineral density among the Saudi population in a primary care setting.
Bone health and osteoporosis are significant health problems in Saudi Arabia. Approximately 40%-50% of women and 25%-33% of men sustain osteoporotic fractures in their lifetimes. Hence, identifying the risk factors for osteoporosis is crucial in reducing the incidence of fractures. We retrospectively reviewed the electronic medical records of 557 patients (female 60%, male 40%) aged ≥18 years (mean age, 66.53 years [standard deviation ± 14.169]) who underwent bone mineral density (BMD) scans at the Department of Family Medicine & Polyclinics, King Faisal Specialist Hospital and Research Centre (KFSH&RC) between January 2004 and June 2019. Data collected included demographics, BMD values, vitamin B12 levels, and folate levels. This study indicated that the prevalence rates of vitamin B12 and folate deficiencies among the study population were 8.4% and 1.3%, respectively. There was a statistically significant association between vitamin B12 levels and fracture risk (P =0.044). However, no statistically significant correlation was observed between BMD at either site (lumbar spine or femoral neck) and vitamin B12 (P =0.926.,070) and folate levels (P =.683.,79). BMD showed a significant positive correlation with body mass index at the lumbar spine and femoral neck (P = 0.000). There was no statistically significant association between vitamin B12 levels and the use of metformin (P =.26). Vitamin B12 is associated with fracture risk; however, vitamin B12 and folate levels are not correlated to BMD (femoral neck and lumbar spine).


Sexually active adolescents and condoms: changes over one year in knowledge, attitudes and use.
Over a year when public health information regarding AIDS intensified, changes in perceptions and use of condoms in a sample of sexually active adolescents in San Francisco were examined. Although perceptions that condoms prevent sexually transmitted diseases (STDs) and the value and importance placed on avoiding STDs remained high, these were neither reflected in increased intentions to use condoms nor in increased use.


A developmental study of novH gene expression in human central nervous system.
The expression pattern of the human nephroblastoma overexpressed (novH) gene in the fetal human central nervous system was examined by in situ hybridization using digoxigenin-labeled novH-specific riboprobes. In the spinal cord, the nov-expressing neurons were first detected both in the ventral region at 16 weeks of gestation (G16W) and in the dorsal region at G38W. In the medulla, nov-expressing neurons were detected in the principal nucleus of the inferior olive, the hypoglossal nucleus and the dorsal motor nucleus of vagus at G16W. Nov-positive neurons were detected at G28W in the nucleus of the spinal tract of the trigeminal and cuneate nucleus, and at G38W in the abducens nucleus of pons, the red nucleus and the substantia nigra of the midbrain, the ventral posterolateral and the mediodorsal thalamic nucleus. A strong labeling was also detected in the striatum of the cerebrum and the cerebral cortex of the parietal lobe. These data established that novH is mainly expressed in somato-motor neurons in the lower central nervous system at early developmental stages and in the higher central nervous system at later stages, suggesting that nov may play an important role in neuronal differentiation.


A Systematic Review of Intra-pancreatic Fat Deposition and Pancreatic Carcinogenesis.
Excess adiposity is considered causally related to pancreatic cancer. While most knowledge on the topic comes from studies on general and visceral adiposity, the role of intra-pancreatic fat deposition in pancreatic carcinogenesis just begins to be elucidated. The aim was to conduct a comprehensive systematic review of clinical studies on intra-pancreatic fat deposition in individuals with pancreatic cancer or pre-malignant lesions. A literature search was conducted independently by two reviewers using three electronic databases. Studies were included if they reported on intra-pancreatic fat deposition determined based on modern radiology or histology. Summary estimates were presented as pooled prevalence or relative risk and 95% confidence interval. A total of 13 studies (encompassing 2178 individuals) were included. The pooled prevalence of intra-pancreatic fat deposition in individuals with pancreatic cancer or pre-malignant lesions was 52% (95% confidence interval, 38-66%). The presence of pancreatic cancer or pre-malignant lesions was associated with a significantly increased risk of intra-pancreatic fat deposition (relative risk 2.78 (95% confidence interval, 1.56-4.94, p < 0.001). Individuals with pancreatic cancer or pre-malignant lesions are characterized by increased intra-pancreatic fat deposition. There are sound grounds for conceptually viewing intra-pancreatic fat deposition as a combination of fat accumulation in the pancreas (due to expansion of excess visceral fat) and fatty replacement of the pancreas (due to changes in cellular identity within the pancreas). Guidelines on reporting intra-pancreatic fat deposition need to be developed with a view to informing a comprehensive and standardized characterization of this clinical entity in future studies.


Feature subset selection using constrained binary/integer biogeography-based optimization.
Feature selection plays a crucial role in applications where data consists of hundreds of features due to curse of dimensionality. This paper presents two feature selection methods by modifying the main operators of Biogeography-Based Optimization algorithm. The difference between these methods is in employing binary or integer coding. The simulations perform on datasets with different feature dimensions and classes. The results indicate the effectiveness of the proposed methods in comparison with other most frequently used meta-heuristic strategies in feature selection problems.


