Transcriptome Analysis Identifies Oncogenic Tissue Remodeling during Progression from Common Nevi to Early Melanoma.
Early detection and treatment of melanoma, the most aggressive skin cancer, improves the median 5-year survival rate of patients from 25% to 99%. Melanoma development involves a stepwise process during which genetic changes drive histologic alterations within nevi and surrounding tissue. Herein, a comprehensive analysis of publicly available gene expression data sets of melanoma, common or congenital nevi (CN), and dysplastic nevi (DN), assessed molecular and genetic pathways leading to early melanoma. The results demonstrate several pathways reflective of ongoing local structural tissue remodeling activity likely involved during the transition from benign to early-stage melanoma. These processes include the gene expression of cancer-associated fibroblasts, collagens, extracellular matrix, and integrins, which assist early melanoma development and the immune surveillance that plays a substantial role at this early stage. Furthermore, genes up-regulated in DN were also overexpressed in melanoma tissue, supporting the notion that DN may serve as a transitional phase toward oncogenesis. CN collected from healthy individuals exhibited different gene signatures compared with histologically benign nevi tissue located adjacent to melanoma (adjacent nevi). Finally, the expression profile of microdissected adjacent nevi tissue was more similar to melanoma compared with CN, revealing the melanoma influence on this annexed tissue.


Effects of muscle fiber distribution on the mechanical efficiency of human locomotion.
To study the effects of muscle fiber distribution (m. vastus lateralis) on the mechanical efficiency of human locomotion, 12 subjects were observed, six in the slow-twitch (ST) group (38.0% +/- 6.1% FT) and six in the fast-twitch (FT) group (63.8% +/- 5.9% FT). Pure positive, pure negative, and a combination of negative and positive work were performed with a special "sledge ergometer." The mechanical efficiency of the pure positive work (eta) was on the average 16.4% +/- 2.5% and 17.1% +/- 2.1% for the ST and FT groups, respectively. The mechanical efficiency of the pure negative work (eta -) was slightly greater in the ST group (94.0% +/- 30.2% vs 79.6% +/- 32.7%, P = NS). The mechanical efficiency of the positive work in the combined negative/positive work (eta +) was on the average in the ST group 36.4% +/- 5.9% and in the FT group 33.2% +/- 5.5% (t = 2.02, P less than 0.05). The eta + and the calculated elastic parameters (work due to elasticity Wel, utilization of the prestretch %El, and relative Wel) together with the EMG analysis demonstrated that the ST group had a better stiffness regulation and elastic performance. It is suggested that the basic differences in the reflex control between the two types of muscles and functional differences between the respective fiber types could be the possible reasons for the results observed under the conditions of the present slow-type stretch-shortening cycle exercises.


Implanting toric implantable collamer lens displays better astigmatism correction than implantable collamer lens combined with manually limbal relaxing incision.
This retrospective study aimed to compare the outcomes of toric implantable collamer lens (TICL) surgery with those of implantable collamer lens (ICL) implantation combined with limbal relaxing incision (LRI) in patients with low myopia and astigmatism. A total of 40 eyes of 28 patients who underwent TICL implantation and 40 eyes of 27 patients who underwent ICL implantation combined with manually LRI between 2021 and 2022 were included. Primary outcomes were manifest sphere and cylinder, intraocular pressure, visual acuity, and astigmatism parameters at 1 day, 1 week, and 1, 3, and 6 months postoperatively. The two surgeries showed comparable effects on manifest sphere and cylinder, intraocular pressure, and visual acuity (all p > 0.1). Surgery-induced astigmatism (SIA) was maintained as stable in the TICL group (1.73 to 1.68, p = 0.420), but was significantly reduced in the ICL/LRI group (1.74 to 1.17, p = 0.001) from preoperative to postoperative 6 months. The TICL group displayed significantly higher SIA and correction index at postoperative 1, 3, and 6 months than the ICL/LRI group (at 6 months: SIA, 1.68 (1.26, 1.96) vs., 1.17 (1.00, 1.64), p = 0.010; CI: 0.98 (0.78, 1.25) vs. 0.80 (0.61, 1.04), p = 0.018). No complications occurred during follow-up. The effects of ICL/LRI are comparable to those of TICL in correcting myopia. TICL implantation displays better astigmatism correction than ICL/LRI.


