In vitro-in vivo correlation of PLGA microspheres: Effect of polymer source variation and temperature.
Development of Level A in vitro-in vivo correlations (IVIVCs) remains challenging for complex long-acting parenterals, such as poly(lactic-co-glycolic acid) PLGA microspheres. The nature of the PLGA polymer excipient has a dominant influence on the performance of PLGA microspheres. These microsphere systems typically exhibit multiphasic in vitro/in vivo release/absorption characteristics and may also show interspecies differences (animal model versus human data). These issues contribute to the difficulties in the development of IVIVCs for PLGA microsphere systems. To gain a better understanding of how to achieve IVIVCs for PLGA microspheres, microsphere formulations with similar as well as different release characteristics were prepared using PLGAs from different sources. Efforts were then made to establish IVIVCs for these formulations using in vitro release profiles obtained at both 37°C (human body temperature) and 39°C (rabbit body temperature) with in vivo data obtained from an animal model (rabbit). Risperidone was selected as the model drug; microsphere formulations were prepared under the same processing methods using apparently similar PLGAs from different sources. Owning to the different physicochemical properties of the PLGAs (such as inherent viscosity, monomer ratio (L/G ratio) and blockiness), the formulations exhibited significant differences in critical quality attributes (such as particle size, particle size distribution, porosity and pore size) and consequently had different in vitro and in vivo performance. IVIVCs were developed and it was shown that model predictability improved when IVIVCs were established using those formulations with comparable release characteristics. In addition, IVIVCs were established with Tscaling factors close to 1 using in vitro release profiles acquired at 39°C, emphasizing the importance of considering the body temperature in understanding interspecies differences. The present work provides a comprehensive understanding of the impact of the PLGA source variation on IVIVC development and predictability for complex long-acting parenterals such as PLGA microspheres.


Three-dimensional biomechanical properties of the human rectum evaluated with magnetic resonance imaging.
A method to evaluate the three-dimensional (3-D) geometry of the human gastrointestinal wall may be valuable for understanding tissue biomechanics, mechano-sensation and function. In this paper we present a magnetic resonance imaging (MRI) based method to determine rectal geometry and validation of data obtained in three volunteers. A specially designed rectal bag was filled in a stepwise manner while MRI and bag pressure were recorded. 3-D models of curvatures, radii of curvature, tension and stress were generated and the circumferential and longitudinal strains were calculated. The computed bag volumes corresponded to the infused volumes. A pronounced bag elongation and decrease in wall thickness was observed during the bag filling. The spatial distributions of the biomechanical parameters were distinctly different between individuals and non-homogeneous throughout the rectal wall due to its complex geometry. The average tension and stress increased as a function of infused volume and circumferential strain. The present study provides a method for characterizing the complex in vivo 3-D geometry of the human rectum. The non-homogenous spatial curvature distribution suggests that simple estimates of tension based on pressure and volume do not reflect the true 3-D biomechanical properties of the rectum.


X-linked creatine transporter defect: an overview.
In 2001 we identified a new inborn error of metabolism caused by a defect in the X-linked creatine transporter SLC6A8 gene mapped at Xq28 (SLC6A8 deficiency, McKusick 300352). An X-linked creatine transporter defect was presumed because of (1) the absence of creatine in the brain as indicated by proton magnetic resonance spectroscopy (MRS); (2) the elevated creatine levels in urine and normal guanidinoacetate levels in plasma, ruling out a creatine biosynthesis defect; (3) the absence of an improvement on creatine supplementation; and (4) the fact that the pedigree suggested an X-linked disease. Our hypothesis was proved by the presence of a hemizygous nonsense mutation in the male index patient and by the impaired creatine uptake by cultured fibroblasts. Currently, at least 7 unrelated families (13 male patients and 13 carriers) with a SLC6A8 deficiency have been identified. Four families come from one metropolitan area. This suggests that SLC6A8 deficiency may have a relatively high incidence. The hallmarks of the disorder are X-linked mental retardation, expressive speech and language delay, epilepsy, developmental delay and autistic behaviour. In approximately 50% of the female carriers, learning disabilities of varying degrees have been noted.


On indications for treatment of the hyperphenylalaninemic neonate.
Of 488 006 neonates tested by Guthrie screening 58 showed values above 2.5 mg/100 ml. Thirty-two showed values between 2.5 mg/100 ml and 15 mg/100 ml. Eighteen of these infants appeared to have phenylketonuria (PKU) and fourteen to have persistent hyperphenylalaninemia (HPA). Neither the initial Guthrie test-value nor the confirmatory test were able to differentiate between these two conditions. Consequently a phenylalanine restricted diet is started in any child with serumphenylalanine values exceeding 10 mh/100 ml (605 micronmol/l). The data show that the course of the dietary tolerance of phenylalanine and a 24-hour phenylalanine load test will differentiate infants with PKU from those with HPA.


Updated systematic review of Australian school-based prevention programmes for alcohol and other drugs: a review protocol.
Adolescent onset substance use is associated with neurodevelopmental, social and psychological harms. Thus, alcohol and other drug prevention programmes are essential to promote health and well-being during this period. Schools are uniquely positioned to deliver such prevention programmes. The last decade has seen a large expansion of school-based alcohol and drug prevention programmes in Australia, warranting an update of the comprehensive review conducted by Teesson et al in 2012. This proposed review aims to (1) identify school-based substance use prevention programmes that have been trialled in Australia since 2011, (2) evaluate their efficacy and (3) identify intervention components associated with effectiveness. This will assist schools in identifying and adopting effective evidence-based programmes and inform future programme development, evaluation and policy. Studies published from 2011 will be identified by searching the electronic databases PubMed, PsycINFO, Medline, Embase, ProQuest and Cochrane Library in addition to grey literature searches. Eligible studies will be controlled trials (including randomised controlled trials, cluster randomised controlled trials and quasi-experimental trials) of programmes measuring drug and alcohol related outcomes that are conducted in a school setting and have been trialled within Australia. Records will be independently screened for eligibility by two review authors, with disagreements being resolved by consensus or a third review author where necessary. Data extraction, risk of bias and study quality will also be completed independently by two review authors. A qualitative synthesis of all eligible studies will be presented. In addition, if there are sufficient data to combine studies, a random-effects meta-analysis will be conducted. This research is exempt from ethics approval as no primary data are collected, with work instead being carried out on published documents. The findings of this proposed review will be disseminated in a peer-reviewed journal and at conferences. CRD42021272959.


Circulating microRNAs in Inflammatory Bowel Diseases.
Inflammatory bowel diseases (IBD) are chronic, idiopathic, polygenic diseases with significant genetic heterogeneity. The two major types of IBD are Crohn's disease (CD) and ulcerative colitis (UlC). It is well known that chronic intestinal inflammation results from the interplay of genetic, immunologic, and environmental factors, so the failure to properly downregulate nonspecific inflammation started by an environmental trigger may lead to the development of IBD. Recent studies indicate several microRNAs (miRNAs) as regulators of important pathways of the immune response and immune cell development, which are crucial to the pathogenesis of a variety of inflammatory diseases, including IBD. Additionally, miRNAs are shown to be crucial regulators of intestinal epithelial barrier function, colonic epithelial cell-derived chemokine expression, and autophagy mechanisms. About 100 miRNAs have been indicated to exhibit altered expression in tissues and blood for UlC and CD, when compared to healthy normal controls. Taking into consideration that to date the diagnosis and follow-up of IBD are performed by invasive colonoscopy, it is well suggested that circulating microRNAs might be promising noninvasive biomarkers for IBD. Therefore, recent studies have focused on comparing miRNAs expression profile in tissue to miRNAs profile in blood, in order to introduce the analysis of circulating microRNAs in the future clinical practice. In this chapter, the role of microRNAs in IBD and the most promising circulating microRNAs will be discussed that could be used as noninvasive biomarkers for IBD diagnosis.


[The role of opiate receptors and ATP-dependent potassium channels of mitochondria in the formation of myocardial adaptive resistance to the arrhythmogenic effect of ischemia and reperfusion].
Preliminary stimulation of opiate receptors (ORs) by intravenous administration of mu agonist DALDA (0.5 mg/kg), delta 1 agonist DPDPE (0.5 mg/kg), and kappa agonist (-)-U-50.488 (1 mg/kg) increases rat myocardial resistance to arrhythmogenic effect of coronary occlusion (10 min) and reperfusion (10 min). Activation of delta 2 ORs (DSLET, 0.5 mg/kg) has no effect on the incidence rate of ischemic and reperfusion arrhythmias. Preliminary administration of glibenclamide (0.3 mg/kg), an inhibitor of KATP channels, blocks the antiarrhythmic effect of DALDA and DPDPE. Repeated short-term exposures of rats to immobilization within two weeks increases the heart tolerance to the arrhythmogenic effect of coronary occlusion and reperfusion. This effect disappears after administration of CTAP (0.5 mg/kg), a mu antagonist, or injection of 5-hydroxydecanoate (5 mg/kg), an inhibitor of mitochondrial KATP channels. The selective antagonists of delta and kappa ORs have no effect on cardiac adaptation-induced resistance to the arrhythmogenic effect of ischemia and reperfusion. We believe that stimulation of mu, delta, and kappa ORs increases myocardial tolerance to the arrhythmogenic effect of ischemia and reperfusion through activation of KATP channels. The antiarrhythmic effect of the adaptation is mediated by stimulation of mu ORs and mitochondrial KATP channels.


[Probiotic associations in the prevention of necrotising enterocolitis and the reduction of late-onset sepsis and neonatal mortality in preterm infants under 1,500g: A systematic review].
Necrotising enterocolitis (NEC) is one of the most common and serious acquired bowel diseases a premature newborn can face. This meta-analysis was performed comparing different probiotic mixtures to ascertain their benefits as a routine tool for preventing necrotising enterocolitis and reducing late-onset sepsis and mortality in premature neonates of less than 1500g. A systematic review of randomised controlled trials, between January 1980 and March 2014, on MEDLINE, the Cochrane Central Register of Controlled Trials, together with EMBASE, was carried out. Studies with infants <1500g or <34 weeks were selected, discarding those with Jadad scores lower than 4. 9 studies were selected for further investigation, pooling a total of 3521 newborns. Probiotics were found to reduce the NEC incidence (RR 0.39; 95%CI: 0.26-0.57) and mortality (RR 0.70; 95%CI: 0.52-0.93), with no difference to placebo regarding late-onset sepsis (RR 0.91; 95%CI: 0.78-1.06). Finally, when analysing the different strands, the use of a 2-probiotic combination (Lactobacillus acidophilus with Bifidobacterium bifidum) proved to be statistically significant in reducing all-cause mortality when compared to other probiotic combinations (RR 0.32; 95%CI: 0.15-0.66, NNT 20; 95%CI: 12-50). Probiotics are a beneficial tool in the prevention of NEC and mortality in preterm neonates. Moreover, the combination of 2 probiotics (Lactobacillus acidophilus with Bifidobacterium bifidum) seems to produce the greatest benefits. However, due to the differences in probiotic components and administration, it would be wise to perform a randomised controlled trial comparing different probiotic mixtures.