Application of Bayesian analyses to doubly randomized delayed start, matched control designs to demonstrate disease modification.
Disease modification is a primary therapeutic aim when developing treatments for most chronic progressive diseases. The best treatments do not simply affect disease symptoms but fundamentally improve disease course by slowing, halting, or reversing disease progression. One of many challenges for establishing disease modification relates to the identification of adequate analytic tools to show differences in a disease course following intervention. Traditional approaches rely on the comparisons of slopes or noninferiority margins. However, it has proven difficult to conclusively demonstrate disease modification using such approaches. To address these challenges, we propose a novel adaptation of the delayed start study design that incorporates posterior probabilities identified by hierarchical Bayesian inference approaches to establish evidence for disease modification. Our models compare the size of treatment differences at the end of the delayed start period with those at the end of the early start period. Simulations that compare several models are provided. These include general linear models, repeated measures models, spline models, and model averaging. Our work supports the superiority of model averaging for accurately characterizing complex data that arise in real world applications. This novel approach has been applied to the design of an ongoing, doubly randomized, matched control study that aims to show disease modification in young persons with schizophrenia (the Disease Recovery Evaluation and Modification (DREaM) study). The application of this Bayesian methodology to the DREaM study highlights the value of this approach and demonstrates many practical challenges that must be addressed when implementing this methodology in a real world trial.


Couple dynamics: PPARγ and its ligand partners.
Ligand-regulated transcriptional activity is the most important property of nuclear receptors, including PPARγ. In this issue of Structure, Hughes et al. determined how the dynamic conformations of ligands and the receptor contribute to the degree of ligand-dependent activation of PPARγ, which provide further insights into design of PPARγ-based anti-diabetic drugs.


Structural basis for the binding of DNP and purine nucleotides onto UCP1.
Uncoupling protein 1 (UCP1) conducts protons through the inner mitochondrial membrane to uncouple mitochondrial respiration from ATP production, thereby converting the electrochemical gradient of protons into heat1,2. The activity of UCP1 is activated by endogenous fatty acids and synthetic small molecules, such as 2,4-dinitrophenol (DNP), and is inhibited by purine nucleotides, such as ATP3-5. However, the mechanism by which UCP1 binds to these ligands remains unknown. Here we present the structures of human UCP1 in the nucleotide-free state, the DNP-bound state and the ATP-bound state. The structures show that the central cavity of UCP1 is open to the cytosolic side. DNP binds inside the cavity, making contact with transmembrane helix 2 (TM2) and TM6. ATP binds in the same cavity and induces conformational changes in TM2, together with the inward bending of TM1, TM4, TM5 and TM6 of UCP1, resulting in a more compact structure of UCP1. The binding site of ATP overlaps with that of DNP, suggesting that ATP competitively blocks the functional engagement of DNP, resulting in the inhibition of the proton-conducting activity of UCP1.


Renal Effects of Sodium-Glucose Co-Transporter Inhibitors.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given chronically, they confer benefit by markedly slowing the rate at which chronic kidney disease progresses and are the first agents to do so since the advent of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Salutary effects on the kidney were first demonstrated in cardiovascular outcomes trials and have now emerged from trials enriched in subjects with type 2 diabetes mellitus and chronic kidney disease. A simple model that unifies the immediate and long-term effects of SGLT2 inhibitors on kidney function is based on the assumption that diabetic hyperfiltration puts the kidney at long-term risk and evidence that hyperfiltration is an immediate response to a reduced signal for tubuloglomerular feedback, which occurs to the extent that SGLT2 activity mediates a primary increase in sodium and fluid reabsorption by the proximal tubule. This model will likely continue to serve as a useful description accounting for the beneficial effect of SGLT2 inhibitors on the diabetic kidney, similar to the hemodynamic explanation for the benefit of ACEIs and ARBs. A more complex model will be required to incorporate positive interactions between SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule and between sodium-glucose co-transporter 1 (SGLT1) and nitric oxide synthase in the macula densa. The implication of these latter nuances for day-to-day clinical medicine remains to be determined.


Total synthesis of psammaplysenes A and B, naturally occurring inhibitors of FOXO1a nuclear export.
[reaction: see text] Two inhibitors of FOXO1a-mediated nuclear export, psammaplysenes A and B, have been synthesized by a flexible and efficient route. A common starting material, 4-iodophenol, was used to prepare both halves of these pseudosymmetric dibromotyrosine-derived metabolites.


A comparative analysis employing a gene- and genome-centric metagenomic approach reveals changes in composition, function, and activity in waterworks with different treatment processes and source water in Finland.
The emergence and development of next-generation sequencing technologies (NGS) has made the analysis of the water microbiome in drinking water distribution systems (DWDSs) more accessible and opened new perspectives in microbial ecology studies. The current study focused on the characterization of the water microbiome employing a gene- and genome-centric metagenomic approach to five waterworks in Finland with different raw water sources, treatment methods, and disinfectant. The microbial communities exhibit a distribution pattern of a few dominant taxa and a large representation of low-abundance bacterial species. Changes in the community structure may correspond to the presence or absence and type of disinfectant residual which indicates that these conditions exert selective pressure on the microbial community. The Archaea domain represented a small fraction (up to 2.5%) and seemed to be effectively controlled by the disinfection of water. Their role particularly in non-disinfected DWDS may be more important than previously considered. In general, non-disinfected DWDSs harbor higher microbial richness and maintaining disinfectant residual is significantly important for ensuring low microbial numbers and diversity. Metagenomic binning recovered 139 (138 bacterial and 1 archaeal) metagenome-assembled genomes (MAGs) that had a >50% completeness and <10% contamination consisting of 20 class representatives in 12 phyla. The presence and occurrence of nitrite-oxidizing bacteria (NOB)-like microorganisms have significant implications for nitrogen biotransformation in drinking water systems. The metabolic and functional complexity of the microbiome is evident in DWDSs ecosystems. A comparative analysis found a set of differentially abundant taxonomic groups and functional traits in the active community. The broader set of transcribed genes may indicate an active and diverse community regardless of the treatment methods applied to water. The results indicate a highly dynamic and diverse microbial community and confirm that every DWDS is unique, and the community reflects the selection pressures exerted at the community structure, but also at the levels of functional properties and metabolic potential.


