Transcriptomic Heterogeneity in Cancer as a Consequence of Dysregulation of the Gene-Gene Interaction Network.
Many pathways are dysregulated in cancer. Dysregulation of the regulatory network results in less control of transcript levels in the cell. Hence, dysregulation is reflected in the heterogeneity of the transcriptome: the more dysregulated the pathway, the more the transcriptomic heterogeneity. We identify four scenarios for a transcriptomic heterogeneity increase (i.e., pathway dysregulation) in cancer: (1) activation of a molecular switch, (2) a structural change in a regulator, (3) a temporal change in a regulator, and (4) weakening of gene-gene interactions. These mechanisms are statistically motivated, explored in silico, and their plausibility to occur in vivo illustrated by means of oncogenomics data of breast cancer studies.


Optimization of prostate biopsy: review of technique and complications.
A 12-core systematic biopsy that incorporates apical and far-lateral cores in the template distribution allows maximal cancer detection and avoidance of a repeat biopsy while minimizing the detection of insignificant prostate cancers. Magnetic resonance imaging-guided prostate biopsy has an evolving role in both initial and repeat prostate biopsy strategies, potentially improving sampling efficiency, increasing the detection of clinically significant cancers, and reducing the detection of insignificant cancers. Hematuria, hematospermia, and rectal bleeding are common complications of prostate needle biopsy, but are generally self-limiting and well tolerated. All men should receive antimicrobial prophylaxis before biopsy.


Discovery of a new Theileria sp. closely related to Theileria annulata in cattle from Sri Lanka.
Theileria annulata is a haemoprotozoan parasite that causes a cancer-like illness known as tropical theileriosis in cattle. In the course of analyzing the genetic diversity of T. annulata in Sri Lanka, we observed that merozoite-piroplasm surface antigen (tams1) and surface protein (tasp)-like gene sequences obtained from bovine blood DNA samples, which were PCR-positive for T. annulata, were conserved but shared low identity with T. annulata GenBank sequences. Moreover, the 18S rRNA sequences from the Sri Lankan samples contained ten unique single-nucleotide polymorphisms compared with all known T. annulata sequences. The cytochrome b (cob) gene sequences isolated from the Sri Lankan samples were highly conserved and shared low identity scores with similarly conserved T. annulata sequences from GenBank. Phylogenetic analysis showed that the Sri Lankan tams1-like, tasp-like, 18S rRNA, and cob sequences clustered together and formed sister clades to the common ancestors of all known T. annulata and Theileria lestoquardi sequences. These findings demonstrated that the Sri Lankan cattle were not infected with T. annulata but with a new Theileria sp. (designated as Theileria sp. Yokoyama) closely related to T. annulata.


[Phosphoenolpyruvate carboxykinase in Calicophoron erschowi (Trematoda: Paramphistomidae)].
The trematode Calicophoron erschowi possesses high active phosphoenolpyruvate carboxykinase. Enzyme activity is concentrated in the cytoplasm. The enzyme has the optimum pH 6.0 and is active in the presence of ions Mn++ and inosine diphosphate. Alanine does not affect its activity. Sulphide oxinide in concentration 1.4-10(-6) M inhibits the activity up to 93%. Some kinetic characteristics are presented.


Two-Second-Annealed 2D/3D Perovskite Films with Graded Energy Funnels and Toughened Heterointerfaces for Efficient and Durable Solar Cells.
The 2D/3D perovskite heterostructures have been widely investigated to enhance the efficiency and stability of perovskite solar cells (PSCs). However, rational manipulation of phase distribution and energy level alignment in such 2D/3D perovskite hybrids are still of great challenge. Herein, we successfully achieved spontaneous phase alignment of 2D/3D perovskite heterostructures by concurrently introducing both 2D perovskite component and organic halide additive. The graded phase distribution of 2D perovskites with different n values and 3D perovskites induced favorable energy band alignment across the perovskite film and boosted the charge transfer at the relevant heterointerfaces. Moreover, the 2D perovskite component also acted as a "band-aid" to simultaneously passivate the defects and release the residual tensile stress of perovskite films. Encouragingly, the blade-coated PSCs based on only ≈2 s in-situ fast annealed 2D/3D perovskite films with favorable energy funnels and toughened heterointerfaces achieved promising efficiencies of 22.5 %, accompanied by extended lifespan. To our knowledge, this is the highest reported efficiency for the PSCs fabricated with energy-saved thermal treatment just within a few seconds, which also outperformed those state-of-the-art annealing-free analogues. Such a two-second-in-situ-annealing technique could save the energy cost by up to 99.6 % during device fabrication, which will grant its low-coast implementation.


A brief motivational intervention for treatment-refusing OCD patients.
Cognitive behavioral therapy involving exposure and response prevention (ERP) is the psychosocial treatment of choice for obsessive-compulsive disorder (OCD). Despite this, ERP is not widely used by mental health practitioners, and so dissemination of ERP and other empirically supported treatment (ESTs) has become a priority. Even so, utilization of ESTs such as ERP remains below 50% even among therapists who self-identify as having a cognitive behavioral orientation. Barriers to the acceptance of ERP include practical obstacles such as lack of training and the cost of treatment, but also patient variables such as treatment refusal. It has been estimated that approximately 25% of OCD patients refuse ERP. This paper describes a brief, 4-session readiness intervention (RI) designed to decrease ERP refusal among patients with OCD. In this study, 12 patients with OCD who had refused ERP were randomized to RI or wait-list (WL). 86% of participants in the RI condition and 20% of participants in WL condition agreed to begin ERP following the 4-week period. ERP following RI, but not WL, was associated with a decrease in OCD symptoms comparable to that observed in OCD patients who did not refuse ERP. However, ERP following RI was associated with a high drop-out rate (50%), a figure that exceeds that typically seen in OCD treatment studies. Techniques to reduce drop-out as well as directions for future research are discussed.


The full-length DNA sequence of Epstein Barr virus from a human gastric carcinoma cell line, SNU-719.
The consistent presence of Epstein-Barr virus (EBV) in malignant cells of EBV-associated gastric carcinoma (EBVaGC) suggests it plays an important role during the development of EBVaGC. However, the entire genomic sequence of EBV from EBVaGC has yet to be determined. This study first determined, annotated, and analyzed the full genomic sequence of EBV from the naturally infected gastric carcinoma cell line SNU-719 using next-generation sequencing and comparative analyses. In consistent with the notion that EBV sequence isolates better reflect their geographic area than tissue origin, the SNU-719 EBV (named as GC1) was categorized as an East Asian type I EBV. Compared with the prototype B95.8 sequence, SNU-719 EBV contained 1372 variations, with 937 and 435 within coding and non-coding regions, respectively. Of the 937 variations, 465 were non-synonymous changes, while 472 synonymous changes included partial internal deletions in the coding regions of LMP1 and gp350. The RNAseq transcriptome revealed that multiple BART transcripts comprised the majority of EBV RNA reads. The SNU-719 EBV expressed high levels of BART, LF3, BHLF1, and BNLF2. Evidence of RNA editing at multiple sites in the host chromosome was found; however, no evidence of genome integration was seen. The annotated SNU-719 EBV sequence will be a useful reference in future EBVaGC studies.


Cell-type specific expression of p11 controls cocaine reward.
The high rate of comorbidity between depression and cocaine addiction suggests shared molecular mechanisms and anatomical pathways. Limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders, yet how different cell types within these structures contribute to the pathogenesis remains elusive. Downregulation of p11 (S100A10), specifically in the NAc, elicits depressive-like behaviors in mice, but its role in drug addiction is unknown. We combined mouse genetics and viral strategies to determine how the titration of p11 levels within the entire NAc affects the rewarding actions of cocaine on behavior (six to eight mice per group) and molecular correlates (three experiments, five to eight mice per group). Finally, the manipulation of p11 expression in distinct NAc dopaminoceptive neuronal subsets distinguished cell-type specific effects of p11 on cocaine reward (five to eight mice per group). We demonstrated that p11 knockout mice have enhanced cocaine conditioned place preference, which is reproduced by the focal downregulation of p11 in the NAc of wild-type mice. In wild-type mice, cocaine reduced p11 expression in the NAc, while p11 overexpression exclusively in the NAc reduced cocaine conditioned place preference. Finally, we identified dopamine receptor-1 expressing medium spiny neurons as key mediators of the effects of p11 on cocaine reward. Our data provide evidence that disruption of p11 homeostasis in the NAc, particularly in dopamine receptor-1 expressing medium spiny neurons, may underlie pathophysiological mechanisms of cocaine rewarding action. Treatments to counter maladaptation of p11 levels may provide novel therapeutic opportunities for cocaine addiction.


Nogo-B promotes angiogenesis and improves cardiac repair after myocardial infarction via activating Notch1 signaling.
Nogo-B (Reticulon 4B) is reportedly a regulator of angiogenesis during the development and progression of cancer. However, whether Nogo-B regulates angiogenesis and post-myocardial infarction (MI) cardiac repair remains elusive. In the present study, we aimed to explore the role and underlying mechanisms of Nogo-B in cardiac repair during MI. We observed an increased expression level of Nogo-B in the heart of mouse MI models, as well as in isolated cardiac microvascular endothelial cells (CMECs). Moreover, Nogo-B was significantly upregulated in CMECs exposed to oxygen-glucose deprivation (OGD). Nogo-B overexpression in the endothelium via cardiotropic adeno-associated virus serotype 9 (AAV9) with the mouse endothelial-specific promoter Tie2 improved heart function, reduced scar size, and increased angiogenesis. RNA-seq data indicated that Notch signaling is a deregulated pathway in isolated CMECs along the border zone of the infarct with Nogo-B overexpression. Mechanistically, Nogo-B activated Notch1 signaling and upregulated Hes1 in the MI hearts. Inhibition of Notch signaling using a specific siRNA and γ-secretase inhibitor abolished the promotive effects of Nogo-B overexpression on network formation and migration of isolated cardiac microvascular endothelial cells (CMECs). Furthermore, endothelial Notch1 heterozygous deletion inhibited Nogo-B-induced cardioprotection and angiogenesis in the MI model. Collectively, this study demonstrates that Nogo-B is a positive regulator of angiogenesis by activating the Notch signaling pathway, suggesting that Nogo-B is a novel molecular target for ischemic disease.