[Inhibition of an immune hemolysis reaction in higher vertebrates by a serum fraction (fraction P) from the pregnant Salamandra salamandra L].
Serum "fraction P" from Salamandra pregnant female (containing essentially an alpha 2-macroglobulin) possesses non specific cellular immunosuppressive properties [2]. This fraction has been tested in an immune hemolysis reaction: hemolytic Rabbit IgG + guinea-pig complement + Sheep erythrocytes. This fraction, after incubation with guinea-pig complement, inhibits immune lysis.


Α γ-tubulin complex-dependent pathway suppresses ciliogenesis by promoting cilia disassembly.
The primary cilium, a microtubule-based sensory organelle, undergoes cycles of assembly and disassembly that govern the cell cycle progression critical to cell proliferation and differentiation. Although cilia assembly has been studied extensively, the molecular mechanisms underlying cilia disassembly are less well understood. Here, we uncover a γ-tubulin ring complex (γ-TuRC)-dependent pathway that promotes cilia disassembly and thereby prevents cilia formation. We further demonstrate that Kif2A, a kinesin motor that bears microtubule-depolymerizing activity, is recruited to the cilium basal body in a γ-TuRC-dependent manner. Our mechanistic analyses show that γ-TuRC specifically recruits Kif2A via the GCP2 subunit and its binding partner Mzt2. Hence, despite the long-standing view that γ-TuRC acts mainly as a microtubule template, we illustrate that its functional heterogeneity at the basal body facilitates both microtubule nucleation and Kif2A recruitment-mediated regulation of ciliogenesis, ensuring cell cycle progression.


Genomic prediction based on data from three layer lines: a comparison between linear methods.
The prediction accuracy of several linear genomic prediction models, which have previously been used for within-line genomic prediction, was evaluated for multi-line genomic prediction. Compared to a conventional BLUP (best linear unbiased prediction) model using pedigree data, we evaluated the following genomic prediction models: genome-enabled BLUP (GBLUP), ridge regression BLUP (RRBLUP), principal component analysis followed by ridge regression (RRPCA), BayesC and Bayesian stochastic search variable selection. Prediction accuracy was measured as the correlation between predicted breeding values and observed phenotypes divided by the square root of the heritability. The data used concerned laying hens with phenotypes for number of eggs in the first production period and known genotypes. The hens were from two closely-related brown layer lines (B1 and B2), and a third distantly-related white layer line (W1). Lines had 1004 to 1023 training animals and 238 to 240 validation animals. Training datasets consisted of animals of either single lines, or a combination of two or all three lines, and had 30 508 to 45 974 segregating single nucleotide polymorphisms. Genomic prediction models yielded 0.13 to 0.16 higher accuracies than pedigree-based BLUP. When excluding the line itself from the training dataset, genomic predictions were generally inaccurate. Use of multiple lines marginally improved prediction accuracy for B2 but did not affect or slightly decreased prediction accuracy for B1 and W1. Differences between models were generally small except for RRPCA which gave considerably higher accuracies for B2. Correlations between genomic predictions from different methods were higher than 0.96 for W1 and higher than 0.88 for B1 and B2. The greater differences between methods for B1 and B2 were probably due to the lower accuracy of predictions for B1 (~0.45) and B2 (~0.40) compared to W1 (~0.76). Multi-line genomic prediction did not affect or slightly improved prediction accuracy for closely-related lines. For distantly-related lines, multi-line genomic prediction yielded similar or slightly lower accuracies than single-line genomic prediction. Bayesian variable selection and GBLUP generally gave similar accuracies. Overall, RRPCA yielded the greatest accuracies for two lines, suggesting that using PCA helps to alleviate the "n ≪ p" problem in genomic prediction.


Renal functional and interstitial fibrotic assessment with non-Gaussian diffusion kurtosis imaging.
To evaluate the application value of diffusion kurtosis imaging (DKI) for monitoring renal function and interstitial fibrosis. Forty-two patients suspected of having primary nephropathy, hypertension or diabetes with impaired renal function were examined with DKI. DKI metrics of renal cortex and medulla on both sides of each patient were measured, including mean kurtosis (MK), axial kurtosis (Ka), radial kurtosis (Kr), mean diffusivity (MD) and fractional anisotropy (FA). The differences in DKI metrics between stable and impaired estimated glomerular filtration rate (eGFR) patients as well as between mild and severe interstitial fibrosis patients were compared. Correlations of DKI metrics with clinical indicators and pathology were analyzed. Diagnostic performance of DKI to assess the degree of renal dysfunction was analyzed. Cortical MK, parenchymal Ka, MD and medullary FA were different in stable vs impaired eGFR patients and mild vs severe interstitial fibrosis patients (all p < .05). Negative correlation was found between Ka and eGFR (cortex: r = - 0.579; medulla: r = - 0.603), between MD and interstitial fibrosis (cortex: r = - 0.899; medulla: r = - 0.770), and positive correlation was found between MD and eGFR (cortex: r = 0.411; medulla: r = 0.344), between Ka and interstitial fibrosis (cortex: r = 0.871; medulla: r = 0.844) (all p < .05). DKI combined with mean arterial blood pressure (MAP) and urea showed good diagnostic power for assessing the degree of renal dysfunction (sensitivity: 90.5%; specificity: 89.5%). Noninvasive DKI has certain application value for monitoring renal function and interstitial fibrosis.


The Old Model of Addiction Treatment Must Change.
Thanks to the Affordable Care Act and Mental Health Parity and Addiction Equity Act, more people have access to addiction treatment, and investors are taking notice. But as new players enter this field, we must ensure that they invest in evidence-based treatment.


Estrogen receptor α attenuates therapeutic efficacy of paclitaxel on breast xenograft tumors.
Through transfection of ERα into ERα- breast cancer BCap37 cells, we previously established a pair of isogenic ERα-/ERα+ tumor cell lines BC-V/BC-ER, and demonstrated that ERα induces chemoresistance in vitro. The present study is designed to investigate whether this ERα-mediated chemoresistance also occurs in xenograft models. Meanwhile, we would test whether fulvestrant, a clinically-used antiestrogen agent, can reverse ERα-mediated chemoresistance in vivo. Xenograft models were established through transplantation of BC-ER and BC-V cells into nude mice. Mice were then treated with vehicle, paclitaxel, with or without administration of estrogen (E2). The potential influence of E2/ERα on the therapeutic efficacy of paclitaxel was then evaluated. Furthermore, we investigated whether fulvestrant can sensitize ERα+ tumors to paclitaxel in vivo. Compared with the group treated with PTX alone, co-treatment of E2 significantly reduced the therapeutic efficacy of paclitaxel in BC-ER tumors (51.23 vs. 36.71%, p < 0.01). Biochemical studies demonstrated that E2 significantly interfered with paclitaxel's cytotoxicity in BC-ER tumors. Importantly, we found that fulvestrant significantly repressed ERα expression, potentiated paclitaxel-induced apoptosis and sensitized BC-ER tumors to PTX in the presence of E2 (39.12 vs. 53.64%, p < 0.01). In summary, this study demonstrated that E2/ERα attenuates therapeutic efficacy of paclitaxel in an isogenic ERα+ xenograft model. Furthermore, we demonstrated that fulvestrant significantly reversed the ERα-mediated chemoresistance in vivo. These findings may have potential implications on the clinical practice of antiestrogen and chemotherapeutic agents.


Complete nucleotide sequence of the leader RNA synthesized in vitro by vesicular stomatitis virus.
The complete nucleotide sequence of the leader RNA synthesized in vitro by the Indiana serotype of vesicular stomatitis virus is presented. The sequence was determined by the technique described by Donis-Keller, Maxam and Gilbert (1977) in combination with the standard two-dimensional fingerprint techniques described by Barrell (1971). The leader RNA contains 48 nucleotides variably terminating at the 3' terminus with cytosine (68%) and adenosine at position 47 (32%). Since the leader RNA is complementary to the 3' terminal portion of the viral genome RNA, the first 48 nucleotides from the 3' end of the genome RNA can be decuded. The leader RNA contains repetitive and palindromic sequences with a polypurine sequence at its 3' terminus. The possible role of some of the sequences is discussed.


Conformation-dependent accessibility of Cys-136 and Cys-155 of the mitochondrial rat carnitine/acylcarnitine carrier to membrane-impermeable SH reagents.
During substrate translocation mitochondrial carriers cycle between the cytoplasmic-state (c-state) with substrate-binding site open to the intermembrane space and matrix-state (m-state) with the binding site open to the mitochondrial matrix. Here, the accessibility of Cys-58, Cys-136 and Cys-155 of the rat mitochondrial carnitine/acylcarnitine carrier (CAC) to membrane-impermeable SH reagents was examined as a function of the conformational state. Reconstituted mutant CACs containing the combinations Cys-58/Cys-136, Cys-58/Cys-155, and Cys-136/Cys-155 transport carnitine with a ping-pong mechanism like the wild-type, since increasing substrate concentrations on one side of the membrane decreased the apparent affinity for the substrate on the other side. In view of this mechanism, the effect of SH reagents on the transport activity of mutant CACs was tested by varying the substrate concentration inside or outside the proteoliposomes, keeping the substrate concentration on the opposite side constant. The reagents MTSES, MTSEA and fluorescein-5-maleimide did not affect the carnitine/carnitine exchange activity of the mutant carrier with only Cys-58 in contrast to mutant carriers with Cys-58/Cys-136, Cys-58/Cys-155 or Cys-136/Cys-155. In the latter, the inhibitory effect of the reagents was more pronounced when the intraliposomal carnitine concentration was increased, favouring the m-state of the carrier, whereas the effect was less when the concentration of carnitine was increased in the external compartment of the proteoliposomes, favouring the c-state. Moreover, the mutant carrier proteins with Cys-136/Cys-155, Cys-58/Cys-136 or Cys-58/Cys-155 were more fluorescent when extracted from fluorescein-5-maleimide-treated proteoliposomes containing 15 mM internal carnitine as compared to 2.5 mM. These results are discussed in terms of conformational changes of the carrier occurring during substrate translocation.