Immunoglobulins G modulate endothelial function and affect insulin sensitivity in humans.
Data from animals suggest that immunoglobulins G (IgG) play a mechanistic role in atherosclerosis and diabetes through endothelial dysfunction and insulin resistance. Patients with common variable immunodeficiency (CVID), who have low circulating levels of IgG and are treated with intravenous polyclonal IgG (IVIgG), may provide an ideal model to clarify whether circulating IgG modulate endothelial function and affect insulin sensitivity in humans. We studied 24 patients with CVID and 17 matched healthy controls (HC). Endothelial function was evaluated as flow mediated dilation (FMD) of the brachial artery at baseline and 1, 7, 14, and 21 days after IVIgG infusion in the CVID patients. We measured also plasma glucose, insulin, and calculated the HOMA-IR index. We also investigated the role of human IgG on the production of Nitric Oxide (NO) in vitro in Human Coronary Artery Endothelial Cells (HCAEC). Compared to HC, FMD of CVID patients was significantly impaired at baseline (9.4 ± 0.9 and 7.6 ± 0.6% respectively, p < 0.05) but rose above normal levels 1 and 7 days after IVIgG infusion to return at baseline at 14 and 21 days. Serum insulin concentration and HOMA-IR index dropped by 50% in CVID patients after IVIgG (p < 0.002 vs. baseline). In vitro IgG stimulated NO production in HCAEC. Reduced IgG levels are associated with endothelial dysfunction and IVIgG stimulates endothelial function directly while improving insulin sensitivity. The current findings may suggest an anti-atherogenic role of human IgG.


Derivation of neural precursors from bovine preimplantation embryos.
Induction of neural differentiation from embryonic pluripotent stem cells (ES/EpiSc), both of mouse and primates, has been extensively published by several research teams. However, direct derivation of organized neuroectoderm in vitro from blastocyst stage embryos of rodents or primates has not been reported so far. Here we describe a method of direct neural differentiation from the inner cell mass cells of preimplantation bovine embryos, without the intermediate step of ES/EpiSc cells derivation (Lazzari et al., Stem cells 24:2514-2521, 2006). Proliferating neural precursors cells lines, and both central and peripheral nervous system derivatives, can be obtained providing a unique in vitro model of early neurulation events in mammals.


Label-free tumor cells classification using deep learning and high-content imaging.
Many studies have shown that cellular morphology can be used to distinguish spiked-in tumor cells in blood sample background. However, most validation experiments included only homogeneous cell lines and inadequately captured the broad morphological heterogeneity of cancer cells. Furthermore, normal, non-blood cells could be erroneously classified as cancer because their morphology differ from blood cells. Here, we constructed a dataset of microscopic images of organoid-derived cancer and normal cell with diverse morphology and developed a proof-of-concept deep learning model that can distinguish cancer cells from normal cells within an unlabeled microscopy image. In total, more than 75,000 organoid-drived cells from 3 cholangiocarcinoma patients were collected. The model achieved an area under the receiver operating characteristics curve (AUROC) of 0.78 and can generalize to cell images from an unseen patient. These resources serve as a foundation for an automated, robust platform for circulating tumor cell detection.


Tandem Synthesis of 10-Dimethylaminobenzo[h]quinazolines from 2-Ketimino-1,8-bis(dimethylamino)naphthalenes via Nucleophilic Replacement of the Unactivated Aromatic NMe2 Group.
It has been found that 2-bromo-1,8-bis(dimethylamino)naphthalene on sequential treatment with n-BuLi and 2 equiv of the same or different aryl(hetaryl) cyanide as a result of [2 + 2 + 2] nucleophilic cascade annulation produces 10-dimethylaminobenzo[h]quinazolines, as yet unknown NMe2/-N═ analogues of the proton sponge. It is even more convenient to use preliminarily prepared 2-ketimino-1,8-bis(dimethylamino)naphthalenes as starting material. The substitution of both peri-NMe2 groups furnishing quinazolino[7,8-h]quinazoline derivatives is also possible. The process is remarkable by surprisingly mild nucleophilic displacement of an unactivated aromatic NMe2 group.