A remote monitoring-enabled home exercise prescription for patients with interstitial lung disease at risk for exercise-induced desaturation.
Alternatives to center-based pulmonary rehabilitation are needed to improve patient access to this important therapy. A critical challenge to overcome is how to maximize safety of unsupervised exercise for at-risk patients. We investigated if a novel remote monitoring-enabled mobile health (mHealth) program is safe, feasible, and effective for patients who experience exercise-induced hemoglobin desaturation. An interstitial lung disease (ILD) commonly associated with pronounced exercise desaturation was investigated - the rare, female-predominant ILD lymphangioleiomyomatosis (LAM). Over a 12-week program, hemoglobin saturation (SpO2) was continuously recorded during all home exercise sessions. Intervention effects were assessed with 6-min walk test (6MWT), maximal cardiopulmonary exercise test (CPET), lower extremity computerized dynamometry, pulmonary function tests, and health-related quality of life (QoL) surveys. Safety was assessed by blood biomarkers of systemic inflammation and cardiac wall stress, and incidence of adverse events. Fifteen LAM patients enrolled and 14 completed the intervention, with high adherence to aerobic (87 ± 15%) and strength (87 ± 12%) training components. An innovative characterization of exercise training SpO2 revealed that while mild-to-moderate desaturation was common during home workouts, participants were able to self-adjust exercise intensity and supplemental oxygen levels to maintain recommended exercise parameters. Significant improvements included 6MWT distance (+36 ± 34 m, p = 0.003), CPET time (p = 0.04), muscular endurance (p = 0.008), QoL (p = 0.009 to 0.03), and fatigue (p = 0.001 to 0.03). Patient acceptability and satisfaction indicators were high, blood biomarkers remained stable (p > 0.05), and no study-related adverse events occurred. A remote monitoring-enabled home exercise program is a safe, feasible, and effective approach even for patients who experience exercise desaturation.


Attempted suicide with pilocarpine eyedrops.
To alert ophthalmologists about the hazards of poisoning with ophthalmic solutions. We treated an 18-year-old man who attempted suicide by drinking and self-injecting pilocarpine eyedrops. He had severe signs of parasympathomimetic poisoning. Because of heavy and repeated vomiting and the early administration of intravenous atropine, he fully recovered. Because they are usually stored in household refrigerators and are readily accessible, the potential hazard of poisoning with ophthalmic solutions is worth emphasizing.


Fear of the unknown as a mechanism of the inverse relation between life meaning and psychological distress.
Although there is accumulating evidence for an inverse relation between life meaning and psychological distress, little is known about the mechanisms of this relation. Using cross-sectional, observational methods, this research examined fear of uncertainty as one potential mechanism. Study 1 (N = 141) was completed with a convenience sample, a unidimensional measure of life meaning, and general measures of anxiety and depression. Study 2 (N = 152) was completed with a sample prescreened for anxiety, a multidimensional measure of life meaning, and clinical measures of anxiety and depression. The results from both studies generally showed an inverse relation between life meaning and psychological distress. Study 2 further indicated that these relations were stronger for the meaning subscale of perceiving life as coherent/comprehensible than the subscales assessing whether participants' lives are perceived as purposeful or significant. Mediation analyses in both studies showed indirect effects of life meaning on psychological distress through fear of uncertainty. These findings support and extend previous research by showing that (i) meaning-as-comprehension may be particularly important in regards to psychological distress, and (ii) fear of uncertainty may mediate the inverse relation between meaning and measures of anxiety and depression.


Genetic Dissection of the Signaling Cascade that Controls Activation of the Shigella Type III Secretion System from the Needle Tip.
Many Gram-negative bacterial pathogens use type III secretion systems (T3SSs) for virulence. The Shigella T3SS consists of a hollow needle, made of MxiH and protruding from the bacterial surface, anchored in both bacterial membranes by multimeric protein rings. Atop the needle lies the tip complex (TC), formed by IpaD and IpaB. Upon physical contact with eukaryotic host cells, T3S is initiated leading to formation of a pore in the eukaryotic cell membrane, which is made of IpaB and IpaC. Through the needle and pore channels, further bacterial proteins are translocated inside the host cell to meditate its invasion. IpaD and the needle are implicated in transduction of the host cell-sensing signal to the T3S apparatus. Furthermore, the sensing-competent TC seems formed of 4 IpaDs topped by 1 IpaB. However, nothing further is known about the activation process. To investigate IpaB's role during T3SS activation, we isolated secretion-deregulated IpaB mutants using random mutagenesis and a genetic screen. We found ipaB point mutations in leading to defects in secretion activation, which sometimes diminished pore insertion and host cell invasion. We also demonstrated IpaB communicates intramolecularly and intermolecularly with IpaD and MxiH within the TC because mutations affecting these interactions impair signal transduction.


Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice.
Fragile X syndrome (FXS) is the most common single gene (FMR1) disorder affecting cognitive and behavioral function in humans. This syndrome is characterized by a cluster of abnormalities including lower IQ, attention deficits, impairments in adaptive behavior and increased incidence of autism. Here, we show that young males with FXS have profound deficits in prepulse inhibition (PPI), a basic marker of sensorimotor gating that has been extensively studied in rodents. Importantly, the magnitude of the PPI impairments in the fragile X children predicted the severity of their IQ, attention, adaptive behavior and autistic phenotypes. Additionally, these measures were highly correlated with each other, suggesting that a shared mechanism underlies this complex phenotypic cluster. Studies in Fmr1-knockout mice also revealed sensorimotor gating and learning abnormalities. However, PPI and learning were enhanced rather than reduced in the mutants. Therefore, these data show that mutations of the FMR1 gene impact equivalent processes in both humans and mice. However, since these phenotypic changes are opposite in direction, they also suggest that murine compensatory mechanisms following loss of FMR1 function differ from those in humans.


Sleep apnea: a proinflammatory disorder that coaggregates with obesity.
Both obesity and sleep apnea are prevalent health conditions that frequently coaggregate. Obesity-associated inflammation may influence asthma control; the relation of sleep apnea to asthma or allergic rhinitis may be bidirectional. Both obesity and sleep apnea are associated with augmented levels of inflammation and oxidative stress, and it is biologically plausible that the proinflammatory effects of one disorder influence the expression of the other disorder. This article elucidates mechanistic associations among obesity, sleep apnea, and systemic inflammation; highlights interrelationships between these factors with cardiopulmonary disease; and identifies specific areas for future research directions.


First molecular evidence of Coxiella burnetii infecting ticks in Cuba.
Coxiella burnetii is the causative agent of Q fever. In order to explore the occurrence of C. burnetii in ticks, samples were collected from horses, dogs and humans living in a Cuban occidental community. The species most commonly recovered were Amblyomma mixtum (67%), Rhipicephalus sanguineus s.l. (27%) and Dermacentor nitens (6%). Specific IS1111 PCR and amplicon sequencing allowed the identification of C. burnetii DNA in A. mixtum collected from a domestic horse. These findings, for first time in Cuba, indicate the need for an in-depth assessment of the C. burnetii occurrence in hosts and humans at risk of infection.


Ameliorative Effects of a Static Magnetic Field on Hyssop (Hyssopus officinalis L.) Growth and Phytochemical Traits Under Water Stress.
The present study was carried out in order to evaluate the promoting effect of a static magnetic field (SMF) on drought tolerance and medicinal properties in Hyssopus officinalis. In the current work, the effect of seed priming with SMF (45, 90, 200, and 250 mT for 5 min) was investigated in 60-day-old hyssop (H. officinalis) plants that were irrigated every 8 days. The assessments consisted of total dry mass, membrane integrity, photosynthetic pigment concentrations, polyphenol content, antioxidant enzyme activities, and antioxidant capacity. Compared with exclusively water stress, magnetopriming, particularly at 200 mT, significantly altered these parameters in the grown plants. At this intensity, the level of total dry mass, total chlorophyll, and polyphenol content increased by 94%, 2.5- and 7.7-fold, respectively. Also, the level of electrolyte leakage and malondialdehyde decreased by 35% and 33%. The reducing power, DPPH (1,1-diphenyl-2-picrylhydrozyl), and superoxide anion-scavenging activities were highly augmented as well. Magnetopriming at 200 mT increased catalase (+92%) and ascorbate peroxidase (+2.3-fold) activities. However, the highest activity of guaiacol peroxidase was recorded at 90 mT. Generally, the present study illustrated the positive effect of magnetopriming (200 mT) on improvement of drought tolerance in H. officinalis through protection of cellular membrane integrity, maintenance of photosynthetic pigment content, and alternation of antioxidant enzyme activities. Furthermore, the data showed this treatment (200 mT) not only had no negative effect on medicinal properties of H. officinalis, but also improved it via increasing total phenolic content and antioxidant capacity. Bioelectromagnetics. 2020;41:403-412. © 2020 Bioelectromagnetics Society.


Anti-idiotypic antibodies specific for a pathologic anti-Pr2 cold agglutinin.
The heterogeneity of human red cell (RBC) autoantibodies may be assessed by using anti-idiotypic antibodies. In this study, mouse monoclonal anti-idiotypic antibodies were produced against a pathologic RBC autoantibody with anti-Pr2 specificity. Epstein-Barr virus-transformed B-cell clones were established from a patient who had splenic lymphoma and associated immune hemolysis due to an anti-Pr2 cold autoantibody. Two of the eight clones producing this autoantibody were used to immunize mice for the establishment of hybridomas, and four monoclonal anti-idiotypic antibodies were isolated (2 IgG1 kappa and 2 IgM kappa). By the use of these anti-idiotypic antibodies, strong crossreactivity was seen on enzyme-linked immunosorbent assay with other anti-Pr2-producing clones from the same patient, but no cross-reactivity was seen with RBC autoantibodies from other individuals having anti-Pr or different specificities. Each of the anti-idiotypic antibodies inhibited hemagglutination (HA) by the patient's anti-Pr2 but failed to inhibit HA by antisera of a different RBC specificity. Cross-competition experiments indicated that all of the anti-idiotypic antibodies may recognize the same or a closely related idiotope on the anti-Pr2 autoantibody. These studies suggested that the four anti-idiotypic antibodies are directed against the same (or closely related) idiotypic determinant(s), unique to this patient's anti-Pr2 and located at or near the antigen-binding site. These anti-idiotypic antibodies may be useful tools for the study of this autoimmune response or for the development of immune therapeutic agents.(ABSTRACT TRUNCATED AT 250 WORDS)


Association between the C3435T polymorphism of ABCB1/MDR1 gene (rs1045642) and colorectal cancer susceptibility : a meta-analysis based on 11,339 subjects.
The association between ABCB1/MDR1 C3435T polymorphism and colorectal cancer has been evaluated. However, the results of these studies on the association remain inconsistent. To derive a more precise estimation of the relationship, a meta-analysis was performed. A comprehensive search was conducted to identify the eligible studies of ABCB1/MDR1 C3435T polymorphism and colorectal cancer risk. Summary odds ratios (OR) and 95 % confidence interval (CI) for ABCB1/MDR1 C3435T polymorphism and colorectal cancer were calculated. Statistical analysis was performed with the Stata (Version 12.0). Thirteen case-control studies, a total of 11,339 persons including 5,485 cases and 5,854 controls, met the included criteria and thus were selected. Collectively, the results of the present study suggest that there were no significant associations of ABCB1/MDR1 C3435T polymorphism with colorectal cancer observed for all comparison models. In the subgroup analysis, the same results were detected for both Caucasian and Asian populations. The results of this meta-analysis suggest that ABCB1/MDR1 C3435T polymorphism might be not related to colorectal cancer susceptibility.