Biological vs. physical explanations for the non-random pattern of host occupation by a macroalga attaching to infaunal bivalve molluscs.
On a shallow sand flat at Princess Royal Harbour near Albany, Western Australia, the brown macrophyte Hormosira banksii attaches to shells of infaunal bivalves. Hormosira occupies shells of Katelysia rhytiphora in preference to K. scalarina. We proposed and tested four hypotheses to explain this host occupation pattern. First, by following the fate of nearly one thousand marked clams of each species, we rejected the hypothesis that K. rhytiphora exhibits greater longevity and simply possesses more frequent Hormosira because of a longer temporal integration of settlement events. Second, we rejected the hypothesis that K. rhytiphora exhibits higher densities in the top 5 mm of sediment and accumulates more Hormosira because its shell is more abundant in the depth range occupied by the attaching base of Hormosira. Third, we showed that K. rhytiphora because of its larger size is more difficult to dislodge from the sediments than K. scalarina, supporting the hypothesis that Hormosira is rare on K. scalarina because storm waves selectively dislodge and carry to the beach Hormosira attached to K. scalarina. This physical explanation for the Hormosira occupation pattern gets further support from the observation that a third infaunal bivalve, the mussel Brachidontes erosus, has a far higher frequency of Hormosira occupation than either Katelysia species, while providing a much more robust anchor because of its extensive byssal attachments to neighboring mussels. The sizes of Hormosira plants also vary consistently with this physical transport hypothesis: Hormosira is smallest on K. scalarina and largest on B. erosus. Successful colonization of initially unoccupied Katelysia during five 3-9 month periods was also more frequent on K. rhytiphora than on K. scalarina. This suggests a fourth explanation for the Hormosira distribution pattern: that spore settlement is selective for K. rhytiphora in preference to K. scalarina. Although this hypothesis requires further testing, evolution of selective spore settlement would be reasonable given the different likelihoods of subsequent host dislodgement during storm waves.


In vitro isoprenylation and membrane association of mouse rod photoreceptor cGMP phosphodiesterase alpha and beta subunits expressed in bacteria.
We investigated the specificity of CAAX box-related isoprenylation of rod photoreceptor cGMP phosphodiesterase (PDE) subunits expressed in bacteria and the consequences of this modification on rod disk membrane association. Full-length cDNA sequences of the alpha and beta subunits of mouse PDE, inserted into bacterial pET expression vectors, were overexpressed as fusion proteins containing 28 (bMP-alpha) and 26 (bMP-beta) additional amino acid residues at their N termini. Both fusion proteins were overexpressed and stored in inclusion bodies. Purified bMP-alpha and bMP-beta were recognized by bovine PDE-specific polyclonal antibodies, but did not associate with depleted rod disk membranes and were catalytically inactive. Using bovine brain or retina extracts as sources of protein prenyltransferases and tritiated farnesyl- or geranylgeranylpyrophosphate as donors, bMP-alpha (CAAX sequence CCIQ) was exclusively farnesylated, and bMP-beta (CAAX sequence CCIL) was exclusively geranylgeranylated. After isoprenylation, bMP-alpha and bMP-beta each associated with rod photoreceptor outer segment disk membranes under isotonic, but not under hypotonic, conditions. The results indicate that isoprenylated bMP-alpha and bMP-beta each interact independently with membranes and that isoprenylation is the key modification that facilitates membrane association.


Prostate-specific antigen screening for prostate cancer: benefits for patients with highly aggressive prostate cancer.
The PSA screening for 25 years in America is the biggest cohort study in a field of public health.27 We should realize not only the significance of the early diagnosis and treatment of PCa, but also the dramatic decrease in PCaMR from 2002 to 2008. The data from the IARC were especially noteworthy.Moreover, the patients with highly aggressive PCa, who account for more than 30% of all PCa patients, could only be diagnosed earlier by PSA screening. The patients would thus gain the opportunity for earlier treatment and would have a prolonged, higher quality life-span. However, the complications of interventional treatments, including biopsy,radical prostatectomy and/or radiation therapy,will become more avoidable in the near future.According to the supporting evidence for the decrease in PCa mortality in PSA screening, we strongly hope that the USPSTF changes the 'D' recommendation for PSA screening.


Exogenous estradiol alters gonadal growth and timing of temperature sex determination in gonads of sea turtle.
Temperature sex determining species offer a model for investigating how environmental cues become integrated to the regulation of patterning genes and growth, among bipotential gonads. Manipulation of steroid hormones has revealed the important role of aromatase in the regulation of the estrogen levels involved in temperature-dependent sex determination. Estradiol treatment counteracts the effect of male-promoting temperature, but the resulting ovarian developmental pattern differs from that manifested with the female-promoting temperature. Hypoplastic gonads have been reported among estradiol-treated turtles; however the estradiol effect on gonadal size has not been examined. Here we focused on the sea turtle Lepidochelys olivacea, which develops hypoplastic gonads with estradiol treatment. We studied the effect of estradiol on cell proliferation and on candidate genes involved in ovarian pattern. We found this effect is organ specific, causing a dramatic reduction in gonadal cell proliferation during the temperature-sensitive period. Although the incipient gonads resembled tiny ovaries, remodeling of the medullary cords and down-regulation of testicular factor Sox9 were considerably delayed. Contrastingly, with ovarian promoting temperature as a cue, exogenous estradiol induced the up-regulation of the ovary factor FoxL2, prior to the expression of aromatase. The strong expression of estrogen receptor alpha at the time of treatment suggests that it mediates estradiol effects. Overall results indicate that estradiol levels required for gonadal growth and to establish the female genetic network are delicately regulated by temperature.


Adsorption performance and mechanism in binding of Reactive Red 4 by coke waste.
The protonated coke waste was used as a new type of adsorbent for the removal of Reactive Red 4. To identify the binding sites in the protonated coke waste, the waste was potentiometrically titrated. As a result, four types of functional groups were present in the waste, which was confirmed by FT-IR analysis. Among functional groups, primary amine groups (-NH2) were likely the binding sites for anionic Reactive Red 4. It was also found that sulfonate, carboxyl and phosphonate groups played a role in electrostatic interference with the binding of dye molecules. The maximum adsorption capacities of the coke waste were 70.3+/-11.1 and 24.9+/-1.8 mg/g at pH 1 and 2, respectively. Kinetic study showed a pseudo-first-order rate of adsorption with respect to the solution. The uptake of Reactive Red 4 was not significantly affected by the high concentration of salts. These results of adsorption performance indicate the coke waste as a potentially economical adsorbent for dye removal.


Removal of heavy metal ions from aqueous solution by zeolite synthesized from fly ash.
Zeolite was synthesized from coal fly ash by a fusion method and was used for the removal of heavy metal ions (Pb(2+), Cd(2+), Cu(2+), Ni(2+), and Mn(2+)) in aqueous solutions. Batch method was employed to study the influential parameters such as adsorbent dosage, pH, and coexisting cations. Adsorption isotherms and kinetics studies were carried out in single-heavy and multiheavy metal systems, respectively. The Langmuir isotherm model fitted to the equilibrium data better than the Freundlich model did, and the kinetics of the adsorption were well described by the pseudo-second-order model, except for Cd(2+) and Ni(2+) ions which were fitted for the pseudo-first-order model in the multiheavy metal system. The maximum adsorption capacity and the distribution coefficients exhibited the same sequence for Pb(2+) > Cu(2+) > Cd(2+) > Ni(2+) > Mn(2+) in both single- and multiheavy metal systems. In the end, the adsorption capacity of zeolite was tested using industrial wastewaters and the results demonstrated that zeolite could be used as an alternative adsorbent for the removal of heavy metal ions from industrial wastewater.


A prototype RF dosimeter for independent measurement of the average specific absorption rate (SAR) during MRI.
To develop a scanner-independent dosimeter for measuring the average radio frequency (RF) power deposition and specific absorption rates (SAR) for human MRI exposure. A prototype dosimeter has a transducer with orthogonal conducting loops surrounding a small signal-generating MRI sample. The loops contain resistors whose values are adjusted to load the scanner's MRI coils equivalent to an average head or body during MRI. The scanner adjusts its power output to normal levels during setup, using the MRI sample. Following calibration, the total power and average SAR deposited in the transducer are measured from the root-mean-square (rms) power induced in the transducer during MRI. A 1.5 Tesla head transducer was adjusted to elicit the same load as the average of nine adult volunteers. Once adjusted, the transducer loads other head coils the same as the head does. The dosimeter is calibrated at up to 20 W total deposited power and 4.5 W/kg SAR in the average head, with about 5% accuracy. This dosimeter provides a simple portable means of measuring the power deposited in a body-equivalent sample load, independent of the scanner. Further work will develop SAR dosimetry for the torso and for higher fields.


Atrial fibrillation ablation in heart failure patients: improved systolic function after cryoballoon pulmonary vein isolation.
Atrial fibrillation (AF) and heart failure (HF) are the most common cardiac diseases and often coexist leading to increased mortality and morbidity compared with AF patients without HF. As shown previously, AF ablation using radio frequency (RF) in HF patients leads to a reduction of AF burden, an increase of left ventricular ejection fraction (LVEF) and consequently to reduced hospitalization and mortality. Previous AF ablation studies on HF patients have been liberal about additional targets beyond pulmonary vein isolation (PVI). Thus, the aim of this study was to assess systematically the impact of a straightforward PVI-only strategy on LVEF, NYHA functional class, and cardiovascular hospitalization rate in HF patients. Out of 414 consecutive patients undergoing PVI, only with the cryoballoon 113 patients with reduced LVEF [mean: 38.4 ± 10.8%, reduced ejection fraction (rEF) group] and 301 patients with normal LVEF (>55%) at baseline were identified [normal ejection fraction (nEF) group]. Remarkably, even though freedom from arrhythmia recurrence after 1 year was significantly lower in the rEF group (64.9%) compared with the nEF group (71.2%, P = 0.036), mean LVEF improved from 38.4 ± 10.8% to 52.5 ± 17.2% (P < 0.001) after cryoballoon ablation in the rEF group. Accordingly, HF-related symptoms as well as hospitalization rate declined significantly in the rEF group during follow-up compared with baseline. The results of the present study suggest that catheter ablation restricted to a straightforward PVI-only strategy using the cryoballoon leads to improved left ventricular ejection fraction as well as improvement of NYHA functional class and increased freedom from cardiovascular rehospitalization.


Prognostic factors in metastatic and hormonally unresponsive carcinoma of the prostate.
Eighty-eight patients with hormone-resistant Stage IV prostate cancer were treated with a five-drug chemotherapy program. Patient demographic data, prior therapy, symptoms, extent of disease, and laboratory studies were analyzed statistically to evaluate the association of these parameters with survival from the onset of chemotherapy. Factors associated with short survival included age greater than 65, severe bone pain, poor performance status, presence of soft tissue metastases, anemia, elevation of serum LDH, SGOT, alkaline and acid phosphatases, and prolactin, and hypoalbuminemia. Race, stage at initial diagnosis, prior radiation therapy, prior orchiectomy, and elevation of CEA had no prognostic association. We suggest that clinical trials of new therapies of hormone-resistant prostate cancer take into account the presence of these prognostic factors in the analysis of the results of therapeutic programs.