Defining Factors Associated with High-quality Surgery Following Radical Cystectomy: Analysis of the British Association of Urological Surgeons Cystectomy Audit.
Radical cystectomy (RC) is associated with high morbidity. To evaluate healthcare and surgical factors associated with high-quality RC surgery. Patients within the prospective British Association of Urological Surgeons (BAUS) registry between 2014 and 2017 were included in this study. High-quality surgery was defined using pathological (absence of positive surgical margins and a minimum of a level I lymph node dissection template with a minimum yield of ten or more lymph nodes), recovery (length of stay ≤10 d), and technical (intraoperative blood loss <500 ml for open and <300 ml for minimally invasive RC) variables. A multilevel hierarchical mixed-effect logistic regression model was utilised to determine the factors associated with the receipt of high-quality surgery and index admission mortality. A total of 4654 patients with a median age of 70.0 yr underwent RC by 152 surgeons at 78 UK hospitals. The median surgeon and hospital operating volumes were 23.0 and 47.0 cases, respectively. A total of 914 patients (19.6%) received high-quality surgery. The minimum annual surgeon volume and hospital volume of ≥20 RCs/surgeon/yr and ≥68 RCs/hospital/yr, respectively, were the thresholds determined to achieve better rates of high-quality RC. The mixed-effect logistic regression model found that recent surgery (odds ratio [OR]: 1.22, 95% confidence interval [CI]: 1.11-1.34, p < 0.001), laparoscopic/robotic RC (OR: 1.85, 95% CI: 1.45-2.37, p < 0.001), and higher annual surgeon operating volume (23.1-33.0 cases [OR: 1.54, 95% CI: 1.16-2.05, p = 0.003]; ≥33.1 cases [OR: 1.64, 95% CI: 1.18-2.29, p = 0.003]) were independently associated with high-quality surgery. High-quality surgery was an independent predictor of lower index admission mortality (OR: 0.38, 95% CI: 0.16-0.87, p = 0.021). We report that annual surgeon operating volume and use of minimally invasive RC were predictors of high-quality surgery. Patients receiving high-quality surgery were independently associated with lower index admission mortality. Our results support the role of centralisation of complex oncology and implementation of a quality assurance programme to improve the delivery of care. In this registry study of patients treated with surgical excision of the urinary bladder for bladder cancer, we report that patients treated by a surgeon with a higher annual operative volume and a minimally invasive approach were associated with the receipt of high-quality surgery. Patients treated with high-quality surgery were more likely to be discharged alive following surgery.


Design and fabrication of chitosan cross-linked bismuth sulfide nanoparticles for sequestration of mercury in river water samples.
The existence of heavy metals in ecological systems poses great threats to living organisms due to their toxicant and bio-accumulating properties. Mercury is a known toxicant with notable malignant impacts. It has long been known to cause toxic threats to the health of living organisms since the break out of Minamata disease. The turbulent expulsion of mercury-based pollutants from the industrial sector, requires a proper solution. Many attempts have been made to design a greener and more efficient route for a satisfactory removal of mercury. In the current study, bismuth sulfide nanoparticles (BiSNPs) have been synthesized via the co-precipitation method. The BiSNPs were supported with crosslinked chitosan to enhance their sorption capacity and avoid leaching. The average size of the BiSNPs was 42 nm based on SEM micrographs. The SEM analysis of the bismuth sulfide chitosan-crosslinked beads (BiS-CB) showed that the beads possessed a spherical and smooth morphology with a size of 1.02 mm. The FTIR analysis showed that the beads possessed the characteristics bands of imine groups of chitosan, bismuth, sulfur, and glycosidic linkages present in the molecules. The XRD analysis confirmed the phase crystallinity of the BiS-CB with an average crystallite size of 11 nm. The BiS-CB was employed for the sorption of mercury from water samples. The maximum sorption capacity of 65.51 mg/g was achieved at optimized conditions of pH 5, concentration 80 ppm, in 45 min at 30 °C. The mechanism studied for mercury removal showed that sorption followed the complexation mechanism according to the SHAB concept. In conclusion, the results showed that the BiS-CB sorbent exhibited an excellent sorption capacity to remove mercury.