Randomised trial of amnioinfusion during labour with meconium stained amniotic fluid.
To assess the effect of amnioinfusion during labour with meconium stained amniotic fluid on caesarean section rate and perinatal outcome. Prospective randomised controlled study. A tertiary care teaching hospital in India. Women in labour at term with meconium stained amniotic fluid. Two hundred women in labour with > or = 37 weeks gestation, single cephalic presentation with moderate or thick meconium were randomised to control and amnioinfusion groups at a 1:1 ratio. Amnioinfusion was performed using 500 mL of normal saline over a period of 30 minutes in a study group. The control group received routine care. Both groups had intermittent auscultation of fetal heart rate during labour. The primary outcome measure was caesarean section rate. Secondary outcome measures were meconium aspiration syndrome, 1 minute and 5 minute apgar < 7, hypoxic ischaemic encephalopathy, neonatal intensive care unit admission, meconium at the level of vocal cords. The caesarean section rate in the amnioinfusion group was less than the control group (RR 0.47; 95% CI 0.24-0.93). Amnioinfusion was associated with a significant decrease in the incidence of meconium at the vocal cords (P = 0.001); improvement in 1 minute apgar scores (P < 0.05), respiratory distress (P = 0.002) and fewer admissions to nursery compared with the controls. This sample size was inadequate to study the impact on meconium aspiration syndrome. Amnioinfusion in an under resourced labour ward decreases caesarean section rates and fetal morbidity.


Silencing of the metastasis-linked gene, AEG-1, using siRNA-loaded cholamine surface-modified gelatin nanoparticles in the breast carcinoma cell line MCF-7.
Cholamine surface-modified gelatin nanoparticles prepared by the double desolvation method using acetone as a dehydrating agent were selected and potentially evaluated as non viral vectors of siRNA targeting a metastatic gene AEG-1 in MCF-7 breast carcinoma cells. The ability of modified gelatin nanoparticle to complex and deliver siRNA for gene silencing was investigated. Hence, Particle size, surface charge (zeta potential) and morphology of siRNA/Gelatin nanoparticles (siGNPs) were characterized via dynamic light scattering (DLS), scanning electron microscopy (SEM) and transmission electron microscope (TEM). Moreover, the nanoparticles cytotoxicity, loading efficiency and interaction with MCF-7 human breast carcinoma cells were evaluated. Cationized GNPs of mean size range of 174nm and PDI of 0.101 were produced. The loading efficiency of siGNPs at a Nitrogen/Phosphate (N/P) ratio (w/w) of 200:1 was approximately 96%. Cellular uptake was evaluated after FITC conjugation where the particles produced high transfection efficiency. Finally, ELISA analysis of AEG-1/MTDH expression demonstrated the gene silencing effect of siGNPs, as more than 75% MTDH protein were inhibited. Our data indicate that cholamine modified GNPs pose a promising non-viral siRNA carrier for altering gene expression in MCF-7 breast cancer cells with many advantages such as relatively high gene transfection efficiency and efficient silencing ability.


TTD consensus document on the diagnosis and management of exocrine pancreatic cancer.
Exocrine pancreatic cancer (PC) is a very aggressive and heterogeneous tumor with several cellular signaling pathways implicated in its pathogenesis and maintenance. Several risk factors increase the risk of developing PC. Therapeutic strategies used are dictated by the extent of disease. Supportive treatment is critical because of the high frequency of symptoms. For localized disease, surgery followed by adjuvant gemcitabine is the standard. Neoadjuvant and new adjuvant chemotherapy regimens are being evaluated. Locally advanced disease should respond best guided by a multidisciplinary team. Various treatment options are appropriate such as chemotherapy alone or chemoradiotherapy with integration of rescue surgery if the tumor becomes resectable. In metastatic disease, chemotherapy should be reserved for patients with ECOG 0-1 using Folfirinox or gemcitabine plus nab-paclitaxel as the most recommended options. Several therapeutic strategies targeting unregulated pathways are under evaluation with an unmet need for biomarkers to guide management.


A novel end point to assess a resident's ability to perform hand-assisted versus straight laparoscopy for left colectomy: is there really a difference?
It has been suggested that hand-assisted colectomy (HAC) may help residents progress along the learning curve, but there is currently no evidence to support this claim. Previous studies address procedures performed by staff surgeons or residents at various skill levels and report operative times and conversion rates as their primary end points. We measured the percentage of cases completed by a resident as the operating surgeon as the primary end point to determine the most effective approach for teaching laparoscopic colectomy. All patients who underwent left-sided HAC or straight laparoscopic colectomy (SLC) by a single resident starting as the primary surgeon were included. If the assisting attending physician assumed the role of the operating surgeon during the case, it was recorded as an incomplete case for the resident. Operative times and conversions were included as secondary end points. A single resident started 147 laparoscopic colectomies as the primary surgeon during residency and colorectal fellowship, including 81 left-sided procedures. There were 44 patients in the HAC group and 37 SLC patients. Cases done by straight laparoscopy were more likely to be completed by the resident than those done by HAC (SLC, 88%; HAC, 72%; p=0.06). There were also differences in mean operative time favoring SLC (HAC, 142 minutes [range 100 to 170 minutes] versus SLC, 133 minutes [range 95 to 195 minutes]; p=0.04). Complications were similar in the 2 groups (HAC, 19% versus SLC, 21%), as were conversions (HAC, 5.6% versus SLC, 4.5%). Both hand-assisted and straight laparoscopic techniques for left colectomy can be applied to successfully train surgical residents with the assistance of a staff surgeon outside of their learning curve. Residents and colorectal fellows may have more success completing straight laparoscopic colectomy than adjusting to the novel hand-assisted approach during training.


Angiotensin II and acetylcholine differentially activate mobilization of inositol phosphates in Xenopus laevis ovarian follicles.
Angiotensin II (AII) evokes a Ca(2+)-dependent Cl- current in Xenopus laevis ovarian follicles that appears to involve a pertussis-toxin-sensitive G protein mediating phosphoinositide hydrolysis and Ca2+ mobilization from intracellular stores. Follicle responses to AII closely resemble the two-component response stimulated by acetylcholine (ACh) in this tissue. Intraoocyte injections of phytic acid, heparin, and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], acting as inhibitors of Ins(1,4,5)P3-induced Ca(2+)-release, resulted in loss of responsiveness to AII and ACh. As previously reported for ACh [Moriarty et al. (1988) Proc Natl Acad Sci USA 85: 8865-8869], pertussis toxin and microinjected GTP[gammaS] were found to inhibit follicle responses to AII, implying the involvement of a G protein. However, ACh and AII responses differ strikingly in the way they mobilize inositol phosphates and in densitization characteristics. We have previously been unable to find significant increases in inositol phosphates after 60 min stimulation (with Li+) by AII, although ACh potently activated increases in these [McIntosh and McIntosh (1990) Arch Biochem Biophys 283: 135-140]. In the present paper, AII was found to activate rapid increases in inositol bis- and trisphosphates after 1 min stimulation without Li+. ACh and AII also exerted different actions on follicle adenylate-cyclase-dependent responses. We conclude that at least two separate inositol-phosphate-linked receptor mechanisms may exist in ovarian follicles, resulting from involvement of one or more pertussis-toxin-sensitive G protein(s).


Reduction of serum parathyroid hormone levels during sympathetic stimulation in man.
The parathyroid glands contain sympathetic nerve endings and the parathyroid cells are endowed with beta-adrenergic receptors. The physiological role of the sympathoadrenal system for the secretion of parathyroid hormone (PTH) has, however, not been clarified. Using the technique of lower body negative pressure (LBNP), which is an established method to achieve sympathetic nerve activation, it was found in 17 healthy subjects that the venous serum levels of PTH were reduced by 7% within 20 min [from 0.79 +/- 0.12 (SD) to 0.74 +/- 0.11 arbU/l, p less than 0.01, paired t test]. The reduction corresponds to 30% of the maximal suppressibility of PTH by induced hypercalcemia or following parathyroidectomy when studied with the same PTH assay and with the short time period involved. After cessation of LBNP the PTH levels returned to baseline within 20 min. There were no concomitant changes of the plasma ionized calcium concentrations. The findings are compatible with a role for the sympathetic nervous system in the physiologic regulation of the secretion of PTH.


Testing pattern synchronization in coupled systems through different entropy-based measures.
Pattern synchronization (PS) can capture one aspect of the dynamic interactions between bivariate physiological systems. It can be tested by several entropy-based measures, e.g., cross sample entropy (X-SampEn), cross fuzzy entropy (X-FuzzyEn), multivariate multiscale entropy (MMSE), etc. A comprehensive comparison on their distinguishability is currently missing. Besides, they are highly dependent on several pre-defined parameters, the threshold value r in particular. Thus, their consistency also needs further elucidation. Based on the well-accepted assumption that a tight coupling necessarily leads to a high PS, we performed a couple of evaluations over several simulated coupled models in this study. All measures were compared to each other with respect to their consistency and distinguishability, which were quantified by two pre-defined criteria-degree of crossing (DoC) and degree of monotonicity (DoM). Results indicated that X-SampEn and X-FuzzyEn could only work well over coupled stochastic systems with meticulously selected r. It is thus not recommended to apply them to the intrinsic complex physiological systems. However, MMSE was suitable for both, indicating by relatively higher DoC and DoM values. Final analysis on the cardiorespiratory coupling validated our results.