The effect of nocturnal CPAP therapy on the intraocular pressure of patients with sleep apnea syndrome.
Few studies have documented that nocturnal continuous positive airway pressure (CPAP) therapy is associated with an increase in intraocular pressure (IOP) in patients with severe obstructive sleep apnea syndrome (OSAS). We re-examined the effect of CPAP therapy on the IOP of OSAS patients. The IOP of two different groups of newly diagnosed OSAS patients was compared at their first sleep lab exam without CPAP treatment (non-CPAP treated group; n = 20) and at the second sleep lab exam with CPAP treatment (CPAP treated group; n = 31). The sleep lab exam (sleep period: from 11:00 p.m. until 6:00 a.m.) included IOP measurements, a complete ophthalmologic exam, and nocturnal hemodynamic recordings. The IOP was measured serially using rebound tonometer (IOP; ICARE® PRO) performed while in sitting and supine positions before, during, and after the sleep period. We compared the difference in IOP of CPAP and non-CPAP groups. The mean IOP of the CPAP and non-CPAP groups measured in sitting position before the sleep period was 13.33 ± 2.04 mmHg and 14.02 ± 2.44 mmHg, respectively (p = 0.9). Assuming a supine position for 1 minute significantly increased the IOP by 1.93 mmHg and 2.13 mmHg for both the non-CPAP and CPAP groups (paired t-test; p = 0.02, p = 0.001 respectively), but this IOP rise showed no difference between the two groups. The IOP increased significantly further after 7 hours of sleep in the supine position, and the mean IOP of the CPAP and non-CPAP groups was 19.2 ± 5.68 mmHg and 19.69 ± 5.61 mmHg respectively (independent t-test; p = 0.74). The rise in IOP for both groups was not correlated with any hemodynamic parameters. Three OSAS patients with glaucoma treated with CPAP had mean IOP of 23.75 mmHg after 7 hours of sleep. OSAS patients have a significant rise in IOP during the sleep period when comparing measurements before and after the sleep period; however, CPAP therapy did not affect the measured IOP. The presented findings suggest that in terms of IOP, CPAP is safe for non-glaucomatous patients, but this may not hold true for glaucomatous patients.


Hepatitis B vaccine: prospects for duration of immunity.
The duration of hepatitis B vaccine-induced immunity was studied in a group of 54 seronegative health professionals who received plasma-derived hepatitis B vaccine (Merck's Heptavax) in 1978 and 1979. Five to seven years later, 52 vaccinees received a booster dose of yeast recombinant hepatitis B vaccine (Merck's Recombivax). Of 54 vaccinees, 47 (87 percent) had a favorable anti-HBs response (greater than 10 S/N RIA units) and 7 (13 percent) had low (2.1-10 S/N) or undetectable levels (less than 2.1 S/N) one year after primary immunization. After five to seven years, the anti-HBs values had declined to undetectable levels in 25 percent and to low levels in 23 percent. A booster dose of vaccine induced an anamnestic response in 90 percent of vaccinees by two weeks. The results of this study indicate that persons who respond favorably to primary immunization may be protected for at least seven years.


Infant neurodevelopment and behavior in Guadeloupe after lead exposure and Zika maternal infection during pregnancy.
Prenatal lead exposure is known to have neurotoxic effects on the developing fetus, while some viral infections may have a tropism for the central nervous system. Our objective was to study whether the effects of prenatal lead exposure on infant development and behaviors at 18 months of age are modified by the occurrence of a maternal infection to Zika virus (ZIKV) during pregnancy. During the ZIKV epidemic in Guadeloupe in 2016 a cohort of pregnant women was set up. Blood samples (pregnancy, childbirth and cord) (n = 297) enabled us to measure blood lead levels aimed to determine prenatal lead exposure and the likelihood of maternal infection during pregnancy (ZIKV status + vs -). The 18 months "Ages and Stages Questionnaire" (ASQ) was used to generate scores for global development, fine and gross motor skills, communication, problem solving, and personal-social skills. The questions from a longitudinal cohort study conducted in Canada (Québec) were used to generate hyperactivity, opposition, inattention and physical aggression scores. Associations were tested by multivariate linear regressions. Prenatal lead exposure was associated with delays in neurodevelopment at 18 months, reflected by lower scores in ASQ totals, and in the fine motor and problem-solving domains. Some of these associations appeared to be sex-specific, observed almost exclusively in boys (ASQ total, fine motor and personal-social scores). Prenatal lead exposure was not associated with behavioral scores. ZIKV infection during pregnancy was associated with a lower fine motor ASQ score, and higher scores for hyperactivity, opposition and physical aggression. Significant interaction between prenatal lead exposure and ZIKV status was observed with a lower personal-social score in ZIKV (-) only, and for hyperactivity and inattention scores, though some of these interactions (ASQ personal-social score, inattention score) were no longer significant when children with microcephaly were excluded from the analyses. Our study confirms previous findings of associations between prenatal exposure to lead at low levels and adverse neurodevelopmental outcomes during infancy and the particular vulnerability of boys. It suggests associations between ZIKV infection during pregnancy and adverse effects on a number of neurodevelopmental functions (fine motor function) and behaviors (opposition, hyperactivity), that need to be confirmed at later age. There is no strong evidence of interaction between ZIKV infection and lead exposure but both prenatal risk factors may affect fine motor function.


RB1-Negative Retinal Organoids Display Proliferation of Cone Photoreceptors and Loss of Retinal Differentiation.
Retinoblastoma is a tumor of the eye in children under the age of five caused by biallelic inactivation of the RB1 tumor suppressor gene in maturing retinal cells. Cancer models are essential for understanding tumor development and in preclinical research. Because of the complex organization of the human retina, such models were challenging to develop for retinoblastoma. Here, we present an organoid model based on differentiation of human embryonic stem cells into neural retina after inactivation of RB1 by CRISPR/Cas9 mutagenesis. Wildtype and RB1 heterozygous mutant retinal organoids were indistinguishable with respect to morphology, temporal development of retinal cell types and global mRNA expression. However, loss of pRB resulted in spatially disorganized organoids and aberrant differentiation, indicated by disintegration of organoids beyond day 130 of differentiation and depletion of most retinal cell types. Only cone photoreceptors were abundant and continued to proliferate, supporting these as candidate cells-of-origin for retinoblastoma. Transcriptome analysis of RB1 knockout organoids and primary retinoblastoma revealed gain of a retinoblastoma expression signature in the organoids, characterized by upregulation of RBL1 (p107), MDM2, DEK, SYK and HELLS. In addition, genes related to immune response and extracellular matrix were specifically upregulated in RB1-negative organoids. In vitro retinal organoids therefore display some features associated with retinoblastoma and, so far, represent the only valid human cancer model for the development of this disease.


Feminizing adrenal adenoma in a boy. Case report and literature review.
Feminizing adrenal tumors in young boys are rare; such patients initially show bilateral gynecomastia, and may have signs of virilization. We present a patient with bilateral gynecomastia, left adrenal adenoma, and elevated estrogen levels but normal levels of 17-ketosteroids.


Fracture of the penis with laceration of the urethra.
Two patients are described with severe injury to the penis sustained during sexual intercourse. The literature is reviewed. A conservative approach to management with suprapubic urinary diversion led to acceptable results.


Talc granulomatosis in the rat. Involvement of bone in the acute-phase response.
We investigated the dynamics of the acute-phase response (APR) and osteoblast trabecular surface in rats with subcutaneous inflammation provoked by magnesium silicate (talc). The first visible indicator of the APR was a rapid and profound hypozincemia, paralleled by a decrease in metaphyseal trabecular surfaces covered with osteoblasts in long bones. Both the intensity of serum APR and the decrease in osteoblast trabecular surface were directly proportional to the number of granulomas. Alterations in bone metabolism were specific for the inflammation, whereas mild hypozincemia and decrease in mononuclear and increase in polymorphonuclear peripheral white blood cell fractions developed in animals pair-fed with rats bearing two or four granulomas. Rats with talc granulomatosis had high serum ACTH and corticosterone levels, but neither adrenalectomy nor high doses of hydrocortisone could revert bone alterations in talc-injected animals. Glucocorticoids were necessary for the development of hypozincemia and hypercupremia seen in talc granulomatosis, as well as for normal bone metabolism. Inhibition of prostaglandin synthesis had no effect on bone alterations and serum APR in rats bearing talc-induced granulomas. We conclude that the decrease in bone formation constitutes an important aspect of the host acute-phase response in a rat model of talc granulomatosis.


Arachidonic acid metabolites in carbon tetrachloride-induced liver injury.
The changes in the levels of leukotrienes (LTs) and prostaglandins (PGs) in the liver tissue of rats with carbon tetrachloride (CCl4)-induced liver injury were studied. As a result, after the administration of CCl4, the levels of LTs increased at an early stage while the levels of PGs increased at a later stage. This suggests that LTs may have an adverse effect on liver injury induced by CCl4, and that PGs may not have a direct effect on liver injury. In addition, serum GOT and GPT levels improved with the administration of AA-861, a 5-lipoxygenase inhibitor, while these levels did not change with the administration of indomethacin, a cyclooxygenase inhibitor. These results suggest that arachidonic acid metabolites may play an important role in the induction of liver cell injury.


Esophageal atresia with tracheoesophageal fistula: end-to-end versus end-to-side repair.
Despite early enthusiasm by some authors for the end-to-side repair of esophageal atresia with tracheoesophageal fistula, many have returned to the end-to-end technique. The present study compares the results of these two operative procedures. A retrospective analysis was made of 52 consecutive cases in which primary repair was performed. The patients were divided according to the three preoperative risk groups descibed by Waterston. The mortality for the end-to-end and end-to-side repairs was similar in each of the three risk groups. Similarly, there was no significant differnences in the incidence of anastomotic leak or recanalization of the fistula. However, the rate of anastomotic stricture in the end-to-end group was significantly higher (p less than 0.001) than in the end-to-side group. A description of the end-to-side technique is given, and its advantages are outlined.


Automatic stimulus breaker for electric dental pulp tester using pain response.
The pulp test provides a means of examining the vitality of dental pulp using physical or chemical stimulation. During electrical pulp testing, an electrical current stimulates the intradental nerve, which may be painful and stressful to patients. The study involved measurement of the electromyogram (EMG) from the anterior belly of the digastric muscle, finger movement and voice response during electrical pulp testing. The excessive stimulus time from the onset time of response (EMG, voice and finger movement) to the end of the stimulation was obtained. The results indicated that the responses occurred in the order: EMG, finger and voice. Based on these results, an automatic stimulus shut-off circuit was developed using the above-mentioned responses to stimulus during electric pulp testing. Excessive stimulus time was reduced by prompt switching-off of the pulp tester output, 64 ms on average after the first detected response (EMG). Consequently, excessive stimulus times were reduced by 284 and 152 ms on average for the subject and examiner disconnection, respectively, using the developed automatic shut-off circuit. Therefore it was possible to minimise pain and stress by reducing excessive pulp stimulation.