Acute hepatitis due to olmesartan: an uncommon entity.
We report the case of a hypertensive 54-year-old female who had been under treatment with olmesartan (40 mg daily) for a month. She was referred due to hypertransaminasemia and also reported asthenia and a 7 kg weight loss.


The concept of quasi-tissue-equivalent nanodosimeter based on the glow peak 5a/5 in LiF:Mg,Ti (TLD-100).
We demonstrate the viability of the concept of using existing molecular nanostructures in thermoluminescent solid-state materials as solid-state nanodosimeters. The concept is based on mimicking radiobiology (specifically the ionization density dependence of double strand breaks in DNA) by using the similar ionization density dependence of simultaneous electron-hole capture in spatially correlated trapping and luminescent centres pairs in the thermoluminescence of LiF:Mg,Ti. This simultaneous electron-hole capture has been shown to lead to ionization density dependence in the relative intensity of peak 5a to peak 5 similar to the ratio of double-strand breaks to single-strand breaks for low energy He ions.


Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts.
1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the biologically active metabolite of Vitamin D(3), not only regulates bone and calcium metabolism but also exerts other biological activities, including immunomodulation via the nuclear Vitamin D receptor expressed in antigen-presenting cells and activated T cells. This regulation is mediated through interference with nuclear transcription factors such as NF-AT and NF-kappaB or by direct interaction with Vitamin D responsive elements in the promoter regions of cytokine genes. Dendritic cells (DCs) are primary targets for the immunomodulatory activity of 1,25(OH)(2)D(3), as indicated by inhibited DC differentiation and maturation, leading to down-regulated expression of MHC-II, costimulatory molecules and IL-12. Moreover, 1,25(OH)(2)D(3) enhances IL-10 production and promotes DC apoptosis. Together, these effects of 1,25(OH)(2)D(3) inhibit DC-dependent T cell activation. Immunomodulation by 1,25(OH)(2)D(3) and its analogs in vivo has been demonstrated in different models of autoimmune diseases and transplantation. Moreover, combining analogs with other immunosuppressants leads to synergism in models of autoimmunity and transplantation. The availability of 1,25(OH)(2)D(3) analogs with immunomodulatory activity at non-hypercalcemic doses may allow exploitation of their immunomodulatory effects in a clinical setting of treatment of autoimmune diseases and prevention of allograft rejection.


Kinetic difference of baicalin in rat blood and cerebral nuclei after intravenous administration of Scutellariae Radix extract.
Scutellariae Radix, the dried root of Scutellaria baicalensis Georgi (Labiatae), was a commonly used traditional Chinese medicine in clinical practice. Baicalin was one of the effective ingredients enriched in Scutellariae Radix. Recent studies revealed baicalin or Scutellariae Radix extract exhibited various pharmacological activities on cerebral functions. In the present study the pharmacokinetic process of baicalin in normal rat blood and cerebral nuclei (cortex, hippocampus, striatum, thalamus and brain stem) was investigated with a newly established reverse-phase HPLC method after intravenous administration of baicalin-enriched Scutellariae Radix extract prepared according to the special protocol. The pharmacokinetic parameters were calculated by the pharmacokinetic program 3P97 and the regulations of baicalin in blood and cerebral nuclei were comparatively analyzed. The results indicated that the distribution of baicalin into brain was a subsequent process and baicalin tends to accumulate in the striatum, thalamus and hippocampus with the exhibition of large area under the concentration-time curve and mean residence time values (p < 0.05). All these pharmacokinetic data of baicalin in blood and cerebral nuclei would be useful to the dosage regime design when baicalin, Scutellariae Radix extract or the prescriptions containing Scutellariae Radix as the main ingredient are prescribed.


Preventable mortality attributable to exposure to air pollution at the rural district of Punjab, India.
Air pollution has emerged as a leading global health risk in recent decades, where its health impacts are primarily focused on urban areas. In India, semi-urban and rural areas are also emerging as air pollution hotspots. As these regions are out of focus, the current study monitored air pollution (PM2.5) at a rural district of Punjab in North India and attempted to study the associated health impacts. Hospital data of outpatient department (OPD), inpatient department (IPD) and all-cause mortality was correlated with change in PM2.5 concentrations. PM2.5 concentrations showed seasonal variations having relatively higher concentrations during post-monsoon and winter seasons. This rise in air pollution (annual average 92 µg/m3) was found to be mainly due to crop residue burning, including local meteorology. In comparison, hospital data shows that hospital visits and admissions were higher during monsoon. This shows that hospital admissions could not be directly linked to air pollution in rural areas as other factors such as short days during winters and self-medication, socio-economic factors and dependency on local unauthorised traditional healers may influence. The application of the AirQ + model for short-term health effects reveals that out of 2582 total deaths, preventable deaths ranging from 246 (WHO guidelines value - 10 µg/m3) to 159 (Indian NAAQS - 40 µg/m3) could be ascribed to air pollution exposure and specifically PM2.5. However, these deaths are avoidable by developing strategies to minimise air pollution in rural areas. Hence, a comprehensive approach is needed to plan air pollution reduction strategies, including urban, semi-urban and rural areas.


Messenger DNA in higher plants.
Evidence is presented that, as in animal and human cells, plant cells can release a newly-synthesized DNA which can freely circulate in the plants. This DNA enters cells and their nuclei where it may be integrated and be expressed so acting, apparently, as a messenger-DNA.