Platelets regulate P-selectin expression and leukocyte rolling in inflamed venules of the pancreas.
Recent data suggest that platelets regulate inflammatory changes and tissue damage in acute pancreatitis although the role of platelets in leukocyte-endothelium interactions in the pancreatic microcirculation is not known. The aim of this study was to define the impact of platelets on leukocyte rolling and adhesion in acute pancreatitis. Acute pancreatitis was induced in C57BL/6 mice by caerulein challenge. Mice were treated with an anti-GP1bα (CD42b) antibody, which depletes platelets, or a control antibody before caerulein. Leukocyte rolling and adhesion were determined by the use of intravital fluorescence microscopy 18 h after the last dose of caerulein. In separate experiments, leukocyte-endothelium interactions were determined before and after administration of an anti-P-selectin, anti-PSGL-1 and a control antibody in mice with caerulein pancreatitis. Circulating platelet-neutrophil aggregates and pancreatic P-selectin mRNA were quantified 1 and 6h respectively after caerulein challenge. Caerulein administration increased leukocyte and platelet interactions in the pancreatic microvasculature, increased tissue damage and expression of P-selectin mRNA in the pancreas as well as platelet-neutrophil complexes in the circulation. Notably, platelet depletion markedly reduced caerulein-provoked leukocyte rolling and adhesion in postcapillary venules. Interestingly, depletion of platelets significantly decreased caerulein-induced gene expression of P-selectin in the pancreas. Moreover, immunoneutralization of P-selectin and PSGL-1 abolished leukocyte rolling in the pancreatic venules triggered by caerulein. Our novel findings demonstrate that platelets regulate leukocyte rolling in acute pancreatitis via induction of P-selectin, which was critical in supporting leukocyte rolling in inflamed venules of the pancreas.


A single-center, open-label, randomized, parallel-group trial to pilot the effectiveness of a peer coach behavioral intervention versus an active control in reducing anxiety and depression in patients scheduled for total knee replacement.
Moving Well is a behavioral intervention for patients with knee osteoarthritis (KOA) scheduled for a total knee replacement (TKR). The objective of this intervention is to help patients with KOA mentally and physically prepare for and recover from TKR. This is an open-label pilot randomized clinical trial that will test the feasibility and effectiveness of the Moving Well intervention compared to an attention control group, Staying Well, to reduce symptoms of anxiety and depression in patients with KOA undergoing TKR. The Moving Well intervention is guided by Social Cognitive Theory. During this 12-week intervention, participants will receive 7 weekly calls before surgery and 5 weekly calls after surgery from a peer coach. During these calls, participants will be coached to use principles of cognitive behavioral therapy (CBT), stress reduction techniques, and will be assigned an online exercise program, and self-monitoring activities to complete on their own time throughout the program. Staying Well participants will receive weekly calls of similar duration from research staff to discuss a variety of health topics unrelated to TKR, CBT, or exercise. The primary outcome is the difference in levels of anxiety and/or depression between participants in the Moving Well and Staying Well groups 6 months after TKR. This study will pilot test the feasibility and effectiveness of Moving Well, a peer coach intervention, alongside principles of CBT and home exercise, to help patients with KOA mentally and physically prepare for and recover from TKR. Clinicaltrials.gov. NCT05217420; Registered: January 31, 2022.


Ageing and parental age effects in Tribolium (review).
The experimental suitability of the flour beetles of the genus Tribolium has attracted ecologists, nutritionists, radiation biologists and geneticists for decades. I have, recently, evaluated their importance to gerontologists. This paper deals with age-related changes and parental age effects which were not included in a previous review. I have, first, discussed the known aspects of age-related changes in morphological, physiological, biochemical, behavioural and pathological parameters as well as on radiation-sensitivity and susceptibility to insecticides. Pre-adult biochemical and physiological changes have also been included, because of the important inter-relationship between growth and ageing. This is followed by an evaluation of parental age effects on physiological and genetic characteristics and of proposed areas for possible research.


Imaging and Quantifying the Endocytosis of IRON-REGULATED TRANSPORTER1 from Arabidopsis.
Iron plays an essential role in plant metabolism and the regulation of its transport is essential for the plant. In Arabidopsis thaliana, iron uptake in root epidermal cells is mediated by the IRT1 (IRON-REGULATED TRANSPORTER 1) broad-spectrum transporter. The regulation of the IRT1 protein is controlled by sophisticated mechanisms that allow it to fine-tune the amount of transporter found at the plasma membrane and to modulate the uptake of iron and divalent metals transported by IRT1. IRT1 shows low selectivity and transports different metals such as manganese, zinc, cobalt, and cadmium. An excess of these non-iron metal substrates of IRT1 is toxic for the plant. The ability of plants to adapt to non-iron metal stress is based on the sensing of their excess, leading to the internalization and degradation of IRT1. IRT1 acts as a bifunctional transporter/receptor directly sensing metal non-iron excess and then undergoes a series of post-translational modifications of the protein culminating in its endocytosis and vacuolar degradation. To monitor the intracellular dynamics of IRT1, we describe in this chapter a live cell imaging approach to follow and quantify IRT1-mCitrine trafficking from the plasma membrane to the vacuole.


Gender identity: A psychosocial primer for providing care to patients with a disorder/difference of sex development and their families [individualized care for patients with intersex (Disorders/differences of sex development): Part 2].
Many parents of infants born with a DSD describe the process of initial sex assignment at birth as highly stressful. Parents of children with a DSD also note high distress when their children engage in behaviors that are not considered typical for their gender. The goal of this article is to provide members of the health care team a brief overview of psychosocial facets of gender and gender identity particularly relevant to DSD for the purposes of enhancing shared decision-making and optimizing support for individuals with a DSD and their families. Gender identity is a multidimensional construct involving related but distinct concepts such as gender typicality, gender contentedness and felt pressure for gender differentiation, and can be assessed via standardized measures. Gender dysphoria is associated with poor psychological adjustment, and is mitigated by family and peer support. Family influences on gender identity include parental modeling of gender behavior and family composition (e.g., same-sex children vs both sons and daughters in a family). Cultural factors that may influence sex assignment include societal views on gender, and gender-related differential resource allocation within a society. In addition, religious beliefs and the presence of a "third-sex" category within a culture may also influence parental gender ideology. Health care providers who work with patients with a DSD must have a strong grasp on the construct of gender identity, and must be able to clearly and consistently communicate with patients and families about gender beliefs in order to optimize family support and gender-related decisions.


Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis.
Important design aspects were decreasingly reported in NSAID trials over the years, whereas the quality of statistical analysis improved. In half of the trials, the effect variables in the methods and results sections were not the same, and the interpretation of the erythrocyte sedimentation rate in the reports seemed to depend on whether a significant difference was found. Statistically significant results appeared in 93 reports (47%). In 73 trials they favored only the new drug, and in 8 only the active control. All 39 trials with a significant difference in side effects favored the new drug. Choice of dose, multiple comparisons, wrong calculation, subgroup and within-groups analyses, wrong sampling units (in 63% of trials for effect variables, in 23% for side effects), change in measurement scale before analysis, baseline difference, and selective reporting of significant results were some of the verified or possible causes for the large proportion of results that favored the new drug. Doubtful or invalid statements were found in 76% of the conclusions or abstracts. Bias consistently favored the new drug in 81 trials, and the control in only one trial. It is not obvious how a reliable meta-analysis could be done in these trials.


Reducing cancer health disparities: perspective of the National Cancer Institute.
The National Cancer Institute created the Special Population Network (SPN) to develop cancer awareness, research and training with partnerships from community and research organizations. Eighteen SPNs were funded with the goals of enlisting community partnerships, enhancing training opportunities for minority scientists, and conducting pilot research projects. The SPN program concluded in 2005 after achieving many major milestones. This paper provides background information about the SPN and one of its programs, the Pacific Islander Cancer Control Network.


Physical Activity Interventions for Neurocognitive and Academic Performance in Overweight and Obese Youth: A Systematic Review.
This article examines cognitive, academic, and brain outcomes of physical activity in overweight or obese youth, with attention to minority youth who experience health disparities. Physically active academic lessons may have greater immediate cognitive and academic benefits among overweight and obese children than normal-weight children. Quasi-experimental studies testing physical activity programs in overweight and obese youth show promise; a few randomized controlled trials including African Americans show efficacy. Thus, making academic lessons physically active may improve inhibition and attentiveness, particularly in overweight youngsters. Regular physical activity may be efficacious for improving neurologic, cognitive, and achievement outcomes in overweight or obese youth.


Thrombocytosis at an early stage of respiratory tract viral infection.
To determine whether thrombocytosis, a platelet count of more than 500 x 10(9)/l, occurs at an early stage of respiratory tract viral infection. The medical records of 345 patients with respiratory syncytial virus (RSV), influenza, measles, adenovirus or human herpes virus 6 infections were retrospectively reviewed. The mean platelet count was significantly higher in RSV patients than in patients with other respiratory infections. Among the 29 patients with thrombocytosis, 24 (82.8%) had RSV infection. When thrombocytosis is positive at an early stage of respiratory tract infection, RSV should be taken into account as a causative agent.


Breast lesions associated with mammographic architectural distortion: a study of 588 core needle biopsies.
Architectural distortion (AD) on mammography is a localized alteration in the uniform texture of the breast characterized by lines radiating from a central point. Radiologic/pathologic correlation is challenging because the types of lesions associated with AD are not well defined and, thus, what signifies a discordant finding requiring excision is less clear. This retrospective case series was performed to elucidate the pathologic lesions associated with AD. Over a 6-year period, 588 core needle biopsies (CNBs) were performed for AD. Thirty-eight percent of the lesions were AD alone (single feature AD) and 62% had additional imaging features (multi-feature AD). Overall, 31% showed invasive carcinoma or ductal carcinoma in situ (DCIS), 37% showed benign lesions likely to correlate with AD, and 32% showed nonspecific benign findings. The invasive carcinomas tended to be low-grade (60%), ER-positive (98%), HER2-negative (98%), and often had lobular features (52%). Ninety-two percent were AJCC pathologic stage group I. Ninety-four cases of benign findings that correlated with AD without atypia underwent excision, and only one was found to have DCIS adjacent to the sclerosing lesion (1%). The remaining cases had benign findings without a clear correlate for AD. Sixty-eight cases without atypia underwent excision, and six multi-feature AD were upgraded to invasive carcinoma (9%). In conclusion, about one-third of CNBs for lesions associated with AD reveal carcinomas that are predominantly invasive, low-grade, ER-positive, HER2-negative, and low stage. Single-feature AD differed from multi-feature AD due to a lower number of carcinomas on CNB (18% vs 39%). For CNBs showing benign lesions on biopsy with a correlate for AD, the finding of malignancy on excision is low (1%). Radiologic/pathologic correlation and decisions to recommend excision will continue to be a challenge after CNB reveals nonspecific findings as some patients with multi-feature AD were found to have undetected invasive carcinomas.