Extracellular vesicles isolated from human renal cell carcinoma tissues disrupt vascular endothelial cell morphology via azurocidin.
Cancer-associated extracellular vesicles (EVs) are intimately involved in establishment of tumor microenvironment and occurrence of metastasis. However, previous studies have mainly relied on experiments with cultured cell lines or mouse models, making it difficult to gain a full understanding of EV functions in human body. Hence, we extracted EVs directly from surgically resected viable clear cell renal cell carcinoma (ccRCC) tissues and adjacent normal renal tissues (n = 20). Quantitative LC/MS analysis identified 3,871 tissue-exudative EV (Te-EV) proteins, among which azurocidin (AZU1) was highly enriched in tumor Te-EVs (p = 2.85 × 10-3 , fold-change = 31.59). Importantly, AZU1 content was also significantly higher in serum EVs from ccRCC patients compared to those from healthy donors. We further found that ccRCC-derived EVs had AZU1-dependent membrane permeabilizing activity for the vascular endothelial cell layer. Thus Te-EVs should be ideal resource for investigation of physiological EV functions.


The effect of massage on heart rate variability in preterm infants.
To test the hypothesis that massage would improve autonomic nervous system (ANS) function as measured by heart rate variability (HRV) in preterm infants. Medically stable, 29- to 32-week preterm infants (17 massage, 20 control) were enrolled in a masked, randomized longitudinal study. Licensed massage therapists provided the massage or control condition twice a day for 4 weeks. Weekly HRV, a measure of ANS development and function, was analyzed using SPSS generalized estimating equations. Infant characteristics were similar between groups. HRV improved in massaged infants but not in the control infants (P<0.05). Massaged males had a greater improvement in HRV than females (P<0.05). HRV in massaged infants was on a trajectory comparable to term-born infants by study completion. Massage-improved HRV in a homogeneous sample of hospitalized, medically stable, preterm male infants and may improve infant response to exogenous stressors. We speculate that massage improves ANS function in these infants.


Baclofen as relapse prevention in the treatment of Gamma- Hydroxybutyrate (GHB) dependence: an open label study.
GHB dependence is a growing health problem in several western countries, especially the Netherlands. Attempts to stop using GHB are often followed by relapse shortly after successful detoxification. Craving for GHB use and co-morbid psychiatric symptom levels are thought to be the major factors contributing to the high relapse rates. Given its pharmacological profile, baclofen might prove an effective anti-craving agent for patients with GHB dependence. The aim of the current study is to assess the potential of baclofen as an anti-craving agent relapse prevention intervention in GHB dependent patients. In an open label non-randomized trial treatment with baclofen to a maximum of 60 mg/day will be compared with treatment as usual (TAU) in recently detoxified GHB dependent patients (n = 80). The primary outcome measure will be the level of GHB use. Secondary outcome measures are craving levels, psychiatric symptom levels and quality of life. Questionnaires will be administered during 12 weeks of baclofen treatment and at follow-up (six months after the start of treatment). It is hypothesized that baclofen treatment compared to TAU will be associated with significantly reduced GHB use. In addition, we hypothesize that baclofen treatment will be associated with decreased craving and anxiety levels, and higher quality of life. If results are in line with our hypotheses, further studies on the efficacy of baclofen using placebo controlled designs and long term follow-up are warranted. The Netherlands Trial Register with number NTR4528 . Registered 19 April 2014.