Androgen binding in the skin of mature male brown trout, Salmo trutta L.
Specific, saturable binding of [3H]testosterone (Kd = 12.5 nM, Nmax = 1.1 pmol mg-1 protein) has been identified in skin cytosol of mature male brown trout. Binding with this affinity and capacity resembles more closely that observed in the plasma of mature male brown trout (Kd = 20.6 nM, Nmax = 6.6 pmol mg-1 protein) than that expected of a specific steroid receptor. However, the fraction of skin cytosol precipitating with 30% ammonium sulphate has a higher affinity for testosterone (Kd = 1.9 nM) and a lower capacity (Nmax = 96.3 fmol mg-1 protein) than does whole cytosol. Furthermore, the high-salt extract of crude skin nuclear pellet binds [3H]testosterone with affinity (Kd = 1.3 nM) and capacity (Nmax = 69.4 fmol mg-1 protein) similar to those of ammonium sulphate-precipitated cytosol. Specific binding in all three fractions of skin is abolished by treatment with proteolytic enzymes and a component of both cytosol and nuclear extract, which binds [3H]testosterone specifically, is retained on DNA-cellulose columns, eluting with high-salt buffer. Specifically bound [3H]testosterone is displaced most efficiently by testosterone. 5 alpha-dihydrotestosterone, estradiol-17 beta, and 11-ketotestosterone also compete but are 5- to 10-fold less potent. Consistent and reproducible binding of [3H]11-ketotestosterone to skin cytosol fractions or nuclear extract could not be demonstrated. It is concluded that testosterone binding with the above characteristics partially fulfills the criteria required of a putative steroid hormone receptor. The results are discussed with reference to the relative roles of testosterone and 11-ketotestosterone during sexual maturation.


Silicone ring tourniquet could be a substitute for a conventional tourniquet in total knee arthroplasty with a longer surgical field: a prospective comparative study in simultaneous total knee arthroplasty.
This study aimed to compare the clinical outcomes of silicon ring tourniquets and conventional pneumatic tourniquets in total knee arthroplasty (TKA). The study compared the operation time, total bleeding amount, length from the tourniquet distal end to the patella superior pole (L_TP), and complications related to the two tourniquet application methods and attempted to determine whether the silicon ring tourniquet has advantages over conventional pneumatic tourniquets. This prospective comparative study included 30 patients who underwent bilateral simultaneous TKA for degenerative osteoarthritis in August to December 2021. All patients underwent TKA on one side with a conventional pneumatic tourniquet, while TKA on the other side with a silicon ring tourniquet. The primary outcomes were the L_TP, operation time, tourniquet time, total bleeding amount, total drainage amount, and postoperative visual analog scale (VAS) score of the tourniquet applied site at 6, 24, and 48 h postoperatively. The secondary outcome was tourniquet-related complications in both groups. L_TP was significantly longer in the silicon ring tourniquet group compared with that in the pneumatic tourniquet group (20.22 ± 2.74 cm versus 15.12 ± 2.40, p < 0.001). No significant difference was found in other results. The tourniquet applied site pain was less in the silicon ring tourniquet group (p = 0.037). Silicon ring tourniquet application resulted in better clinical outcomes than conventional pneumatic tourniquets in TKA. Because we can obtain a wider surgical field using silicon ring tourniquets without complications, silicon ring tourniquets could be a substitute for conventional pneumatic tourniquets in total knee arthroplasty or distal femoral surgeries.


Essential role for TRPM6 in epithelial magnesium transport and body magnesium homeostasis.
Magnesium is an important cofactor for many biological processes such as protein synthesis, nucleic acid stability and neuromuscular excitability. The extracellular magnesium concentration is regulated tightly by the extent of intestinal absorption and renal excretion. Despite their critical role in magnesium handling, the molecular mechanisms mediating transepithelial transport are still not understood completely. Recently, genetic studies in patients with primary hypomagnesaemia and secondary hypocalcaemia (HSH), a combined defect of intestinal magnesium absorption and renal magnesium conservation, have identified "transient receptor potential (melastatin) 6" (TRPM6) as the first component involved directly in epithelial magnesium reabsorption. TRPM7, the closest homologue of TRPM6, has a central role in Mg(2+) uptake in vertebrate cells since TRPM7-deficient cells become Mg(2+) deficient and are not viable. TRPM7 has been characterized functionally as a constitutively active ion channel permeable for a variety of cations including calcium and magnesium and regulated by intracellular concentrations of magnesium and/or magnesium-nucleotide complexes. Both proteins share the unique feature of cation channels fused to serine/threonine kinase domains. This review summarizes recent data that has emerged from molecular genetic, biochemical and electrophysiological studies on these fascinating two new proteins and their involvement in epithelial magnesium transport.


Preliminary experience of magnetic resonance imaging in neurosarcoidosis.
Twelve MR scans performed on seven patients with neurosarcoidosis are presented. The most common abnormalities were ventricular enlargement (four patients) and diffuse periventricular white matter changes (three patients). Infarcts were seen in three patients and mass lesion in one. The lesions were seen in both T1 and T2 weighted images. The results are compared with CT findings. MRI seems to be more sensitive than CT in detecting white matter changes and infarcts. Ventricular enlargement and granulomas were equally well seen with both modalities.


Explaining the interaction of mangiferin with MMP-9 and NF-ƙβ: a computational study.
Mangiferin is a glycosylated xanthone widely distributed in nature, which exhibits wide pharmacological activities, highlighting its anti-cancer properties. Mangiferin interferes with inflammation, lipid, and calcium signaling, which selectively inhibits multiple NFkB target genes as interleukin-6, tumor necrosis factor, plasminogen, and matrix metalloproteinase, among others. In this work, the interactions of this polyphenol with MMP-9 and NF-κβ are characterized by using computational chemistry methods. The results show MMP-9 inhibition by mangiferina is characterized for the interact with the catalytic Zn atom through a penta-coordinate structure. It is also demonstrated through a strong charge transfer established between mangiferin and Zn in the QM/MM study. Concerning the mangiferin/NF-κβ system, the 92.3% of interactions between p50 sub-unity and DNA are maintained with a binding energy of - 8.04 kcal/mol. These findings indicate that mangiferin blocks the p50-p65/DNA interaction resulting in the loss of the functions of this hetero-dimeric member and suggesting inhibition of the cancer progression. Experimental results concerning the anti-cancer properties of mangiferin show that this natural compound can inhibit selectively MMP-9 and NF-ƙβ. Although the anti-tumor properties of mangiferin are well defined, its molecular mechanisms of actions are not described. In this work, a computational study is carried out to characterize the interactions of mangiferin with these molecular targets. The results obtained corroborate the anti-proliferative and anti-apoptotic activity of mangiferin and provide a depiction of its mechanisms of action.


Medicare program; health care infrastructure improvement program; selection criteria of loan program for qualifying hospitals engaged in cancer-related health care. Interim final rule with comment period.
This interim final rule with comment period sets forth the criteria for implementing a loan program for qualifying hospitals engaged in research in the causes, prevention, and treatment of cancer as specified in section 1016 of the Medicare Prescription Drug, Improvement and Modernization Act of 2003 (MMA) (Pub. L. 108-173). Specifically, this rule establishes a loan application process by which qualifying hospitals including specified entities may apply for a loan for the capital costs of health care infrastructure improvement


A review on agro-industrial waste (AIW) derived adsorbents for water and wastewater treatment.
There is a large amount of studies surrounding the usage of agro-industrial waste (AIW) for the adsorptions of organic pollutants (dyes) and inorganic pollutants (heavy metals) in water/wastewater. This method is normally treated as an alternative approach to the conventional water/wastewater treatment. However, there are some increasing interests for investigators to identify novel adsorption materials for pollutants removal. It is particularly noteworthy that most AIW wastes are not currently used at the original state, but modified in a variety of ways to reinforce the porosity and adsorption surface area of the material. Nanostructuring, activation, carbonization, and grafting are some common modification technologies of agricultural waste adsorbents. Besides, the characteristic, preparation and application of adsorbents from various industrial wastes, including natural materials and biosorbents, were summarized. Additionally, the challenges and perspectives for future researches of waste-derived adsorbents were studied. This review provides an important insight on using AIWs as precursor materials for preparing adsorbents in water/wastewater treatment.


Different types of bombesin receptors on neurons in the dorsal raphe nucleus and the rostral hypothalamus in rat brain slices in vitro.
The actions of the peptides bombesin (BN), gastrin releasing peptide (GRP), neuromedin C (NMC), litorin and neuromedin B (NMB) were studied on neurons in slices of rat brain maintained in vitro to determine the BN receptor type present in different brain areas. Intracellular and extracellular recordings were made from hypothalamic neurons on the border of the periventricular nucleus (PVN) and suprachiasmatic nucleus (SCN) and from mesencephalic 5-HT sensitive neurons in the dorsal raphe nucleus. In the region of the brain containing the SCN and PVN, BN and the BN-related peptides excited 31 out of 77 neurons on which they were tested. There was little difference in the potency of the BN-related peptides as excitants of neurons, the EC50 being about 10 nM. The response to the peptides usually lasted between 5 and 15 min with little sign of desensitization. Using NMC, GRP and NMB as agonists, the equilibrium constant for the GRP receptor antagonist [D-Phe6]-BN-(6-13)-ethylamide was approximately 10 nM. The response to the peptides fully recovered on washout of the antagonist. The CCKB/gastrin receptor antagonist CI-988 (1 microM) had no effect on either GRP- or NMC-mediated excitation. In the dorsal nucleus 40 of 75 neurons were sensitive to the BN-related peptides. BN, [Tyr4]-BN, NMB and litorin, were 10-20 times more potent than GRP and NMC. The responses to the BN-related peptides were not blocked by the selective GRP receptor antagonists [D-Phe6]-BN-(6-13)-methylester, [DF5Phe6][D-Ala11]-BN-(6-13)-methylester and [D-Phe6]-BN-(6-13)- ethylamide.(ABSTRACT TRUNCATED AT 250 WORDS)


Metatarsal Transfer Associated with Microsurgical Flap in Exposed Foot Fracture: A Case Report and 10-Year Follow-up.
A 35-year-old female patient presented with an exposed forefoot fracture with bone and dermal loss after a vehicular accident. There was a bone defect at the level of the second toe and the third metatarsal. She was treated by second toe resection and second metatarsal transfer to augment the third metatarsal diaphysis ray (nonvascularized, without any soft-tissue envelope) and a microsurgical forearm flap. As one option among the reconstruction techniques available for a metatarsal segmental defect, metatarsal transfer associated with a fasciocutaneous radial forearm flap proved to be effective in this patient.