Current and future prospects for CRISPR-based tools in bacteria.
CRISPR-Cas systems have rapidly transitioned from intriguing prokaryotic defense systems to powerful and versatile biomolecular tools. This article reviews how these systems have been translated into technologies to manipulate bacterial genetics, physiology, and communities. Recent applications in bacteria have centered on multiplexed genome editing, programmable gene regulation, and sequence-specific antimicrobials, while future applications can build on advances in eukaryotes, the rich natural diversity of CRISPR-Cas systems, and the untapped potential of CRISPR-based DNA acquisition. Overall, these systems have formed the basis of an ever-expanding genetic toolbox and hold tremendous potential for our future understanding and engineering of the bacterial world.


Morphological changes of urothelial and intestinal mucosa after ureterosigmoidostomy during experimental urogenic carcinogenesis.
To analyze the effect of chemical carcinogens on urothelial and intestinal mucosa on 214 female Wistar rats an ureterosigmoidostomy was performed. After 10-14 days 123 surviving rats were randomly divided into 4 groups: Group I-III received 0.05 per cent N-Butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) in drinking water over a period of 15 weeks. Group IV received normal drinking water over the same period. The defunctionalized bladders were instilled each second day: Group I: physiologic saline solution, Group II: urine of normal rats, Group III and IV: urine of BBN-treated rats. 30 rats without diversion but BBN treatment served as a control. The evaluation of the histological data gave the following results: In the control group urothelial tumors were found in the bladder exclusively. Dependent on the grade of obstruction in the BBN-treated groups, with diversion urothelial tumors in the renal pelvis and ureter could be documented, whereas in the bladder no tumor growth could be shown. In the intestinal mucosa of BBN-treated animals a high incidence of adenocarcinoma was found. The chemical tumor induction by BBN is related to the urine and takes place by direct contact to the mucosa when the metabolites excreted by the kidneys are activated in the urine. BBN or other urogenic carcinogens seem to have no urothelial specificity. The incidence of bowel carcinoma after diversion must lead to intensive long-term follow up.


In vivo distribution studies of radioactively labelled platinum complexes; cis-dichlorodiammine platinum(II), cis-trans-dichlorodihydroxy-bis-(isopropylamine) platinum(IV), cis-dichloro-bis-cyclopropylamine platinum(II), and cis-diammine 1,1-cyclobutanedicarboxylate platinum(II) in patients with malignant disease, using a gamma camera.
The in vivo distribution in man of the four platinum derivatives cis-dichlorodiammine platinum(II) (DDP), cis-trans-dichlorodihydroxy-bis-(isopropylamine) platinum (IV) (CHIP), cis-dichloro-bis-cyclopropylamine platinum(II) (CP), and cis-diammine 1, 1-cyclobutanedicarboxylate platinum(II) (CBDCA) has been observed. The availability of these compounds labelled with the radioactive isotope of platinum, platinum-191, has made serial in vivo imaging of their distribution possible. Injection of 17-35 MBq (5-28 mg) of the labelled compound IV was followed by imaging, using a gamma camera, with particular reference to the kidneys, liver, and tumour site. Hepatic and renal clearances were observed in all nine patients, but no unequivocal evidence of tumour uptake was found. The left kidney uptake was estimated at times up to 7 days after injection. Mathematical analysis of some of the uptake curves failed to show any significant difference between the clearance times observed. However, the two patients who received CBDCA did show a higher initial renal uptake, falling within the 1st day to levels comparable with those of the other compounds, and the three patients who received DDP showed consistently liver uptake.


Snowflake-inspired and blink-driven flexible piezoelectric contact lenses for effective corneal injury repair.
The cornea is a tissue susceptible to various injuries and traumas with a complicated cascade repair process, in which conserving its integrity and clarity is critical to restoring visual function. Enhancing the endogenous electric field is recognized as an effective method of accelerating corneal injury repair. However, current equipment limitations and implementation complexities hinder its widespread adoption. Here, we propose a snowflake-inspired, blink-driven flexible piezoelectric contact lens that can convert mechanical blink motions into a unidirectional pulsed electric field for direct application to moderate corneal injury repair. The device is validated on mouse and rabbit models with different relative corneal alkali burn ratios to modulate the microenvironment, alleviate stromal fibrosis, promote orderly epithelial arrangement and differentiation, and restore corneal clarity. Within an 8-day intervention, the corneal clarity of mice and rabbits improves by more than 50%, and the repair rate of mouse and rabbit corneas increases by over 52%. Mechanistically, the device intervention is advantageous in blocking growth factors' signaling pathways specifically involved in stromal fibrosis whilst preserving and harnessing the signaling pathways required for indispensable epithelial metabolism. This work put forward an efficient and orderly corneal therapeutic technology utilizing artificial endogenous-strengthened signals generated by spontaneous body activities.


Outpatient antibiotic therapy in long-term care facilities.
OPAT in LTCFs is a viable clinical tool that should optimize patient care while limiting expenditures. Numerous opportunities exist to investigate avenues to improve this vehicle and articulate the standards by which this care should be delivered.


Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT4R) partial agonist and 5-HT6R antagonist activities, as potential treatment of Alzheimer's disease.
5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip.


Strategies to encourage freestall use in dairy heifers.
Dairy cattle can experience problems adjusting to freestalls when first introduced, resulting in a marked reduction in lying time and increased abnormal behaviors such as lying in the alley or lying backward in a stall. Our objective was to evaluate 2 strategies to ease the transition of heifers to freestalls: using an older, experienced heifer as a social model [experiment (Exp.) 1] or using brushes mounted in the stalls as an attractant (Exp. 2). In Exp. 1, 44 naïve heifers (129 ± 37 d of age, mean ± standard deviation) were assigned in pairs (n = 11 pairs/treatment) to either the control or social model (with an older heifer, 200 ± 24 d of age, as an experienced social companion) treatments. In Exp. 2, 52 naïve heifers (146 ± 9 d of age) were preassigned in pairs (n = 13 pairs/treatment) to either control or brush treatments. In both studies, heifers were initially housed in pens with a bedded pack (for 5 and 7 d in Exp. 1 and 2, respectively) before moving to pens in the same barn with sand-bedded freestalls. On d -2, 0, and 4 relative to the move to the freestalls, standing, perching (with the front hooves on the bedding and rear hooves in the alley), and lying (location: bedding vs. alley; direction in stall on d 0 and 4: forward or backward) were recorded at 5-min intervals. In addition, starting on d 0 relative to the move, latency to first lie down in a stall was recorded continuously. In both studies, time budgets did not differ between treatments. On the day heifers were moved, they spent less time lying relative to d -2 [Exp. 1: -1.8 h/d, standard error (SE): 0.4 h/d; Exp. 2: -3.0 h/d, SE: 0.3 h/d] and more time standing and perching. By d 4, lying and standing returned to d -2 baseline levels, although heifers continued to spend more time perching. When heifers moved to freestalls, no treatment differences were observed in the latency to lie down in a stall, but latencies differed between Exp. 1 (averaging approximately 3.8 h across treatments) and Exp. 2 (averaging 31.4 h across treatments). After moving to freestalls, the percentage of total lying time that heifers spent facing forward in a stall increased (Exp. 2: 53 vs. 77%, SE: 7%) or tended to (Exp. 1: 84 vs. 92%, SE: 3%) between d 0 and 4 of exposure, with no effect of treatment. Although lying behavior improved with days of exposure to freestalls, some heifers continued to lie down in the alley or backward in a stall, suggesting the need for additional work to ease the adjustment to freestall housing.


The impact on emotional well-being of being a palliative care volunteer: An interpretative phenomenological analysis.
Much palliative care provision relies on the support of volunteers. Attention is paid to the risks to professionals providing care, such as stress and burnout, but understanding if this is an issue for volunteers is little understood. It is important to understand the impact their role has on volunteers emotional well-being. To explore the experiences of palliative care volunteers and how the role impacted on their emotional well-being. Interpretative phenomenological analysis, with data collected through semi-structured interviews. Volunteers in patient-facing roles within palliative and end-of-life care services in the UK. Volunteers (n = 10) across three palliative and end-of-life care services. Four themes were developed: (1) it can be challenging; (2) it's where I'm meant to be; (3) managing death; (4) the importance of connection. Challenges included frustrations and questioning themselves. Although difficult at times, volunteers expressed the importance of the role, doing well and that they benefitted too. They also had to manage death and discussed beliefs about life and death, acceptance and managing patients' fears. Connection with the hospice, patients, staff and other volunteers was important, with a need for everyone to feel valued. Although there are psychosocial benefits for volunteers in their role, it is important to understand the challenges faced and consider ongoing support to help volunteers manage these challenges. This could be addressed through the consideration of coping mechanisms, further training and reflective practice for volunteers.


Schistosoma mattheei in the ox: the serological response.
Thirty Friesian steers were infected with Schistosoma mattheei and the antibody response was followed for up to 76 weeks by the complement fixation (CF), indirect haemagglutination (IH) and indirect immunofluorescent (IF) tests. CF and IF antibodies rose to a peak at about 25 weeks and then fell, while IH antibodies rose more slowly and remained high. Peak IH and IF titres were proportional to the level of infection. Peak CF titres were reduced in animals on a low plane of nutrition. There was a strong cross-reaction to Fasciola gigantica and Paramphistomum microbothrium in the CF test while the IH and IF tests were specific. The IF test proved of value in the diagnosis of naturally occurring clinical schistosomiasis.


Ethanol production from lignocellulosic byproducts of olive oil extraction.
The recent implementation of a new two-step centrifugation process for extracting olive oil in Spain has substantially reduced water consumption, thereby eliminating oil mill wastewater. However, a new high sugar content residue is still generated. In this work the two fractions present in the residue (olive pulp and fragmented stones) were assayed as substrate for ethanol production by the simultaneous saccharification and fermentation (SSF) process. Pretreatment of fragmented olive stones by sulfuric acid-catalyzed steam explosion was the most effective treatment for increasing enzymatic digestibility; however, a pretreatment step was not necessary to bioconvert the olive pulp into ethanol. The olive pulp and fragmented olive stones were tested by the SSF process using a fed-batch procedure. By adding the pulp three times at 24-h intervals, 76% of the theoretical SSF yield was obtained. Experiments with fed-batch pretreated olive stones provided SSF yields significantly lower than those obtained at standard SSF procedure. The preferred SSF conditions to obtain ethanol from olives stones (61% of theoretical yield) were 10% substrate and addition of cellulases at 15 filter paper units/g of substrate.