Accuracy of 2 Different Continuous Glucose Monitoring Systems in Patients Undergoing Cardiac Surgery.
Continuous glucose monitoring (CGM) is today provided by various techniques. This study aims to compare two different CGM-systems: the FreeStyle Libre subcutaneous continuous glucose monitoring system (SC-CGM) and the Eirus intravascular microdialysis continuous glucose monitoring system (MD-CGM) in patients undergoing cardiac surgery. A total of 26 patients were equipped with both the SC-CGM and the MD-CGM systems. The SC-CGM system was placed subcutaneously in the left upper-arm and the MD-CGM system was placed in the superior vena cava. Reference blood glucose values were obtained by analyzing arterial blood in a blood gas analyzer. Reference glucose values were then paired with glucose values from both CGM-systems and analyzed for accuracy. In all, 514 paired MD-CGM/arterial blood gas glucose values and 578 paired SC-CGM/arterial blood gas glucose values were obtained. Mean difference (SD) for the MD-CGM system was 0.9 (15.1) mg/dl and for the SC-CGM system -43.4 (20) mg/dl. ISO criteria (ISO15197:2013) were not met by either CGM system. In the Clarke error grid, all paired samples were within the zones AB for the MD-CGM system, and 94% in zone A. For the SC-CGM system, 99.1% of the paired samples were within zones AB, and 18.9% in zone A. Both the MD-CGM and the SC-CGM systems were reliable and used without complications. These results indicate that the Eirus intravascular microdialysis system monitors glucose continuously with superior accuracy compared to the FreeStyle Libre subcutaneous glucose monitoring system, which repeatedly measured a glucose value that was lower than the reference method.


Syndromic approach to sexually transmitted infections in Tunisian women: bacteriological validation.
The World Health Organization emphasizes an integrated primary care approach using syndromic management of sexually transmitted infections. The objective of our study was to evaluate the quality of care of the syndromic management of sexually transmitted disease in women in Rabta hospital in Tunisia. Algorithms have been developed for: cervicitis due to Neisseria gonorrhoeae or Chlamydia (algorithm 3a), vaginitis due to Trichomonas vaginalis or Chlamydia trachomatis (algorithm 3b) and vaginitis due to Candida (algorithm 3c). A total of 116 women were enrolled in the study during February 2003 to April 2004. The prevalence of each bacterium was Chlamydia (10%), N. gonorrhoeae (1%), Treponema pallidum (1%), T. vaginalis (5%) and Candida (21%). Algorithm '3a' had a sensitivity of 45%, a specificity of 42% and positive predictive value (PPV) of 11.9%. Algorithm '3b' had a sensitivity of 35.7%, a specificity of 68.9% and PPV of 20.8%. Algorithm '3c' had a sensitivity of 12%, a specificity of 88% and PPV of 33.3%. To improve the sensitivity of the syndromic approach, we suggest improving the quality of history taking.


Molecular Pathogenesis of Hodgkin Lymphoma: Past, Present, Future.
Our understanding of the tumorigenesis of classical Hodgkin lymphoma (cHL) and the formation of Reed-Sternberg cells (RS-cells) has evolved drastically in the last decades. More recently, a better characterization of the signaling pathways and the cellular interactions at play have paved the way for new targeted therapy in the hopes of improving outcomes. However, important gaps in knowledge remain that may hold the key for significant changes of paradigm in this lymphoma. Here, we discuss the past, present, and future of cHL, and review in detail the more recent discoveries pertaining to genetic instability, anti-apoptotic signaling pathways, the tumoral microenvironment, and host-immune system evasion in cHL.