Sensory fibers containing vanilloid receptor-1 (VR-1) mediate spinal cord stimulation-induced vasodilation.
Spinal cord stimulation (SCS) is used to improve peripheral blood flow in selected populations of patients with ischemia of the extremities. Previous studies show that antidromic activation of sensory fibers is an important mechanism that contributes to SCS-induced vasodilation. However, the characteristics of sensory fibers involved in vasodilation are not fully known. This study investigated the contribution of vanilloid receptor type 1 (VR-1) containing fibers to SCS-induced vasodilation. A unipolar ball electrode was placed on the left dorsal column at the lumbar 2-3 spinal cord segments (L2-L3) in sodium pentobarbital anesthetized, paralyzed and ventilated rats. Cutaneous blood flows from both ipsilateral (left) and contralateral (right) hind foot pads were recorded with laser Doppler flow perfusion monitors. SCS (50 Hz; 0.2 ms) was applied through the ball electrode at 30%, 60%, 90% and 300% of motor threshold (MT). Resiniferatoxin (RTX), an ultra potent analog of capsaicin and VR-1 receptor agonist, was used to suppress the activities of VR-1 containing sensory fibers. SCS at 30%, 60%, 90% and also at 300% of MT significantly increased cutaneous blood flow in the ipsilateral foot pad compared to that in the contralateral side. RTX (2 microg/kg, i.v.) significantly attenuated SCS-induced vasodilation of the ipsilateral side (P<0.05, n=7) compared with responses prior to RTX administration. A pledget of cotton soaked with RTX (2 microg/ml) placed on L2-L3 spinal cord significantly decreased SCS-induced vasodilation of the ipsilateral side at 30%, 60%, 90% and 300% of MT (P<0.05, n=7) compared with responses prior to RTX administration. Additionally, topical application of a pledget of cotton soaked with RTX (2 microg/ml) on the sciatic nerve at the middle level of the thigh or on the tibial nerve at the lower level of the lower hindlimb also decreased SCS-induced vasodilation (n=5). SCS-induced vasodilation is predominantly mediated via VR-1 containing sensory fibers.


Translational machinery of senegalese sole (Solea senegalensis Kaup) and Atlantic halibut (Hippoglossus hippoglossus L.): comparative sequence analysis of the complete set of 60s ribosomal proteins and their expression.
Ribosomal proteins (RPs) comprise a large set of highly evolutionarily conserved proteins that are often over-represented in complementary DNA libraries. They have become very useful markers in comparative genomics, genome evolution, and phylogenetic studies across taxa. In this study, we report the sequences of the complete set of 60S RPs in Senegalese sole (Solea senegalensis) and Atlantic halibut (Hippoglossus hippoglossus), two commercially important flatfish species. Amino-acid sequence comparisons of the encoded proteins showed a high similarity both between these two flatfish species and with respect to other fish and human counterparts. Expressed sequence tag analysis revealed the existence of paralogous genes for RPL3, RPL7, RPL41, and RPLP2 in Atlantic halibut and RPL13a in Senegalese sole as well as RPL19 and RPL22 in both species. Phylogenetic analysis of paralogs revealed distinct evolutionary histories for each RP in agreement with three rounds of genome duplications and lineage-specific duplications during flatfish evolution. Steady-state transcript levels for RPL19 and RPL22 RPs were quantitated during larval development and in different tissues of sole and halibut using a real-time polymerase chain reaction approach. All paralogs were expressed ubiquitously although at different levels in different tissues. Most RP transcripts increased coordinately after larval first-feeding in both species but decreased progressively during the metamorphic process. In all cases, expression profiles and transcript levels of orthologous genes in Senegalese sole and Atlantic halibut were highly congruent. The genomic resources and knowledge developed in this survey will be useful for the study of Pleuronectiformes evolution.


Manifestation of diabetes mellitus on mouse follicular and pre-embryo development: effect of hyperglycemia per se.
Animal models of diabetes mellitus during pregnancy have repeatedly suggested that maternal hyperglycemia was teratogenic during organogenesis, and thus may contribute to diabetic teratogenesis. However, little attention has been focused on the effects of hyperglycemia on pre-organogenic development. In this report, we examine the effect of hyperglycemia (950 mg glucose/dL) on the development of mouse pre-embryos in vitro. B6C3F1 mice were superovulated with 5 U pregnant mare serum gonadotropin (PMSG) followed by 5 U human chorionic gonadotropin (hCG) 48 hours later. Two cell pre-embryos were recovered 48 hours later, pooled together, and randomly assigned to different treatment groups. Cultures were performed in HAM's F-10 media (Gibco, Long Island, NY) with 0.1% bovine serum albumin (BSA; Sigma, St. Louis, MO) BSA at 37 degrees C in an atmosphere of 5% CO2, 5% O2, and 90% N2 with 15 to 30 embryos per milliliter of culture fluid. Cultures were viewed daily at 24, 48, and 72 hours after culturing, with recording of the development. Compared with control pre-embryos (n = 216), embryos cultured in elevated glucose levels (950 mg/dL) (n = 226) demonstrated marked growth retardation as assessed both by (1) distribution of developmental stages at each observation point (24 hours, P less than .001; 48 hours, P less than .006; 72 hours, P less than .001); and (2) a difference in the average rank sums indicating a delay in maturation (P less than .005). In a second protocol group, pre-embryos were cultured in an equivalent amount of L-glucose; no impairment in development compared with controls was noted.(ABSTRACT TRUNCATED AT 250 WORDS)


Pattern-reversal electroretinograms and high-pass resolution perimetry in suspected or early glaucoma.
Twenty-one patients, age 28 to 78 years, with elevated intraocular pressure (IOP) in one or both eyes, were examined with pattern-reversal electroretinograms (PERG), high-pass resolution perimetry (HRP), and conventional computer-assisted perimetry (CAP). Among the 42 eyes, 33 were hypertensive (IOP greater than or equal to 22 mmHg) and nine were normotensive (IOP less than or equal to 20 mmHg). The optic disc was judged abnormal in 14 of the hypertensive and one of the normotensive eyes. Fourteen abnormal PERGs and 19 abnormal HRPs were observed in the 33 hypertensive eyes. Conventional CAP gave abnormal results in three of the hypertensive eyes. Seven of the nine normotensive eyes were normal in all examinations. HRP was abnormal in one of the normotensive eyes and conventional CAP was abnormal in another. Thus, PERG and HRP showed a high incidence of optic nerve dysfunction in suspected or early glaucoma. These new methods should be clinically useful for diagnosis and management of conditions with increased IOP.


Comparison of reading performance with low add bifocal and extended depth of focus intraocular lenses implanted with mini-monovision.
To evaluate reading performance, preferred reading distance, and spectacle independence in patients implanted with a low add multifocal or an extended depth of focus (EDOF) intraocular lens (IOL) after phacoemulsification. In this prospective study, patients were randomized into two groups: the diffractive multifocal Tecnis + 2.75 D (ZKB00) IOL (Tecnis + 2.75 group; 15 patients) or the EDOF Tecnis Symfony (ZXR00) IOL (Symfony group; 14 patients) for bilateral implantation with mini-monovision. Reading performance parameters (reading acuity [RA], critical print size [CPS], and maximum reading speed [MRS]) were evaluated with MNREAD acuity charts at 40 cm, and preferred reading distances and spectacle independence for near activities were assessed preoperatively and at the postoperative 1st, 3rd, and 6th months. At the postoperative 6th month, binocular logMAR UNVA and DCNVA were significantly better in the Symfony group than in the Tecnis + 2.75 group (UNVA: 0.15 ± 0.07 vs. 0.22 ± 0.08, p = 0.046; DCNVA: 0.21 ± 0.05 vs. 0.28 ± 0.07, p = 0.043; respectively). There was no significant difference in reading performance parameters between the groups; however, the Symfony group preferred significantly closer reading distance than the Tecnis + 2.75 group (42.00 ± 4.67 cm; 45.87 ± 5.32 cm, respectively, p = 0.030). At the postoperative 6th month, 14.3% and 26.7% of patients reported that they needed spectacles, rarely or occasionally, for near activities in the Symfony and Tecnis + 2.75 groups, respectively (p > 0.05). When implanted with mini-monovision, although functional near visual acuity and a high degree of spectacle independence at near distances were achieved with both IOLs, patients implanted with the EDOF IOL preferred closer reading distance than those implanted with the low add diffractive multifocal IOL.


Pre-treatment intravoxel incoherent motion diffusion-weighted imaging predicts treatment outcome in nasopharyngeal carcinoma.
To evaluate whether pre-treatment intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) can predict treatment outcome after 2 years in patients with nasopharyngeal carcinoma (NPC). One hundred and sixty-one patients with newly diagnosed NPC underwent pre-treatment IVIM-DWI. Univariate Cox regression analysis was performed to evaluate the correlation of the mean values of the pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction and apparent diffusion coefficient with local relapse-free survival (LRFS), regional relapse-free survival (RRFS), distant metastases-free survival (DMFS) and disease-free survival (DFS). Significant diffusion parameters, together with staging, age, gender and treatment as confounding factors, were added into a multivariate model. The area under the curves (AUCs) of significant parameters for disease relapse were compared using the Delong test. Disease relapse occurred in 30 % of the patients at a median follow-up time of 52.1 months. The multivariate analysis showed that high D and T-staging were correlated with poor LRFS (p = 0.042 and 0.020, respectively) and poor DFS (p = 0.023 and 0.001, respectively); low D* and high T-staging with poor RRFS (p = 0.020 and 0.033, respectively); and high N-staging with poor DMFS (p = 0.006). D with the optimal threshold of ≥0.68 × 10-3 mm2/s and T-staging showed similar AUCs (AUC = 0.614 and 0.651, respectively; p = 0.493) for predicting disease relapse. High D and low D* were predictors of poor locoregional outcome but none of the diffusion parameters predicted DMFS in NPC.


N-acetylcysteine decreases dopamine transporter availability in the non-lesioned striatum of the 6-OHDA hemiparkinsonian rat.
This study aimed to explore the beneficial effects of the antioxidant N-acetylcysteine (NAC) on the degenerated dopamine system. The short- and long-term regulatory mechanisms of NAC on the 6-OHDA hemiparkinsonian rat model were longitudinally investigated by performing positron emission tomography (PET) imaging using the specific dopamine transporter (DAT) radioligand [18F]FE-PE2I. The results demonstrate that after a unilateral dopamine insult NAC has a strong influence on the non-lesioned hemisphere by decreasing the levels of DAT in the striatum early after the lesion. We interpret this early and short-term decrease of DAT in the healthy striatum of NAC-treated animals as a beneficial compensatory effect induced by NAC.