Risk of adverse fetal outcomes following nonobstetric surgery during gestation: a nationwide population-based analysis.
Literature suggests that nonobstetric surgery during gestation is associated with a higher risk of spontaneous abortion, prematurity, and a higher cesarean section rate, but the direct impact on fetal outcomes is still unclear. In this study, we aimed to investigate whether nonobstetric surgery during pregnancy is associated with negative fetal outcomes by analysing a nation-wide database in Taiwan. This population-based retrospective observational case-control study was based on the linkage of Taiwan's National Health Insurance Research Database, Birth Reporting Database, and Maternal and Child Health Database between 2004 and 2014. For every pregnancy with nonobstetric surgery during gestation, four controls were randomly matched according to maternal age and delivery year. We estimated adjusted odds ratios (aOR) and 95% confidence intervals (CIs) of adverse fetal outcomes with the non-surgery group as the reference. The primary outcomes involved stillbirth, prematurity, low birth weight, low Apgar scores, and neonatal and infant death. Among 23,721 identified pregnancies, 4,747 underwent nonobstetric surgery. Pregnancies with nonobstetric surgery had significantly higher risks of prematurity (aOR: 1.46; 95% CI: 1.31-1.62), lower birth weight (aOR: 1.49; 95% CI: 1.33-1.67), Apgar scores < 7 (1 min, aOR: 1.58; 95% CI: 1.33-1.86; 5 min, aOR: 1.34; 95% CI: 1.03-1.74), neonatal death (aOR: 2.01; 95% CI: 1.18-3.42), and infant death (aOR: 1.69; 95% CI: 1.12-2.54) than those without nonobstetric surgery after adjustment for socioeconomic deprivation, hospital level, and other comorbidities. Surgery performed in the third trimester was associated with a significantly increased rate of prematurity (aOR: 1.38; 95% CI: 1.03-1.85), but lower rates of stillbirth (aOR: 0.1; 95% CI: 0.01-0.75) and Apgar score < 7 at the 5th minute (aOR: 0.2; 95% CI: 0.05-0.82), than surgery performed in the first trimester. Pregnancies with nonobstetric surgery during gestation were associated with increased risks of prematurity, low birth weight, low Apgar scores, neonatal and infant death, longer admission, and higher medical expenses than those without surgery. Furthermore, surgery in the third trimester was associated with a higher rate of prematurity than surgery performed in the first trimester. Not applicable.


Expression of calcium-binding proteins S100A8, S100A9 and S100A12 in otitis media.
Calgranulins (calcium-binding proteins S100A8, S100A9 and S100A12) are predominant cytoplasmic proteins of neutrophils and produced by various cells, playing multiple functions in innate immunity and the inflammatory process. Although up-regulated expression of S100A8 and S100A9 genes were observed in an animal model of otitis media (OM), their expressions have not been studied in human middle ear epithelial cells in response to the OM pathogen or in patients with recurrent or chronic OM (recurrent OM/RecOM or chronic OM with effusion/COME). Gene expressions were compared between Streptococcus pneumoniae (SP)-infected and non-infected human middle ear epithelial cells (HMEECs) as well as between chronic OM patients and control patients (CI). Gene expressions were profiled by quantitative real time PCR (qPCR). S100 proteins in OM patient and CI middle ear biopsies were detected by immunostaining. S100A8, S100A9 and S100A12 gene expressions were elevated in SP-infected HMEECs in time-dependent manner. S100A8 and S100A9 but not S100A12 gene expression was significantly elevated in the middle ear mucosa of OM patients. S100A8 and S100A9 protein were observed in middle ear mucosa of OM, but not CI patients. Minimal co-localization was observed between S100A8 and S100A9 with neutrophil elastase and cytokeratin in ME sections of OM patients. Elevated S100A8 and S100A9 gene expression in SP-infected HMEECs and in the middle ear mucosa of OM, minor co-localized with neutrophil markers suggests that middle ear epithelial cell secretion of S100A8 and S100A9 may play a role in the pathogenesis of recurrent and chronic OM.


Histopathology and surgical anatomy of patients with primary hyperparathyroidism and calcium phosphate stones.
Using a combination of intra-operative digital photography and micro-biopsy we measured renal cortical and papillary changes in five patients with primary hyperparathyroidism and abundant calcium phosphate kidney stones. Major tissue changes were variable papillary flattening and retraction, dilation of the ducts of Bellini, and plugging with apatite deposits of the inner medullary collecting ducts and ducts of Bellini. Some of the papillae in two of the patients contained plentiful large interstitial deposits of Randall's plaque and where the deposits were most plentiful we found overgrowth of the attached stones. Hence, this disease combines features previously described in brushite stone formers--dilation, plugging of ducts and papillary deformity--with the interstitial plaque and stone overgrowth characteristic of routine idiopathic calcium oxalate stone formers, suggesting that these two patterns can coexist in a single patient.


Clinical and infection dynamics of foot-and-mouth disease in beef feedlot cattle: An expert survey.
Parameterizing mathematical models of foot-and-mouth disease virus (FMDv) transmission is challenging due to knowledge gaps on the variable dynamics in susceptible populations. Expert opinion surveys are an approach to gather data on topics where no data have been reported. The objective of this study was to collect-via an expert-opinion survey-key parameter values of the potential FMD natural history and transmissibility in beef feedlot cattle in the U.S. Experts with experience working with FMD in endemic and non-endemic settings were targeted. Parameters surveyed were: duration of infection and disease stages, proportions of animals with specific clinical manifestations, duration and extent of the reduction in feed consumption, and probabilities of severe clinical disease and FMDv transmission. We surveyed the parameter values for infections by strains of different virulence, different infection doses, and routes of transmission. Twenty-seven experts from around the world agreed to participate and 16 (59%) completed the survey. The expert responses to individual questions were resampled via Monte Carlo simulations; to the resulting distributions, candidate theoretical distributions were fitted using the maximum likelihood method and the sought parameter values estimated based on the best-fit distributions. Of the infection stages, the estimates of the expected FMD latent period in beef feedlot ranged from 1.7 to 5.3 days and the infectious period from 5.6 to 10.9 days. Of the disease stages, the estimated incubation period ranged from 2.9 to 6.1 days, subclinical period from 1.2 to 2.8 days, and clinical period from 4.2 to 7.5 days. Probability of developing clinical disease after infection varied from 82% (IQ range 90-70%) with high-virulent to 63% (IQ range 89-60%) with low-virulent strains. Reduction in feed consumption was estimated to last 5 (SD ± 2) days in cattle infected by a low-virulent FMDv strain and 7 (SD ± 2) days for high virulent strains. The study results can be used in combination with experimental and outbreak investigation data to parameterize FMDv-transmission models to evaluate intervention responses during hypothetical FMD epidemics in beef feedlot populations in the U.S.


Alpha-fetoprotein mRNA: variation of half-life in rat hepatoma cell lines and destabilization by sodium butyrate.
The half-life of alpha-fetoprotein (AFP) mRNA was determined in two rat hepatoma cell lines. In the 7777 cell line, AFP mRNA half-life is 30-35 h, consistent with earlier observations (Innis and Miller, 1979). However, the half-life in McA-RH8994 cells is only 14-16 h. Dexamethasone does not affect AFP mRNA half-life in either cell line, indicating that glucocorticoid-mediated alterations in AFP mRNA levels in these cells is at the transcriptional level. The naturally-occurring fatty acid sodium butyrate did, however, cause significantly more rapid degradation of AFP mRNA in McA-RH8994 cells, decreasing the half-life from 14-16 h to only 5-6 h. The ability of sodium butyrate to block glucocorticoid action on AFP gene expression in this cell line is therefore due to both transcriptional and post-transcriptional effects.


Evaluation of Chest X-ray and Thoracic Computed Tomography in Patients with Suspected Tuberculosis.
To investigate if there is any correlation between positive findings detected by posterior-anterior (PA) chest radiograph and thoracic computerized tomography (CT) in cases with suspected lung tuberculosis (TB) due to positive tuberculin skin test (TST) results. This is a retrospective evaluation of the medical files of patients who visited the Department of Pediatrics, Istanbul University, Istanbul Faculty of Medicine from 2006, through 2011 as outpatients and had positive TST (>15 mm) results. A total of 326 patients were included in the study; 45.7 % (n = 149) were girls, and the mean age was 9.0 ± 4.1 y (range: 1-17 y). In total, 14.4 % (n = 47) had TB findings, all of which were in the form of hilar lymphadenopathy. Among the 47 cases with TB findings in PA chest X-ray, 45 (95.7 %) also had findings in thoracic CT. Only 2 (4.3 %) patients had normal thoracic CT results although their PA chest X-ray results were positive. Evaluation for pulmonary TB in children with positive isolated TSTs should be made primarily with PA chest X-ray. A routine thoracic CT scan is not necessary for asymptomatic patients with only hilar lymphadenopathy findings in PA chest radiographs.


Optimal Timing of Surveillance Ultrasounds in Small Aortic Aneurysms.
Small abdominal aortic aneurysms (AAA) surveillance intervals remain controversial and difficult to standardize. Current Society for Vascular Surgery guidelines lack quality evidence. The objective of this study is to examine patients followed in a high volume non-invasive vascular laboratory, determine if the current guidelines are fitting in clinical practice, and attempt to further identify risk factors for accelerated aneurysm growth. A retrospective analysis of patients who underwent at least two ultrasounds for AAA in the vascular laboratory during 2008 -2018 with baseline diameter less than 5.0 cm was conducted. Patient demographics were collected. Groups were then created for comparison using the size criteria according to SVS guidelines. In addition, we compared overall growth rates specifically evaluating rapid growth (rate of at least 1.0 cm/year and size change of at least 0.5 cm from previous imaging), expected growth (any growth below 1.0 cm/year and of at least 0.5 cm from baseline) and no growth. A total of 1581 patients (1232 male and 349 female) were identified with a total of 5945 ultrasound studies. The median age was 73 years and mean follow-up was 27.8 months. Baseline AAA size was 3.0 -3.9 cm in 986 patients and 4.0 -4.9 cm in 595 patients. The average maximum growth rate was 0.18 cm/year for AAAs 3.0 -3.9 cm and 0.36 cm/year for AAAs 4.0 -4.9 cm (P <0.001). Patients with AAA 4.0 -4.9 cm at baseline were more likely to be white, male, hypertensive and have chronic kidney disease (P <0.05). 1078 patients (68.2%) demonstrated no growth over the observed time period with 342 patients (21.6%) demonstrating expected growth and 161 (10.2%) rapid growth. Male gender and baseline AAA size of 4.0 -4.9 cm were more likely to demonstrate rapid growth (P = 0.002) and eventual repair (P <0.001). Metformin use was more common in the AAA group with no growth (P <0.05). Freedom from rapid growth and repair indication at 2 years was significantly lower in those patients with baseline aneurysms 3.0 -3.9 cm (P <0.001). The overall low rate of events in small AAAs supports continued surveillance every 3 years for AAAs 3.0-3.9 cm and yearly for male patients with AAAs 4.0 -4.9 cm as recommended by the SVS Guidelines. Female gender may have less rapid growth than previously reported but likely merit more rigorous surveillance particularly as the AAAs approach 5.0 cm. Metformin use continues to demonstrate it may abrogate aneurysmal growth. Lastly, there is a subset of patients that exhibit more rapid growth of their small AAAs, and further study will be required to classify these patients.