Effectiveness and cost effectiveness of digital hearing aids in patients with tinnitus and hearing loss: a randomised feasibility trial (THE HUSH Trial).
Education and advice is provided for tinnitus management in all UK audiology clinics. Sound therapy, including provision of hearing aids may be offered, but this is often dependent on a clinician's decision rather than UK policy. This inconsistent management reflects a lack of evidence around the effectiveness of hearing aids for tinnitus. This open-label, two-arm multicentre randomised controlled feasibility trial gathered data around recruitment, acceptability and outcome assessments to determine the feasibility of conducting a large randomised controlled trial investigating the effectiveness of hearing aids for tinnitus management. Adults referred to audiology for tinnitus, with an aidable hearing loss were recruited at five UK audiology clinics. They were randomised 1:1 to either education and advice (treatment as usual (TAU), n = 41) or TAU plus hearing aids (n = 42). Outcomes were collected by questionnaires 12 weeks after randomisation. After participation, interviews were conducted with a subset of both participants and clinicians from each trial centre. Eighty three participants from five sites were randomised. Non-aidable hearing loss was the main reason for ineligibility to participate in the trial reported by the sites. Seventy three percent of participants returned the 12-week questionnaires, with return rates by site ranging from 61 to 100%. Fifteen out of 33 participants (45%) reported using hearing aids for the clinician-recommended time, or longer, during the day. The Tinnitus Functional Index (TFI) was the outcome measure most responsive to change. The majority of participants also agreed it was relevant to their tinnitus and hearing loss. Qualitative data demonstrated that the trial was acceptable to participants. Feedback from clinicians revealed a potential lack of equipoise. It also highlighted the differences in referral and treatment pathways between departments and differences in audiometric criteria for fitting hearing aids. Health economic measures were well completed for those returned. No change in health-related quality of life was observed. Costs were higher in the intervention arm, but self-reports of healthcare service use indicated participant confusion in treatment pathways. This feasibility trial is the first step towards obtaining high quality evidence to determine potential clinical effectiveness and cost effectiveness of hearing aids for tinnitus versus usual care. A definitive trial was deemed to be feasible, with some modifications based on feasibility findings and using the TFI as the primary outcome. This trial was funded by the National Institute for Health Research, Research for Patient Benefit Programme (PB-PG-0816-20,014) and registered with ISRCTN (ISRCTN14218416).


Time optimization in primary care - chronic prescription cost.
Time optimization is a common goal to most health information institutions. In several countries, chronic electronic renewal prescriptions were one of the main focuses when implementing information systems. In Portugal, Electronic Medical Prescription (PEM®) software is used for most electronic prescriptions. This study aims to quantify the time spent in chronic prescription renewal appointments (CPRA) in primary care and its impact in the Portuguese National Health System (SNS). Eight general practitioners (GP) were included in the study during February 2022. The average duration of 100 CPRA was obtained. To determine the number of CPRA performed every year, a primary care BI-CSP® platform was used. Using Standard Cost Model and average medical doctor hourly rate in Portugal we estimated CPRA global costs. Each doctor spent on average 1:55 ± 01:07 min per CPRA. There were 8295 GP working in 2022. A total 635 561 CPRA were performed in 2020 and 774 346 in 2021. In 2020, CPRA costs ranged 303 088 ± 179 419€, and in 2021 that number increased to 369 272 ± 218 599€. This is the first study to quantify CPRA's real cost in Portugal. A PEM® software update would allow daily savings, ranging from 830€ (± 491€) in 2020 and 1011€ (± 598€) in 2021. That change could allow hiring 8 ± 5 GP in 2020 and 12 ± 7 in 2021.


Dutch population structure across space, time and GWAS design.
Previous genetic studies have identified local population structure within the Netherlands; however their resolution is limited by use of unlinked markers and absence of external reference data. Here we apply advanced haplotype sharing methods (ChromoPainter/fineSTRUCTURE) to study fine-grained population genetic structure and demographic change across the Netherlands using genome-wide single nucleotide polymorphism data (1,626 individuals) with associated geography (1,422 individuals). We identify 40 haplotypic clusters exhibiting strong north/south variation and fine-scale differentiation within provinces. Clustering is tied to country-wide ancestry gradients from neighbouring lands and to locally restricted gene flow across major Dutch rivers. North-south structure is temporally stable, with west-east differentiation more transient, potentially influenced by migrations during the middle ages. Despite superexponential population growth, regional demographic estimates reveal population crashes contemporaneous with the Black Death. Within Dutch and international data, GWAS incorporating fine-grained haplotypic covariates are less confounded than standard methods.


Determination of threshold conditions for a non-linear stochastic partnership model for heterosexually transmitted diseases with stages.
When comparing the performance of a stochastic model of an epidemic at two points in a parameter space, a threshold is said to have been crossed when at one point an epidemic develops with positive probability; while at the other there is a tendency for an epidemic to become extinct. The approach used to find thresholds in this paper was to embed a system of ordinary non-linear differential equations in a stochastic process, accommodating the formation and dissolution of marital partnerships in a heterosexual population, extra-marital sexual contacts, and diseases such as HIV/AIDS with stages. A symbolic representation of the Jacobian matrix of this system was derived. To determine whether this matrix was stable or non-stable at a particular parameter point, the Jacobian was evaluated at a disease-free equilibrium and its eigenvalues were computed. The stability or non-stability of the matrix was then determined by checking if all real parts of the eigenvalues were negative. By writing software to repeat this process for a selected set of points in the parameter space, it was possible to develop search engines for finding points in the parameter space where thresholds were crossed. The results of a set of Monte Carlo simulation experiments were reported which suggest that, by combining the stochastic and deterministic paradigms within a single formulation, it was possible to obtain more informative interpretations of simulation experiments than if attention were confined solely to either paradigm.