Sensory Symptoms and Effects on Health-related Quality of Life of Patients Undergoing Lumbar Spine Surgery.
Patients with lumbar degenerative spine diseases (LDSDs) commonly report sensory symptoms before and after lumbar spine surgery. To explore the changing patterns of sensory symptoms-namely pain, numbness, stinging, itching, and burning-and investigate the influences of sensory symptom changes on the health-related quality of life (HRQoL) of patients who experienced lumbar spine surgery. All sensory symptoms (i.e., pain, numbness, paresthesia) were measured using a visual analog scale. The Chinese versions of the Oswestry Disability Index, Pittsburgh Sleep Quality Index, Clinically Useful Depression Outcome Scale, and EuroQol-five dimensions (EQ-5D) Scale were used to assess patients 1 week prior to surgery and 6 weeks and 6 months after surgery. A generalized estimating equation was used for data analysis. A total of 101 patients with mean age of 58.38 years were included. All sensory symptoms declined significantly over time (all p < .05) with the exception of itching (feeling on toes and thighs). Patients experiencing moderate-to-severe pain had poorer QoL over time, even after controlling for other sensory symptoms and potential confounders. Sensory symptoms gradually declined after surgery, but itching symptom did not. Moderate-to-severe pain was the only sensory symptom that influenced HRQoL over time in patients with LDSDs.


Dynamic molecules: molecular dynamics for everyone. An internet-based access to molecular dynamic simulations: basic concepts.
Molecular dynamics is a rapidly developing field of science and has become an established tool for studying the dynamic behavior of biomolecules. Although several high quality programs for performing molecular dynamic simulations are freely available, only well-trained scientists are currently able to make use of the broad scientific potential that molecular dynamic simulations offer to gain insight into structural questions at an atomic level. The "Dynamic Molecules" approach is the first internet portal that provides an interactive access to set up, perform and analyze molecular dynamic simulations. It is completely based on standard web technologies and uses only publicly available software. The aim is to open molecular dynamics techniques to a broader range of users including undergraduate students, teachers and scientists outside the bioinformatics field. The time-limiting factors are the availability of free capacity on the computing server to run the simulations and the time required to transport the history file through the internet for the animation mode. The interactive access mode of the portal is acceptable for animations of molecules having up to about 500 atoms.


Neurolathyrism: mitochondrial dysfunction in excitotoxicity mediated by L-beta-oxalyl aminoalanine.
beta-N-Oxalyl amino-L-alanine (L-BOAA); synonym beta-N-oxalyl-alpha,beta-diaminopropionic acid (beta-ODAP) is a naturally occurring non-protein amino acid present in the chickling pea from the plant Lathyrus sativus grown in drought prone areas. Ingestion of L-BOAA as a staple diet results in a progressive neurodegenerative condition, neurolathyrism, a form of motor neuron disease which affects the upper motor neurons and anterior horn cells of the lumbar spinal cord. L-BOAA is an excitatory acid and acts as an agonist at the AMPA receptor. One of the primary effects of L-BOAA toxicity is the inhibition of mitochondrial complex I selectively in the motor cortex and lumbar spinal cord. Recent evidence has suggested that the mitochondrial dysfunction is a consequence of oxidation protein thiol groups as a result of generation of reactive oxygen species. Mitochondrial complex I is highly to vulnerable to inactivation through oxidation of vital sulfhydryl groups. Thiol antioxidants such as alpha-liopic acid offer a method of protecting mitochondrial function. A common mechanism involving oxidation of protein thiol groups may underlie neurodegeneration occurring through mitochondrial dysfunction induced by excitatory amino acid.


More lessons from linalool: insights gained from a ubiquitous floral volatile.
Linalool (3,7-dimethyl-1,6-octadien-3-ol) is a common floral volatile with two distinct enantiomers and related metabolites involved in the full spectrum of plant-pollinator interactions. Recent studies reveal a complex interplay between pollinator attraction and plant defense mediated by linalool and its derivatives, from the smallest (Arabidopsis, Mitella) to the largest (Datura) flowers studied. Accordingly, fig wasps, fungus gnats and moths of all sizes show remarkable electrophysiological, neural and behavioral sensitivity to different enantiomers and quantitative ratios of linalool in floral bouquets. The diverse functions of linalool, ranging from toxin to long distance pollinator attractant are discussed in the broader context of floral volatile ecology and evolution.