Urinary growth differentiation factor 15 predicts renal function decline in diabetic kidney disease.
Sensitive biomarkers can enhance the diagnosis, prognosis, and surveillance of chronic kidney disease (CKD), such as diabetic kidney disease (DKD). Plasma growth differentiation factor 15 (GDF15) levels are a novel biomarker for mitochondria-associated diseases; however, it may not be a useful indicator for CKD as its levels increase with declining renal function. This study explores urinary GDF15's potential as a marker for CKD. The plasma and urinary GDF15 as well as 15 uremic toxins were measured in 103 patients with CKD. The relationship between the urinary GDF15-creatinine ratio and the uremic toxins and other clinical characteristics was investigated. Urinary GDF15-creatinine ratios were less related to renal function and uremic toxin levels compared to plasma GDF15. Additionally, the ratios were significantly higher in patients with CKD patients with diabetes (p = 0.0012) and reduced with statin treatment. In a different retrospective DKD cohort study (U-CARE, n = 342), multiple and logistic regression analyses revealed that the baseline urinary GDF15-creatinine ratios predicted a decline in estimated glomerular filtration rate (eGFR) over 2 years. Compared to the plasma GDF15 level, the urinary GDF15-creatinine ratio is less dependent on renal function and sensitively fluctuates with diabetes and statin treatment. It may serve as a good prognostic marker for renal function decline in patients with DKD similar to the urine albumin-creatinine ratio.


Analyzing depression tendency of web posts using an event-driven depression tendency warning model.
The Internet has become a platform to express individual moods/feelings of daily life, where authors share their thoughts in web blogs, micro-blogs, forums, bulletin board systems or other media. In this work, we investigate text-mining technology to analyze and predict the depression tendency of web posts. In this paper, we defined depression factors, which include negative events, negative emotions, symptoms, and negative thoughts from web posts. We proposed an enhanced event extraction (E3) method to automatically extract negative event terms. In addition, we also proposed an event-driven depression tendency warning (EDDTW) model to predict the depression tendency of web bloggers or post authors by analyzing their posted articles. We compare the performance among the proposed EDDTW model, negative emotion evaluation (NEE) model, and the diagnostic and statistical manual of mental disorders-based depression tendency evaluation method. The EDDTW model obtains the best recall rate and F-measure at 0.668 and 0.624, respectively, while the diagnostic and statistical manual of mental disorders-based method achieves the best precision rate of 0.666. The main reason is that our enhanced event extraction method can increase recall rate by enlarging the negative event lexicon at the expense of precision. Our EDDTW model can also be used to track the change or trend of depression tendency for each post author. The depression tendency trend can help doctors to diagnose and even track depression of web post authors more efficiently. This paper presents an E3 method to automatically extract negative event terms in web posts. We also proposed a new EDDTW model to predict the depression tendency of web posts and possibly help bloggers or post authors to early detect major depressive disorder.


Recurrence of endometriosis in women with bilateral adnexectomy (with or without total hysterectomy) who received hormone replacement therapy.
To estimate the risk of recurrence after administration of hormone replacement therapy (HRT) among women who have had endometriosis and who underwent bilateral salpingo-oophorectomy (BSO). Prospective randomized trial (115 women receiving HRT and 57 not receiving HRT). SETTING; Public university hospital. Women with a histologic diagnosis of endometriosis in whom BSO was performed; 91.8% had a total hysterectomy. Periodical clinical examination, vaginal ultrasound, and CA-125 levels; surgical evaluation and histologic study. Recurrence rate, prognostic factors, and a mean follow-up time of 45 months. There was no recurrence among women who did not receive HRT, versus a 3.5% rate (4 out of 115), or 0.9% per year, in women who received HRT. Two recurrences required abdominal surgery. There was one additional patient who required surgery, but the relationship to the endometriosis recurrence was controversial. Among women receiving HRT, the following risk factors were detected: peritoneal involvement > 3 cm (2.4% recurrence per year vs. 0.3%) and incomplete surgery (22.2% per patient vs. 1.9%). Patients with a history of endometriosis in whom total hysterectomy and bilateral salpingo-oophorectomy have been performed have a low risk of recurrence when HRT is administered. In those patients, HRT is a reasonable option. However, in cases with peritoneal involvement > 3 cm, the recurrence rate makes HRT a controversial option; if HRT is indicated, it should be monitored closely.


The segregation of Escherichia coli minichromosomes constructed in vivo by recombineering.
Circularized regions of the chromosome containing the origin of replication, oriC, can be maintained as autonomous minichromosomes, oriC plasmids. We show that oriC plasmids containing precise, pre-determined segments of the chromosome can be generated by a simple in vivo recombineering technique. We generated two such plasmids carrying fluorescent markers. These were transferred to a recipient strain with a different fluorescent marker near the chromosomal copy of oriC. Thus the fates of the oriC plasmid and chromosomal origins could be followed independently in living cells by fluorescence microscopy. In contrast to a previous report, we show that there is a strong tendency of oriC plasmid copies to accumulate at the cell center as a single or double focus at the plane of cell division. This is not simply due to exclusion from the nucleoid space but rather appears to be a specific recognition and retention of the plasmid by some central-located cell site.


Post-operative complications following total hip arthroplasty for trauma: A multicentre cohort study comparing dual mobility with conventional acetabular bearings.
Dislocation of a total hip replacement is a serious complication after total hip arthroplasty (THA). Dislocation rates are higher when surgery is performed following trauma. Our study compares post-operative dislocation rates between conventional acetabular bearing (CAB) and dual mobility acetabular bearing (DMB) THA performed for neck of femur fracture alongside post-operative periprosthetic fracture, revision and mortality. A retrospective multicentre cohort study at 9 hospital trusts in the United Kingdom of all THA performed for neck of femur fracture between March 2018 and February 2019. A total of 295 operations were performed. 64% (189) were CAB and 36% (106) were DMB. Average age was 75 years (38-98). 223 Female: 72 Male. The follow-up period was an average of 42 months (36-48). Overall revision rate was 1.6%,8 peri-prosthetic fracture rate was 6 (2%) and overall mortality was 9.8% (29) with no significant difference between cohorts for any outcome. The posterior approach (PA) was favoured 82% (242) vs the lateral approach (LA) 18% (53) with the PA used more often in patients undergoing DMB 96% (102) vs CAB 74% (140) p = 0.001. Patients approached posteriorly at the time of their index procedure were significantly less likely to sustain a simple dislocation following a DMB 0 (0%) vs. CAB 8 (5.7%) p = 0.015. Our study demonstrates that the risk of dislocation following THA for trauma is more than four times higher than when conventional bearings are used compared to dual mobility acetabular components. This effect is most pronounced when the PA is utilised for the index procedure. The use of these bearings does not impact mortality, peri-prosthetic fracture or revision rate. We would encourage the use of dual mobility acetabular bearings in patients undergoing THA for fracture via a PA.


A drift-barrier model drives the genomic landscape of a structured bacterial population.
Bacterial populations differentiate over time and space to form distinct genetic units. The mechanisms governing this diversification are presumed to result from the ecological context of living units to adapt to specific niches. Recently, a model assuming the acquisition of advantageous genes among populations rather than whole genome sweeps has emerged to explain population differentiation. However, the characteristics of these exchanged, or flexible, genes and whether their evolution is driven by adaptive or neutral processes remain controversial. By analysing the flexible genome of single-amplified genomes of co-occurring populations of the marine Prochlorococcus HLII ecotype, we highlight that genomic compartments - rather than population units - are characterized by different evolutionary trajectories. The dynamics of gene fluxes vary across genomic compartments and therefore the effectiveness of selection depends on the fluctuation of the effective population size along the genome. Taken together, these results support the drift-barrier model of bacterial evolution.


Contralateral prophylactic mastectomy is associated with a survival advantage in high-risk women with a personal history of breast cancer.
The aim of this study was to investigate whether contralateral prophylactic mastectomy (CPM) in addition to therapeutic mastectomy (TM) is associated with a survival advantage in high-risk women with breast cancer. A total of 385 women with stage I or II breast cancer and a family history of breast cancer who underwent TM and CPM between 1971 and 1993 were evaluated and compared to 385 patients matched on age at diagnosis, tumor stage, nodal status, and year of diagnosis who underwent TM-only. Contralateral breast cancer (CBC) events and survival outcomes were compared. At a median follow-up of 17.3 years, 2 CBCs (0.5%) developed in the CPM cohort and 31 (8.1%) in the TM-only cohort, representing a 95% decreased risk of CBC (hazard ratio [HR] = 0.05, 95% confidence interval [95% CI] 0.01-0.22, P < 0.0001). One hundred twenty-eight women in the CPM group and 162 women in the TM-only group have died, resulting in 10-year overall survival estimates of 83 and 74%, respectively (HR 0.68, 95% CI 0.54-0.86, P = 0.001). This difference in overall survival persisted in multivariate analysis (HR 0.77, P = 0.03). Disease-free survival (DFS) was better in the CPM cohort than the TM-only group (HR 0.66, 95% CI 0.53-0.82, P = 0.0002) and remained significant in multivariate analysis (HR 0.67, P = 0.0005). In this retrospective cohort study, CPM was associated with decreased CBC event and improved overall survival and disease free survival.