A Supramolecular Injectable Methacryloyl Chitosan-Tricine-Based Hydrogel with 3D Printing Potential for Tissue Engineering Applications.
Printable hydrogels have attracted significant attention as versatile, tunable, and spatiotemporally controlled biomaterials for tissue engineering (TE) applications. Several chitosan-based systems are reported presenting low or no solubility in aqueous solutions at physiological pH. Herein, a novel neutrally charged, biomimetic, injectable, and cytocompatible dual-crosslinked (DC) hydrogel system based on a double functionalized chitosan (CHT) with methacryloyl and tricine moieties (CHTMA-Tricine), completely processable at physiological pH, with promising three-dimensional (3D) printing potential is presented. Tricine, an amino acid typically used in biomedicine, is capable of establishing supramolecular interactions (H-bonds) and is never explored as a hydrogel component for TE. CHTMA-Tricine hydrogels demonstrate significantly greater toughness (ranging from 656.5 ± 82.2 to 1067.5 ± 121.5 kJ m-3 ) compared to CHTMA hydrogels (ranging from 382.4 ± 44.1 to 680.8 ± 104.5 kJ m-3 ), highlighting the contribution of the supramolecular interactions for the overall reinforced 3D structure provided by tricine moieties. Cytocompatibility studies reveal that MC3T3-E1 pre-osteoblasts cells remain viable for 6 days when encapsulated in CHTMA-Tricine constructs, with semi-quantitative analysis showing ≈80% cell viability. This system's interesting viscoelastic properties allow the fabrication of multiple structures, which couple with a straightforward approach, will open doors for the design of advanced chitosan-based biomaterials through 3D bioprinting for TE.


The susceptibility of urokinase to affinity labeling by peptides of arginine chloromethyl ketone.
Pro-Gly-ArgCH2Cl, a reagent corresponding to the C-terminal sequence generated in plasminogen on activation by urokinase (EC 126.96.36.199) and probably by other plasminogen activators, was prepared. Pro-Gly-ArgCH2Cl was effective in the inactivation of urokinase at the 10(-6) M level (Ki 68 micrometers and k2 0.47 min-1). In contrast, only a slow inactivation was obtained by 10(-2) M N-tosyllysine chloromethyl ketone. Glu-Gly-ArgCH2Cl, N,N-dimethylaminonaphthalene-5-sulfonyl-Glu-Gly-ArgCH2Cl, and Ac-Gly-Gly-ArgCH2Cl were more reactive than Pro-Gly-ArgCH2Cl against urokinase by factors of 25, 6, and 3, respectively. The effectiveness of arginine chloromethyl ketones as affinity labels is highly dependent on binding in the S2 and S3 sites, thus sequence variations in the reagents exhibited differences in reactivity of up to four orders of magnitude. The most effective reagents had Gly in P2. Ac-Gly-Gly-ArgCH2Cl inactivates urokinase 50 times more rapidly than it does plasmin, thus providing a means of distinguishing the activity of plasmin from its activating protease whereas urokinase is almost inert to Ala-Phe-LysCH2Cl, a reagent which inactivates plasmin at the 10(-7) M level.


Investigator beliefs and reported success in recruiting minority participants.
Attaining adequate minority participation in clinical trials has been challenging and limited by the lack of data on the role that investigator perceptions play in minority recruitment. We sought to determine what investigator and study factors were associated with investigators' reported success in recruiting minority populations in research. Principal investigators (PIs) who conducted clinical research funded by the National Heart, Lung and Blood Institute in 2001 were surveyed about their success in recruiting minority populations, perceptions about the importance of minority recruitment, use of recruitment strategies, and barriers to minority recruitment. Logistic regression was used to identify factors associated with PIs' reports of success in minority recruitment. A total of 440 PIs completed the survey about minority recruitment. PIs who agreed more strongly about the importance of minority inclusion in their research reported being more successful in minority recruitment. PIs who reported midstream modifications to their recruitment strategies to increase minority participation and those who reported more barriers reported less success in recruiting minority populations. PIs' reports of success in recruiting ethnic/racial minority populations for research are associated with the value investigators place on inclusion of minority participants in their research. PIs' perceptions should be considered in minority recruitment efforts as they may influence minority participation rates.


The two zinc finger-like domains of GATA-1 have different DNA binding specificities.
The GATA-1 transcription factor has been shown to be important in the regulation of globin and non-globin genes in erythroid, megakaryocytic and mast cell lineages. It is a member of a family of GATA proteins which both overlap in their expression patterns and bind the motif (A/T)GATA(A/G). The GATA family of proteins are also members of the superfamily of zinc finger-like domain proteins and have two similar domains of the type Cys-X2-Cys-X17-Cys-X2-Cys which direct the DNA binding of the protein. A random oligonucleotide selection procedure has been employed to further elucidate the mechanism of GATA-1-DNA recognition. The resulting oligonucleotides were tested for binding activity to both wild-type and mutant GATA-1 proteins. Two classes of GATA-1-DNA interaction have been defined, the first requiring only the carboxy finger of GATA-1 to bind and having the motif GAT(A/T), the second requiring both finger domains to bind and having the core motif (T/C)AAG. By using sequence comparison and depurination analysis it is concluded that the two finger-like domains of GATA-1 have different DNA binding recognition motifs. Binding of GATA-1 to GAT(A/T) motifs is associated with transcriptional activation of linked genes. The only known (T/C)AAG motif is in the distal CAAT-box promoter region of the human A gamma-globin gene where the binding of GATA-1 appears to regulate the correct developmental suppression of gamma-globin expression.