Environmental noise and health in low-middle-income-countries: A systematic review of epidemiological evidence.
Evidence of the health impacts from environmental noise has largely been drawn from studies in high-income countries, which has then been used to inform development of noise guidelines. It is unclear whether findings in high-income countries can be readily translated into policy contexts in low-middle-income-countries (LMICs). We conducted this systematic review to summarise noise epidemiological studies in LMICs. We conducted a literature search of studies in Medline and Web of Science published during 2009-2021, supplemented with specialist journal hand searches. Screening, data extraction, assessment of risk of bias as well as overall quality and strength of evidence were conducted following established guidelines (e.g. Navigation Guide). 58 studies were identified, 53% of which were from India, China and Bulgaria. Most (92%) were cross-sectional studies. 53% of studies assessed noise exposure based on fixed-site measurements using sound level meters and 17% from propagation-based noise models. Mean noise exposure among all studies ranged from 48 to 120 dB (Leq), with over half of the studies (52%) reporting the mean between 60 and 80 dB. The most studied health outcome was noise annoyance (43% of studies), followed by cardiovascular (17%) and mental health outcomes (17%). Studies generally reported a positive (i.e. adverse) relationship between noise exposure and annoyance. Some limited evidence based on only two studies showing that long-term noise exposure may be associated with higher prevalence of cardiovascular outcomes in adults. Findings on mental health outcomes were inconsistent across the studies. Overall, 4 studies (6%) had "probably low", 18 (31%) had "probably high" and 36 (62%) had "high" risk of bias. Quality of evidence was rated as 'low' for mental health outcomes and 'very low' for all other outcomes. Strength of evidence for each outcome was assessed as 'inadequate', highlighting high-quality epidemiological studies are urgently needed in LMICs to strengthen the evidence base.


Indium-111 platelet scintigraphy and two-dimensional echocardiography for detection of left ventricular thrombus: influence of clot size and age.
Two-dimensional echocardiography and indium-111 platelet scintigraphy were performed on 50 dogs to determine the influence of clot age and size on the detection of experimentally induced left ventricular mural thrombus. Thrombus was induced by apical infarction and injection of a sclerosing agent and thrombin. The animals were classified into four groups according to the time of indium-111 platelet injection after thrombus induction: Group I (17 dogs, 1/2 hour after induction; 3 dogs, before induction), Group II (12 dogs, 24 hours after induction) and Group III (12 dogs, 1 week after induction). In Group IV (six control dogs) apical infarction was produced, but thrombin was not injected; indium-111 platelets were injected 1/2 to 1 hour after infarction. The dogs were studied by indium-111 platelet scintigraphy and by two-dimensional echocardiography 1/2 to 5 hours (Group I) and 1 to 5 and up to 72 hours (Groups II to IV) after platelet administration and before death was induced. Two-dimensional echocardiography showed the best overall sensitivity for detection of acute thrombus (97%; 29 of 30). The sensitivity of indium-111 platelet scintigraphy was 86% (18 of 21) for clots greater than or equal to 0.08 ml in size, and 67% (20 of 30) for detection of all clots. Thrombus did not form in 14 dogs of Groups I to III and in 6 of 6 control dogs. The specificity of scintigraphy was 100% (20 of 20) compared with 80% (16 of 20) for echocardiography. Echocardiography was more sensitive than scintigraphy for detecting very small clots in this experimental model.(ABSTRACT TRUNCATED AT 250 WORDS)


Model construction and application for effluent prediction in wastewater treatment plant: Data processing method optimization and process parameters integration.
Wastewater treatment based on the activated sludge process is complex process, which is easily affected by influent quality, aeration time and other factors, leading to unstable effluent. Facing increasingly stringent sewage discharge standards in China, it is necessary to build a prediction model for early warning of effluent quality. In this study, nine machine learning algorithms were adopted to construct models for the prediction of effluent Chemical Oxygen Demand (COD). In order to improve the prediction accuracy of the models, model optimization was conducted by introducing the hysteresis condition [Hydraulic Retention Time (HRT) of 18 h], data processing method (K-FOLD) and process parameters [dissolved oxygen (DO), sludge return ratio (SRR) and mixed liquid suspended solids (MLSS)]. Results showed that both K-Nearest Neighbour (KNN) and Gradient Boosting Decision Tree (GBDT) displayed excellent prediction effects, the best results of MAPE, RMSE and R2 were 7.34%/1.29/0.92(COD, KNN). The optimized models were further applied to the prediction of effluent total phosphorus (TP), total nitrogen (TN) and pH. The MAPE/RMSE/R2 were 7.43%/0.92/0.93(TN, GBDT), 17.81%/0.19/0.99(TP, KNN), 0.53%/0.16/0.99 (pH, KNN) respectively, indicating high prediction accuracy. The change and comparison of modeling conditions provide a new insight to wastewater prediction models. In addition, this study is close to the actual application scenario of WWTPs operation and management, also laying a foundation for the reverse regulation of energy saving and consumption reduction of wastewater treatment plants (WWTPs).


A novel mutation in the LMNA gene causes congenital muscular dystrophy with dropped head and brain involvement.
We describe a 22-month-old girl with axial muscle and diaphragmatic weakness as well as motor developmental delay without mental retardation. The striking clinical feature was a dropped head, although she could walk unaided. T2/FLAIR brain MRI revealed a focal abnormality with high signal intensity in the white matter including U-fibers. A muscle biopsy showed active necrotic and regenerative processes. These distinct clinical findings prompted a mutational analysis of the lamin A (LMNA) gene, and we identified a novel heterozygous mutation in LMNA (c.1330_1338dup9). This is the first report of an Asian patient with LMNA-related congenital muscular dystrophy (L-CMD) and a dropped head.


Improved diastolic dysfunction is associated with higher forward flow and better prognosis in chronic heart failure.
The benefit of repeat assessment of left ventricular (LV) systolic and diastolic function in heart failure (HF) remains uncertain. We assessed the prognostic value of repeat echocardiographic assessment of LV filling pressure (LVFP) and its interaction with cardiac index (CI) in ambulatory patients with chronic HF and reduced ejection fraction (HFrEF). We enrolled 357 patients (age 68 ± 11 years; 22% female) with chronic HFrEF. Patients underwent a clinical and echocardiographic examination at baseline. LVFP as assessed by the 2016 Guidelines and Doppler-derived CI were estimated. After the second echocardiographic examination, patients were followed for a median time of 30 months. The study endpoint included all-cause death and hospitalization for worsening HF. Patients who normalized LVFP or showed persistently normal LVFP at the follow-up examination had a significantly lower mortality rate than those with worsening or persistently raised LVFP (p < 0.0001). After stratification by CI, patients with elevated LVFP and CI < 2.0 l/min/m2 had a further worse outcome than those with elevated LVFP and CI ≥ 2.0 l/min/m2 (p < 0.0001). Multivariate survival analysis confirmed an independent prognostic impact of changes in LVFP, incremental to that of established clinical, laboratory and echocardiographic predictors. Repeat assessment of LVFP and CI significantly improved risk stratification of chronic HFrEF outpatients compared to baseline evaluation.


Novel probiotic-bound oxidized Bletilla striata polysaccharide-chitosan composite hydrogel.
As a new strategy for wound management, probiotics are highly sensitive to the external environment during use. In this study, an attempt is made to apply oxidized Bletilla striata polysaccharide (OBSP) hydrogel as a delivery system to put up a physical barrier to probiotics. Bletilla striata, as a famous traditional Chinese medicine, has been widely used for over 1500 years to promote wound healing. Firstly, probiotic-bound OBSP-Chitosan composite hydrogel (OBSP-CS-LP hydrogel) was prepared by a simple and environmentally friendly approach. Subsequently, the SEM image, swelling and rheological properties of the OBSP-CS-LP hydrogel were investigated. Notably, composite probiotics to wounds are an attractive novel intervention that significantly improves the antibacterial properties of the hydrogel and avoids the pitfalls of many antibiotic therapies. Furthermore, the full-thickness skin defect model in vivo indicated an outstanding wound healing efficacy. Therefore, OBSP-CS-LP hydrogel could be applied as a promising dressing in the wound healing.


Evaluation and surgery for stress urinary incontinence: A FIGO working group report.
To review available evidence regarding evaluation and treatment of stress urinary incontinence (SUI) and provide recommendations for management of urinary incontinence under specific conditions determined by the International Federation of Gynecology and Obstetrics (FIGO) Working Group. The FIGO Working Group discussed the management of SUI during meetings and assessed the evidence. The search of evidence was performed using MEDLINE® and Cochrane databases as well as additional searches from societies and major organizations for additional guidelines and recommendations and hand searches from bibliographies. Initial searches from 1985 to December 31, 2012 extended until July 15, 2015. After review, recommendations are made based on levels of evidence according to the recommendations from Oxford EBM Center. Initial evaluation of SUI consists of history and physical examination; cough stress test, evaluation for urinary tract infections (UTI), assessment of urethral mobility, and post-void residual volumes (LOE 5). Urodynamic studies are not necessary to evaluate patients with uncomplicated SUI (LOE 1a). Conservative treatment should be tried prior to surgery and more importantly in areas of low resources (LOE 5). Midurethral slings (MUS), pubovaginal (traditional suburethral) slings (PVS), and Burch colposuspension are effective in treating SUI (LOE 1a). Patients with SUI with ISD or UUI appear to have lower cure rates than patients without (LOE 2-4). There are limited data on surgical outcomes under limited resources (LOE 5). MUS, PVS, and Burch colposuspension are effective treatments for SUI. Evidence for recommendations to treat patients in underserved low resource areas is lacking. Neurourol. Urodynam. 36:518-528, 2017. © 2016 Wiley Periodicals, Inc.


Rationale and methods of the Advanced R2Eperfusion STrategies for Refractory Cardiac Arrest (ARREST) trial.
Venoarterial extracorporeal membrane oxygenation has emerged as a prominent therapy for patients with refractory cardiac arrest. However, the optimal time of initiation remains unknown. The aim was to assess the rate of survival to hospital discharge in adult patients with refractory ventricular fibrillation/pulseless ventricular tachycardia out-of-hospital cardiac arrest treated with 1 of 2 local standards of care: (1) early venoarterial extracorporeal membrane oxygenation-facilitated resuscitation for circulatory support and percutaneous coronary intervention, when needed, or (2) standard advanced cardiac life support resuscitation. Phase II, single-center, partially blinded, prospective, intention-to-treat, safety and efficacy clinical trial. Adults (aged 18-75), initial out-of-hospital cardiac arrest rhythm of ventricular fibrillation/pulseless ventricular tachycardia, no ROSC following 3 shocks, body morphology to accommodate a Lund University Cardiac Arrest System automated cardiopulmonary resuscitation device, and transfer time of <30 minutes. Hospital-based. Primary: survival to hospital discharge. Secondary: safety, survival, and functional assessment at hospital discharge and 3 and 6 months, and cost. Assuming success rates of 12% versus 37% in the 2 arms and 90% power, a type 1 error rate of .05, and a 15% rate of withdrawal prior to hospital discharge, the required sample size is N = 174 evaluated patients. The ARREST trial will generate safety/effectiveness data and comparative costs associated with extracorporeal cardiopulmonary resuscitation, informing broader implementation and a definitive Phase III clinical trial.