A database of radionuclide activity and metal concentrations for the Alligator Rivers Region uranium province.
This paper presents a database of radionuclide activity and metal concentrations for the Alligator Rivers Region (ARR) uranium province in the Australian wet-dry tropics. The database contains 5060 sample records and 57,473 concentration values. The data are for animal, plant, soil, sediment and water samples collected by the Environmental Research Institute of the Supervising Scientist (ERISS) as part of its statutory role to undertake research and monitoring into the impacts of uranium mining on the environment of the ARR. Concentration values are provided in the database for 11 radionuclides (227Ac, 40K, 210Pb, 210Po, 226Ra, 228Ra, 228Th, 230Th, 232Th, 234U, 238U) and 26 metals (Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, Hg, K, Mg, Mn, Na, Ni, P, Pb, Rb, S, Sb, Se, Sr, Th, U, V, Zn). Potential uses of the database are discussed.


Psychological approaches to the assessment and treatment of anxiety and depression.
Clinical psychology offers a unique and often complementary approach to assessment and treatment of anxiety and depression. Current practices are examined for their scientific validity and clinical utility.


Interpreting results from oncology clinical trials: a comparison of denosumab to zoledronic acid for the prevention of skeletal-related events in cancer patients.
Critically reviewing the design, endpoints, and results of clinical trials can be challenging to health care professionals. This paper will review the basic methods of presenting clinical outcomes in randomized trials and will focus on the number needed to treat (NNT) concept. NNT will then be applied to the case of bone-targeted therapies denosumab and zoledronic acid, which are used for the prevention of skeletal-related events (SREs) in a variety of disease sites. A Medline search was performed to identify randomized trials comparing denosumab to zoledronic acid for the prevention of SREs in patients with advanced breast, prostate, and other cancer sites. The data were extracted, and point estimates for the primary and secondary trial endpoints were converted into the NNT parameter. NNT represents the number of patients that need to be treated with a new intervention in order to avoid one additional patient developing the event and is a powerful approach that can be used to make sense of numerical results from clinical trials. In patients with advanced breast, prostate, and other cancer sites, 18, 22, and 21 patients, respectively, would need to be treated with denosumab for at least 24 months to avoid one patient developing an SRE. The NNT approach is a simple and effective method to express the findings of randomized trials in a clinically meaningful way. In this analysis, the incremental benefits of denosumab would be realized when a minimum of 18 to 22 patients are treated for a prolonged duration. Clinicians would have to weigh the costs and benefits between denosumab and zoledronic acid when bone-targeted therapy is indicated.


Airway and parenchyma immune cells in influenza A(H1N1)pdm09 viral and non-viral diffuse alveolar damage.
Diffuse alveolar damage (DAD), which is the histological surrogate for acute respiratory distress syndrome (ARDS), has a multifactorial aetiology. Therefore it is possible that the immunopathology differs among the various presentations of DAD. The aim of this study is to compare lung immunopathology of viral (influenza A(H1N1)pdm09) to non-viral, extrapulmonary aetiologies in autopsy cases with DAD. The lung tissue of 44 patients, was divided in the H1N1 group (n = 15) characterized by severe pulmonary injury due to influenza A(H1N1)pdm09 infection; the ARDS group (n = 13), characterized by patients with DAD due to non-pulmonary causes; and the Control group (n = 16), consisting of patients with non-pulmonary causes of death. Immunohistochemistry and image analysis were used to quantify, in the parenchyma and small airways, several immune cell markers. Both DAD groups had higher expression of neutrophils and macrophages in parenchyma and small airways. However, there was a higher expression of CD4+ and CD8+ T lymphocytes, CD83+ dendritic cells, granzyme A+ and natural killer + cell density in the lung parenchyma of the H1N1 group (p < 0.05). In the small airways, there was a lower cell density of tryptase + mast cells and dendritic + cells and an increase of IL-17 in both DAD groups (p < 0.05). DAD due to viral A(H1N1)pdm09 is associated with a cytotoxic inflammatory phenotype, with partially divergent responses in the parenchyma relative to the small airways. In non-viral DAD, main immune cell alterations were found at the small airway level, reinforcing the role of the small airways in the pathogenesis of the exudative phase of DAD.


Inhibition of hepatocyte lipogenesis by nitric oxide donor: could nitric oxide regulate lipid synthesis?
Tissue lipogenesis is variably controlled by substrate supply and hormones. The possibility that nitric oxide (NO) might regulate lipogenesis derives from the action of NO on coenzyme A (CoA) to produce metabolically inactive S-nitrosoCoA. The effect of the nitric oxide donor S-nitrosoglutathione (GSNO) on long chain fatty acid and cholesterol synthesis was measured in isolated cultured rat hepatocytes. [1-14C] Butyrate was used as substrate to measure 14C incorporation into lipids as butyrate is twice as effective as acetate in hepatic lipogenesis and is ketogenic via the Lynen cycle. NO very significantly (P < 0.01) impaired long chain fatty acid and cholesterol synthesis an observation dependent upon time of exposure (3 h pre-incubation or 6 h continuous exposure) and concentration of GSNO (500 microM to 2.0 mM). Decrease in hepatic lipogenesis was paralleled by decrease in ketogenesis. ATP levels remained unchanged following short-term exposure to GSNO. Exposure of hepatocytes to GSNO together with 2.0 mM glutathione significantly diminished the inhibition of lipogenesis induced by GSNO alone. Impairment of lipogenesis by GSNO appears not to be limited by energy supply and now adduced, but not proven, to be operative via the degree of inactivation of cytosolic CoA. NO control of lipogenesis could be clinically important where NO production is increased as in demyelinating diseases, chronic arthritis or colitis and in wasting diseases such as AIDS.


Cotranslational incorporation of non-standard amino acids using cell-free protein synthesis.
Over the last years protein engineering using non-standard amino acids has gained increasing attention. As a result, improved methods are now available, enabling the efficient and directed cotranslational incorporation of various non-standard amino acids to equip proteins with desired characteristics. In this context, the utilization of cell-free protein synthesis is particularly useful due to the direct accessibility of the translational machinery and synthesized proteins without having to maintain a vital cellular host. We review prominent methods for the incorporation of non-standard amino acids into proteins using cell-free protein synthesis. Furthermore, a list of non-standard amino acids that have been successfully incorporated into proteins in cell-free systems together with selected applications is provided.


Perioperative Management for the First Uterine Transplant in Southern Europe: A Case Report.
The aim of this study was to describe perioperative management concerning the living donor uterine transplantation program at the Hospital Clinic (Barcelona, Spain), in the first successful procedure in Southern Europe. Before the date of surgery, both the donor and the recipient are evaluated in the outpatient clinic to detect any possible comorbidities that might complicate or altogether disallow the procedure. In the donor, with a robotically performed surgery, complications regarding cerebral and upper airway edema, as well as reduced access to the patient once docking occurs, are of utmost importance. An aggressive antithrombotic regimen must be in place that includes heparin administered both to the donor and the recipient and aspirin to the recipient. Different strategies to reduce ischemia-reperfusion injury have been studied, with reduced ischemia times currently being the most effective. After surgery, both donor and recipient were taken to the intensive care unit overnight, transferred to the conventional ward the following day and discharged from the hospital within the week. The recipient had her first menstrual period 47 days after the surgery. The description of challenges regarding perioperative care of women who undergo uterine transplant programs and the rationale in anesthetic management may help other teams implant this program as a solution for a disease that profoundly impairs quality of life.


Gentle facemask ventilation during induction of anesthesia.
To determine the level of inspiratory pressure minimizing the risk of gastric insufflation while providing adequate pulmonary ventilation. In this prospective, randomized, double-blind study, patients were allocated to one of the two groups (P10, P15) defined by the inspiratory pressure applied during controlled-pressure ventilation: 10 and 15 cm H2O. Anesthesia was induced using propofol and sufentanil; no neuromuscular-blocking agent was administered. Once loss of eyelash reflex occurred, facemask ventilation was started for a 2-min period. The cross-sectional antral area was measured using ultrasonography before and after facemask ventilation. Respiratory parameters were recorded. Forty patients were analyzed. Mean tidal volume was about 7 ml/kg in group P10, and was >11 ml/kg in group P15 in the same period. As indicated by ultrasonography test, the antral area in P15 group was markedly incresed compared with P10 group. Inspiratory pressure of 10 cm H2O allowed for reduced occurrence of gastric insufflation with proper lung ventilation during induction of anesthesia with sufentanil and propofol in nonparalyzed and nonobese patients.


Distribution of thyrotropin-releasing hormone receptor mRNA in rat peripheral tissues.
Since the thyrotropin-releasing hormone receptor (TRH-R) cDNA was isolated, the distribution of TRH-R mRNA has been investigated in the central nervous system (CNS) and the pituitary. However, there has been less genetical studies on the distribution of TRH-R mRNA in the peripheral tissues, although TRH exists not only in CNS but also in the peripheral tissues. In this study we investigated the distribution of TRH-R mRNA in rat peripheral tissues by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis. TRH-R mRNA was detected in almost all of the peripheral tissues tested, although the amount varied considerably depending on the tissues. In the uterus, thymus, ovary, and testis, TRH-R mRNA levels appeared to be relatively high. These results suggest that TRH and its receptor have specific functions in the peripheral tissues as well as in CNS and in the pituitary.


Factors affecting the ability of radiographers to deliver imaging services in rural parts of Zambia.
Medical imaging in healthcare plays a vital role in the assessment, confirmation, and documentation of the course of many diseases and injuries. However, literature reports that the urban population in Sub-Saharan Africa have more access to imaging services than the rural population. This imbalance can affect radiographers working in rural areas. The aim of this study was to explore factors affecting the ability of radiographers to deliver imaging services in rural parts of Zambia. This study employed a qualitative exploratory research design. Semi-structured interviews were used to collect data from a stratified and purposive sample of six rural radiographers and three stakeholders [Ministry of Health (MOH), Radiological Society of Zambia (RSZ), and Schools of Radiography] across the country. Data were audio-recorded, transcribed, and subjected to manual thematic analysis. Four themes emerged following thematic analysis: procurement processes and resources, imaging equipment, job satisfaction, and education and training. Factors, such as donated equipment, the introduction of new imaging services and continuous professional development (CPD) were positive elements that assisted rural radiographers in the delivery of imaging services. However, an unequal distribution of equipment between urban and rural areas, old and obsolete equipment, lack of maintenance and servicing, lack of postgraduate courses, bureaucratic procurement processes, lack of consumables, workload, and low salaries, negatively affected the ability of rural radiographers. Lack of maintenance and servicing of equipment, as well as bureaucratic procurement processes were the main challenges identified by radiographers to imaging services in rural Zambia. There is a need to decentralise the procurement processes and establish a culture of regular maintenance and servicing of equipment. This research highlights the importance of supporting rural radiographers in the delivery of imaging services.