Limited-sampling strategy for mycophenolic acid in renal transplant recipients reciving enteric-coated mycophenolate sodium and tacrolimus.
Substantial research has been conducted to develop limited-sampling strategies (LSS) to estimate the area under the curve (AUC(0-12h)) in patients treated with mycophenolate mofetil. However, no LSS has been validated for enteric-coated mycophenolate sodium (EC-MPS). Our aim was to develop an LSS to measure the AUC(0-12h) of mycophenolic acid in kidney recipients treated with tacrolimus and EC-MPS. Thirteen serial blood samples were collected over 12 hours from 71 patients treated with tacrolimus and EC-MPS. Mycophenolic acid was measured in plasma using the enzyme-multiplied immunoassay. LSSs were developed and validated by multiple regression analysis using a 2-group method (test, n = 47; validation, n = 24). The best LSS obtained in the test group were for 3 and 4 time points AUC(0-12h) (mg·h(-1)·L(-1)) = 15.99 + 0.87C1 h + 0.68C2 h + 7.85C4 h and AUC(0-12h) (mg·h(-1)·L(-1)) =11.15 + 0.68C1 h + 0.45C1.5 h + 0.57C2 h + 8.16C4 h, respectively. When these LSS were tested in the validation group, the results were acceptable (adjusted r(2) = 0.71, bias =-0.214 [95% confidence interval (CI): -7.91 to 7.48], precision = 7.48 (95% CI: 3.69-19.39) for 3 time points and adjusted r(2) = 0.76, bias = -1.48 (95% CI: -8.23 to 5.27), precision = 7.68 (95% CI: 4.23-13.50) for 4 time points). : An LSS using time points at C(1h)-C(2h)-C(4h) or C(1h)-C(1.5h)-C(2h)-C(4h) provides the most reliable and accurate estimation of the AUC(0-12h) of mycophenolic acid in stable renal transplant recipients treated with EC-MPS and tacrolimus.


Optimal treatment strategy for recurrent hepatocellular carcinoma based on recurrence time and tumor size: A propensity score matching study.
Recurrent hepatocellular carcinoma (RHCC) is commonly treated with transcatheter arterial chemoembolization (TACE) combined with microwave ablation (MWA) or repeated hepatectomy(RH), but the optimal treatment strategy is still controversial. This study aimed to compare the efficacy and safety of TACE-MWA and RH in RHCC patients after initial radical hepatectomy. A total of 210 RHCC patients were included between June 2014 and January 2021, with 126 patients in the TACE-MWA group and 84 patients in the RH group. The primary endpoints were median repeat recurrence-free survival (rRFS) and overall survival (OS), and the secondary endpoint was complications. Propensity-score matching (PSM) was conducted to minimize bias. Subgroup analysis based on recurrence patterns (recurrence time and tumor size) was performed, and prognostic factors were studied. Before PSM, the RH group had better median OS (37.0 vs 26.0 months, P<0.001) and rRFS (15.0 vs 14.0 months, P = 0.003). After PSM, the RH group also had a better median OS (33.5 vs 29.0 months, P = 0.038), but there was no significant difference in median rRFS between the two groups (14.0 vs 13.0 months, P = 0.099). Subgroup analysis showed that when RHCC diameter>5 cm, RH had a better median OS (33.5 vs 25.0 months, P = 0.013) and rRFS (14.0 vs 10.9 months, P = 0.030). When the RHCC diameter was≤5 cm, there was no significant difference in the median OS (37.0 vs 31.0 months, P = 0.338) and rRFS (15.0 vs 17.0 months, P = 0.758) between the two groups. When RHCC relapses in the early stage (≤2 years), there is no significant difference in the median OS (26.0 vs 26.0 months, P = 0.310) and rRFS (12.0 vs 10.5 months, P = 0.089) between the two groups. When RHCC relapses in the late stage (>2 years), the RH group has better median OS (41.0 vs 33.0 months, P<0.001) and rRFS (30.0 vs 20.0 months, P = 0.010). Individualized therapy is necessary for RHCC. TACE -MWA may be a good choice for RHCC with early recurrence or tumor diameter ≤5 cm. However, RH should be the first choice for RHCC with late recurrence or tumor diameter>5 cm.


The Malat1 long non-coding RNA is upregulated by signalling through the PERK axis of unfolded protein response during flavivirus infection.
Flavivirus infection causes host cell death by initiation of an unfolded protein response (UPR). UPR is initiated following activation of three ER-membrane resident sensors, PERK, IRE1α and ATF6, which are otherwise kept inactive through association with the ER-chaperone GRP78. Activation precedes cellular and molecular changes that act to restore homeostasis but might eventually initiate apoptosis. These changes involve influencing function of multiple genes by either transcriptional or post-transcriptional or post-translational mechanisms. Transcriptional control includes expression of transcription factor cascades, which influence cognate gene expression. Malat1 is a long non-coding RNA which is over-expressed in many human oncogenic tissues and regulates cell cycle and survival. In this report, for the first time we show activation of Malat1 following infection by two flaviviruses, both of which activate the UPR in host cells. The temporal kinetics of expression was restricted to later time points. Further, Malat1 was also activated by pharmacological inducer of UPR, to a similar degree. Using drugs that specifically inhibit or activate the PERK or IRE1α sensors, we demonstrate that signalling through the PERK axis activates this expression, through a transcriptional mechanism. To our knowledge, this is the first report of an UPR pathway regulating the expression of an lncRNA.


The right to a healthy newborn.
A woman's right to health includes her right to a healthy childbirth and newborn, and the baby possesses his or her own right to life as well. While overall child mortality has declined, 4 million newborns still die each year, primarily in the first days of life. Most could be prevented through existing, cost-effective interventions. Field trials and programs show that low-cost, home- or community-based neonatal care can quickly lead to dramatic decline in neonatal mortality. Newborn health should be integrated with maternal and child health-and these programs should be strengthened and expanded-in order to achieve both the child and maternal survival Millennium Development Goals. Policies and programs should include participatory household and community-based care, with links to the formal health system. Despite recent attention to newborn health, much remains to be done to achieve sustained, high coverage of effective interventions, especially in poor communities where most newborns are born and die, mostly in the first week of life.