The impact of prolonged delay to loop ileostomy closure on postoperative morbidity and hospital stay: A retrospective cohort study.
There is increasing evidence that delayed loop ileostomy closure is associated with an increase in postoperative morbidity. In the context of a publicly funded health service with constrained theatre access, we review the impact of delay in loop ileostomy closure. A retrospective cohort study of patients undergoing loop ileostomy closure at the Dunedin Public Hospital between 2000-2017 was performed. Cases and complications were identified from the prospectively maintained Otago Clinical Audit database. Patient demographics, ASA score, indications for ileostomy, reasons for delay in closure, length of stay (LOS) after ileostomy closure and complications were collected. LOS and overall complication rate were assessed using univariable and multivariable analyses. A total of 292 patients were included in the study, of whom 74 (25.3%) were waiting for longer than 12 months for ileostomy closure. The overall complication rate was 21.5%. This was 8% up to 90 days, 20% between 90-360 days, 28% between 360-720 days and 54% after 720 days. Delay was associated with an increased risk of any complication (RR 1.06 for every 30 days with stoma, p < 0.001), including Ileus (OR [95% CI] 1.06 [1.00-1.11], p = 0.024). Overall mean LOS was 5.9 days (range 1-63), being 4.6 days up to 180 days, 5.6 between 180-720 days and 8.7 after 720 days. LOS significantly increased with increasing stoma duration (p = 0.04). Increasing time with loop ileostomy is detrimental for patients, being associated with an increase in complication rates, and is detrimental for hospitals due to increased length of stay. Resources should be allocated for timely closure of loop ileostomies.


Brief cognitive-behavioral therapy for temporomandibular disorder pain: effects on daily electronic outcome and process measures.
We used patient daily electronic ratings of outcome (activity interference, pain intensity, jaw use limitations, negative mood) and process (pain-related beliefs, catastrophizing, and coping) variables to evaluate a brief cognitive-behavioral (CB) treatment for chronic temporomandibular disorder (TMD) pain. TMD clinic patients (N=158) were assigned randomly to four biweekly sessions of either CB pain management training (PMT) or an education/attention control condition [self-care management (SCM)] and were asked to complete electronic interviews three times daily for the 8-week treatment. We analyzed diary data from 126 participants who completed >50% of requested interviews for >6 weeks. Multilevel regression analyses indicated no statistically significant difference between the study groups in rate of within-subject change over time on the daily outcome measures, but consistently greater within-subject improvement in the PMT group on the daily process measures. Significantly (P<0.05) greater proportions of PMT than of SCM patients showed clinically important (>50%) improvement from weeks 1 to 8 in daily activity interference and jaw use limitations. This study is novel in its application of electronic diary methods for assessing outcome and process variables in a chronic pain treatment trial, and supports the feasibility and utility of such methods. The brief CB treatment was efficacious in decreasing catastrophizing and increasing perceived control over pain, and in improving activity interference and jaw use limitations for a subgroup of patients. Longer-term follow-ups are ongoing to determine if there is an impact on outcomes over time.


Cortical neurons express PSI, a novel isoform of phosphacan/RPTPbeta.
Phosphacan is a chondroitin sulfate proteoglycan representing the secreted extracellular part of a transmembrane receptor protein tyrosine phosphatase (RPTP-beta). These isoforms have been implicated in cell-extracellular matrix signaling events associated with myelination, axon growth, and cell migration in the developing central nervous system and may play critical roles in the context of brain pathologies. Recently, we have reported the identification of a new isoform of phosphacan, the phosphacan short isoform (PSI), the expression of which peaks in the second postnatal week. PSI interacts with the neuronal receptors L1 and F3/contactin and can promote neurite growth of cortical neurons. In this study, we have assessed, by in situ hybridization, the expression profile of PSI in the rat brain at postnatal day 7. PSI is largely expressed in the gray matter of the developing cerebral cortex in which it colocalizes with phosphacan, whereas the expression of RPTPbeta receptor forms is restricted to the ventricular area in which PSI has not been observed. Neurons from all layers of the cortex express PSI. In the cerebellum, on the other hand, no expression of PSI has been detected, although the other phosphacan/RPTP-beta isoforms show strong PSI expression here. Overall, our study suggests that PSI is expressed during the postnatal period in differentiated neurons of the cortex but is absent from structures in which proliferation and migration occur. The significance of these observations is discussed in the context of previous models of phosphacan/RPTP-beta functions.


KRAS Mutations Impact Clinical Outcome in Metastatic Non-Small Cell Lung Cancer.
There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PT) and immune checkpoint blockade (ICB). Here, we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC). All consecutive patients molecularly assessed and diagnosed between 2016−2018 with Stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. The primary study outcome was overall survival (OS). Out of 580 Stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.478, 95% CI 1.207−1.709, p < 0.001). When treated with first-line platinum doublet (n = 195), KRASMUT was a negative factor for survival (p = 0.018), with median OS of 9 months vs. KRASWT at 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95% CI 1.124−2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1highKRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significantly (p = 0.006) better outcome than KRASWT patients, with a median OS of 23 vs. 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95% CI 0.148−0.822, p = 0.016). kRAS mutations are associated with better response to treatment with immune checkpoint blockade and worse response to platinum doublet chemotherapy as well as shorter general OS in Stage IV NSCLC.


Success rate of dental implants inserted in horizontal and vertical guided bone regenerated areas: a systematic review.
This study assessed the success rate of implants placed in horizontal and vertical guided bone regenerated areas. A systematic review was carried out of all prospective and retrospective studies, involving at least five consecutively treated patients, that analysed the success rate of implants placed simultaneously or as second surgery following ridge augmentation by means of a guided bone regeneration (GBR) technique. Studies reporting only the survival rate of implants and studies with a post-loading follow up less than 6 months were excluded. From 323 potentially relevant studies, 32 full text publications were screened and 8 were identified as fulfilling the inclusion criteria. The success rate of implants placed in GBR augmented ridges ranged from 61.5% to 100%; all studies, apart from three, reported a success rate higher than 90% (range 90-100%). The data obtained demonstrated that GBR is a predictable technique that allows the placement of implants in atrophic areas. Despite that, studies with well-defined implant success criteria after a longer follow-up are required.


The emergence of fetal behaviour. III. Individual differences and consistencies.
Intra- and inter-fetal consistencies and differences in motor activity were studied in 12 healthy nulliparous women during the first half of gestation. Real-time ultrasound observations, lasting 60 min, were performed weekly from 7 to 15 weeks of gestation and at 17 and 19 weeks. The various types of movements were categorized according to a previously developed classification system. Data on general movements during the second half of gestation were carried out on the same group of women and these results are also included in this study. Intra-individually there appeared to be a relative week-to-week consistency in the amount of total motor activity, i.e. the sum of all the movement patterns. There was a slight tendency of intra-fetal consistency when the incidence of general movements during the first half of gestation was compared to that during the second half. The other movement patterns did not show these consistencies, namely, each fetus showed large fluctuations in the week-to-week incidences. Inter-individually there were large differences in the amount of the different types of movements at the various ages, which resulted in wide ranges. The sum of the rank orders which for total activity and general movements, were found weekly, were compared to those which could be expected to occur in a homogeneous population. Two fetuses appeared to be significantly different from the others on mathematical grounds. One consistently showed a high and one a low motor output. Week-to-week stability in the rank orders of the various movement patterns was studied by adding up a sum score of all the weekly changes in ranks. Three fetuses were found to be stable and three showed large fluctuations. The others were in between these extremes. The ranks of the movements from high to low frequency, appeared to be strictly age dependent, whereby all the fetuses followed the same developmental trend. There were no differences between female and male fetuses in any of the movement patterns.


The variability of polychlorinated biphenyls levels in urban soils from five European cities.
The concentration of PCBs in topsoils from five European cities was assessed and the highest levels were found in Glasgow (Scotland), followed by Torino (Italy), Aveiro (Portugal), Ljubljana (Slovenia) and Uppsala (Sweden). All cities showed the presence of local sources in addition to diffuse contamination from global atmospheric transport. The association of general soil parameters with PCBs in Glasgow and with heavier congeners in Torino and Ljubljana indicates that retention of these compounds is occurring. The profiles obtained resemble Aroclor 1254 and 1260, which are important local sources. Nevertheless, differences in PCB profiles were observed among cities, due to the combined effects of the age of the contamination (which determines the time available for volatilisation and degradation), different sources of PCBs and differences in climate (which influence volatilisation and deposition).


Allogeneic hematopoietic cell transplantation for multiple myeloma: A retrospective analysis of the Polish Myeloma Group.
In this multicenter retrospective analysis of the Polish Myeloma Group we assessed the real-life application of allogeneic transplantations (alloHCT) in multiple myeloma (MM) outside clinical trials in Poland. Anonymized clinical data of patients who underwent alloHCT were retrospectively collected from eight transplant centers and analyzed to identify factors affecting the outcome. Sixty patients (34 males, 26 females) at median age of 45 (22-59) years who received alloHCT between 1993 and 2016 were included. In this group, 16 (27%) patients underwent myeloablative conditioning and 44 (73%) reduced-intensity conditioning alloHCT. Acute graft versus host disease (GvHD) occurred in 27 (45%) patients, while chronic GvHD was diagnosed in 13 (22%) patients. With the median observation time after alloHCT of 10 months, the relapse rate was 38%. Median progression-free survival (PFS) reached 9 months (0-183) while median overall survival (OS) was 23 months (0-183). Main causes of death included disease progression in 16 (43%), infections in 10 (27%), and GvHD in 7 patients (19%). Presence of chronic GvHD was the only factor associated with prolonged PFS (28 vs. 6 months; p = 0.05), however its impact on OS was not statistically significant (73 vs. 8 months; p = 0.09). In this relatively small and heterogeneous study we observed that alloHCT was associated with high risk of severe complications, but resulted in long-term survival in a proportion of patients. Decisions on optimal indications and timing of the alloHCT in MM need to be taken in the broader context of reported outcomes including data from large studies.