Auditory gamma oscillations predict global symptomatic outcome in the early stages of psychosis: A longitudinal investigation.
The gamma-band auditory steady-state response (ASSR) is thought to reflect the function of parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and may be a candidate biomarker in early psychosis. Although previous cross-sectional studies have shown that gamma-band ASSR is reduced in early psychosis, whether reduced gamma-band ASSR could be a predictor of the long-term prognosis remains unknown. In this longitudinal study, we investigated the association between gamma-band ASSR reduction and future global symptomatic or functional outcome in early psychosis. We measured 40-Hz ASSR in 34 patients with recent-onset schizophrenia (ROSZ), 28 ultra-high risk (UHR) individuals, and 30 healthy controls (HCs) at baseline. After 1-2 years, we evaluated the global assessment of functioning (GAF) in the ROSZ (N = 20) and UHR (N = 20) groups. The 40-Hz ASSR was significantly reduced in the ROSZ and UHR groups. The attenuated 40-Hz ASSR was correlated with the future global symptomatic outcome in the ROSZ, but not in the UHR groups. A reduction in the gamma-band ASSR after the onset of psychosis may predict symptomatic outcomes in early psychosis. Gamma-band ASSR may be a potentially useful biomarker of the long-term prognosis in patients with recent-onset schizophrenia.


Comparison of the Shear Bond Strength of Resin Modified Glass Ionomer to Enamel in Bur-Prepared or Lased Teeth (Er:YAG).
The purpose of this study was to evaluate the effect of Er:YAG laser on the shear bond strength of resin modified glass ionomer (RMGI) to enamel. Twenty extracted caries-free human premolars were selected. The teeth were embedded in acrylic resin. The buccal surfaces of each sample were ground to plane enamel with carbonated disc. The teeth were randomly divided in two groups. In the first group, the surfaces were treated by Er:YAG laser (350mJ/10Hz). The second group was prepared by carbide bur. Fuji IX RMGI was adhered to surfaces of the samples in both groups in rod shape. The shear bond strength of samples was measured by a universal testing machine. The results of the two groups were analyzed by T- test. The means and standard deviations of shear bond strength of the laser-treated group and the bur-treated group were 6.75 ± 1.99 and 4.41 ± 1.62 Mpa, respectively. There is significant difference in the shear bond strength of RMGI between the two groups (P-value=0.01). The laser group showed better results. Er:YAG laser can be an alternative technology in restorative dentistry.


Restoration of hemodynamics in apnea struggle phase in association with involuntary breathing movements.
Involuntary breathing movements (IBM) that occur in the struggle phase of maximal apneas produce waves of negative intrathoracic pressure. This could augment the venous return, increasing thereby the cardiac output and gas exchange, and release the fresh blood from venous pools of spleen and liver. To test these hypotheses we used photoplethysmography and ultrasound for assessment of hemodynamics and spleen size before, during and after maximal dry apneas at large lung volume in 7 trained divers. During the easy-going phase cardiac output was reduced about 40%, due to reduction in stroke volume and in presence of reduced inferior vena cava venous return, while the spleen contracted for about 60 ml. Towards the end of the struggle phase, in presence of intense IBM, the spleen volume further decreased for about 70 ml, while cardiac output and caval flow almost renormalized. In conclusion, IBM coincide with splenic volume reduction and restoration of hemodynamics, likely facilitating the use of the last oxygen reserves before apnea cessation.


A social score for kwashiorkor: explaining the look in the child's eyes.
Following the observation that many children with kwashiorkor had a deprived look in their eyes, the guardians of 107 children with kwashiorkor and 111 controls were interviewed about their home life, in a survey made at New Mulago Hospital, Kampala, between 1969 and 1972. A child's age, sex and tribe were found to have an influence on the nutritional state, therefore 50 of each group were matched for these variables. Ten significant associations were found which distinguished kwashiorkor patients from the control group. Children with kwashiorkor were more likely to be attended by someone other than the mother; to have changed attendants when ill; to have a pregnant mother; and to have separated parents. Further to these, singletons of split partnerships were at special risk; breast-feeding had stopped; weaning was begun for bad reasons; a child was more often living away from the parents and had been sent away coincident with weaning. The fathers tended to be poor. It is suggested that these 10 factors could be used as a social scoring system in assessing the risk of incipient kwashiorkor.


Retrospective review of carvedilol administration in 38 dogs with preclinical chronic valvular heart disease.
Report the effect of carvedilol administration on clinical and echocardiographic parameters and outcome in dogs with preclinical (ACVIM Stage B) chronic valvular heart disease (CVD). Retrospective case series of 38 client-owned dogs. Demographic, physical examination and diagnostic imaging findings, blood pressure (BP), administration details and outcome were obtained from medical records of dogs receiving carvedilol for preclinical CVD. When possible, additional follow-up information was obtained through telephone interviews with referring veterinarians and owners. Baseline data and follow-up were evaluated. Median and interquartile range (IQR) for age and weight were 8.6 (7.2-10.8) years and 8.5 (7.6-9.6)kg. 14/38 were male; 33/38 were Cavalier King Charles Spaniels; 33/38 had Stage B2 CVD. The initial dose of carvedilol was 0.31 (0.26-0.35)mg/kg PO twice daily. The carvedilol dose achieved following up titration was 1.11 (0.81-1.32)mg/kg twice daily. No adverse effects were recorded during up titration. Median survival for all dogs was 48.5 months with a 95% CI of 38.3-58.6. This study suggests that carvedilol at the dose reported herein is well tolerated in small breed dogs with preclinical CVD. Prospective studies to evaluate efficacy are warranted.


Independent Predictors of Repeat Emergency Room Presentations: Insights from a Cohort of 1066 Consecutive Patients with Non-Cardiac Chest Pain Generating 4770 Repeat Presentations.
Chest pain (CP) is one of the most frequent presentations to the emergency department (ED), a large proportion of which is non-cardiac chest pain (NCCP). Repeat attendances to ED are common and impose considerable burden to overstretched departments. Our aim was to determine drivers for repeat ED presentations using NCCP as the primary cause of index presentation. This was a retrospective cohort study of 1066 consecutive presentations with NCCP to a major urban hospital ED in North England. Index of Multiple Deprivation (IMD), a postcode-derived validated index of deprivation, was computed. Charlson comorbidity index (CCI) was determined by reference to known comorbidity variables. Repeat presentation to ED to any national hospital was determined by a national linked database (population 53.5 million). Independent predictors of ED representation were computed using logistic regression analysis. Median age was 43 (IQR 28-59), and 50.8% were male. Furthermore, 27.8%, 8.1% and 3.8% suffered from chronic obstructive pulmonary disease (COPD), hypertension and diabetes mellitus, respectively. The most frequent diagnoses, using ICD-10 coding, were non-cardiac chest pain (55.1%), followed by respiratory conditions (14.7%). One-year incidence of adjudicated myocardial infarction, urgent or emergency coronary revascularisation and all-cause death was 0.6%, 2% and 5.3%, respectively. There was a total of 4770 ED repeat presentations 1 year prior to or following index presentation with NCCP in this cohort. Independent (multivariate) predictors for frequent re-presentation (defined as ≥2 representations) were a history of COPD (OR [odds ratio] 2.06, p = 0.001), previous MI (OR3.6, p = 0.020) and a Charlson comorbidity index ≥1 (OR 1.51, p = 0.030). The frequency of previous MI was low as only 3% had sustained a previous MI. This analysis indicates that COPD and complex health care needs (represented by high CCI), but not socio-economic deprivation, should be health policy targets for lessening repeat ED presentations. What is already known on this topic: Repeat presentations with non-ischaemic chest pain are common, placing a considerable burden on emergency departments. COPD and complex health care needs, denoted by Charlson comorbidity index, are implicated as drivers for repeat presentation to accident and emergency department. Socio-economic deprivation was not an independent predictor of re-presentation. How might this study affect research, practice, or policy: Community-based support for COPD and complex health care needs may reduce frequency of ED attendance.


The role of bile acids in phalloidin poisoning.
Glycocholate and other bile acids inhibit the response of isolated hepatocytes to phalloidin in a concentration dependent manner. It is suggested that the inhibition is due to a block of phalloidin uptake. This interaction might explain the high specificity of phalloidin for liver tissue.


Design, synthesis and antiproliferative screening of newly synthesized acrylate derivatives as potential anticancer agents.
A new series of acrylic acid and acrylate ester derivatives as modified analogs of tubulin polymerization inhibitors were designed and synthesized. The antiproliferative activity of the constructed molecules was investigated against MCF-7 breast carcinoma cells using CA-4 as positive molecule. Methyl acrylate ester 6e emerged as the most potent cytotoxic agent against MCF-7 cells, with an IC50 value of 2.57 ± 0.16 μM. Also, methyl acrylate ester molecule 6e showed good β-tubulin polymerization inhibition activity. Cellular cycle analysis showed that compound 6e can arrest MCF-7 cells at the G2/M phase. In addition, this compound produced a significant increase in apoptotic power as compared to control untreated MCF-7 cells. Furthermore, the effect of acrylate ester 6e on the gene expression levels of p53, Bax and Bcl-2 was investigated. This molecule increased the expression levels of both p53 and Bax, and decreased the gene expression level of Bcl-2 as compared to control untreated MCF-7 carcinoma cells.


Hemodynamical analysis of MHD two phase blood flow through a curved permeable artery having variable viscosity with heat and mass transfer.
A numerical investigation of MHD blood flow through a stenosed permeable curved artery has been done in this study. Blood flow is considered in two-phases; core and plasma region, respectively. Viscosity of the core region is considered as temperature-dependent, while constant viscosity is considered in plasma region. The governing equations of the proposed two-phase blood flow model are considered in the toroidal coordinate system. The second-order finite difference method is adopted to solve governing equations with [Formula: see text] tolerance in the iteration process. A comparative study of Darcy number (Da) is performed to understand the influence of permeable and impermeable wall conditions. The effect of various physical parameters such as magnetic field (M), viscosity variation parameter ([Formula: see text]), Darcy number (Da), heat source (H) and chemical reaction parameter ([Formula: see text]) is displayed graphically on the flow velocity, temperature, concentration, wall shear stress and frictional resistance profiles. A comparison with published work has also been displayed through the graph to validate the present model, and it is in fair agreement with the existing work. The present study suggested that the curvature and permeability of the arterial wall raise the risk of atherosclerosis formation, while the implication of heat source on the blood flow lower this risk.


[Description of electrocardiographic data in children and adolescents. Apropos of more than 100,000 ECGs].
The authors record the most frequent electrocardiographic anomalies in children and teenagers. The course of the frequency of ectopic rhythms and right focal blocks is studied. Variations in the duration and axis of the electrocardiographic complexes are described in terms of age and sex, and reference figures are presented.


An Implantable Scaffold Allows for Rapid Production of Efficacious CARs.
MASTER-produced CAR T cells are functional with improved expansion and persistence compared to conventional CARs.