Adverse fetal outcomes in patients with IUGR are related with fetal diaphragm evaluation parameters.
The aim of the present study was to evaluate the relationship between diaphragmatic thickness, during both inspiratory (DTI) and expiratory (DTE) stages; diaphragmatic excursion (DE); diaphragm thickening fraction (DTF); and adverse fetal outcomes in pregnant women with intrauterine growth restriction (IUGR). A total of 77 participants were included in this case-control study. The case group was diagnosed as having both symmetric and asymmetric IUGR (n = 39). The control group included gestational age (GA)-matched healthy pregnant women (n = 38). DTI, DTE, DE (reflecting the capability of diaphragmatic movement during the respiratory cycle), and DTF were analyzed. Maternal demographic characteristics were similar between groups. DTI and DTE were significantly lower in the IUGR group compared to the control group (p < 0.001 and p < 0.001). DE was similar between the groups (p = 0.07). Additionally, in the IUGR group, DTI, DTE, and DE were significantly altered in newborns that required treatment in the neonatal intensive care unit (NICU). ROC curve analysis determined that the DTI cut-off was 1.36 for NICU admission with 78% sensitivity and 100% specificity. DTE cut-off was 1.195 for NICU admission with 78% sensitivity and 96% specificity. DE cut-off was 4.25 for NICU admission with 71% sensitivity and 80% specificity. Measurement of DTI, DTE and DE may help clinicians to predict whether newborns with IUGR would require NICU hospitalization.


Ferritins: a family of molecules for iron storage, antioxidation and more.
Ferritins are characterized by highly conserved three-dimensional structures similar to spherical shells, designed to accommodate large amounts of iron in a safe, soluble and bioavailable form. They can have different architectures with 12 or 24 equivalent or non-equivalent subunits, all surrounding a large cavity. All ferritins readily interact with Fe(II) to induce its oxidation and deposition in the cavity in a mineral form, in a reaction that is catalyzed by a ferroxidase center. This is an anti-oxidant activity that consumes Fe(II) and peroxides, the reagents that produce toxic free radicals in the Fenton reaction. The mechanism of ferritin iron incorporation has been characterized in detail, while that of iron release and recycling has been less thoroughly studied. Generally ferritin expression is regulated by iron and by oxidative damage, and in vertebrates it has a central role in the control of cellular iron homeostasis. Ferritin is mostly cytosolic but is found also in mammalian mitochondria and nuclei, in plant plastids and is secreted in insects. In vertebrates the cytosolic ferritins are composed of H and L subunit types and their assembly in a tissues specific ratio that permits flexibility to adapt to cell needs. The H-ferritin can translocate to the nuclei in some cell types to protect DNA from iron toxicity, or can be actively secreted, accomplishing various functions. The mitochondrial ferritin is found in mammals, it has a restricted tissue distribution and it seems to protect the mitochondria from iron toxicity and oxidative damage. The various functions attributed to the cytosolic, nuclear, secretory and mitochondrial ferritins are discussed.


Mechanistic modeling of arsenic retention on natural red earth in simulated environmental systems.
Arsenic retention on natural red earth (hereafter NRE) was examined as a function of pH, ionic strength, and initial arsenic loading using both macroscopic and spectroscopic methods. Proton binding sites on NRE were characterized by potentiometric titrations yielding an average pH(zpc) around 8.5. Both As(III)- and As(V)-NRE surface configurations were postulated by vibration spectroscopy. Spectroscopically, it is shown that arsenite forms monodentate complexes whereas arsenate forms bidendate complexes with NRE. When 4<pH<8 and [total arsenic as As(III) or As(V)]=0.385 micromol/L both arsenite and arsenate exhibit near 100% adsorption for a 10-fold variation of ionic strength that is ascribed to inner-sphere complexation of surface bonding. Arsenite exhibits an apparent bond-switching mechanism from inner-sphere to outer-sphere at excess As(III) loading (total arsenic as As(III) or As(V)]=38.5 micromol/L. Competitive effect of arsenate for arsenite adsorption sites was observed when [initial As]=0.385 micromol/L. In dual adsorbate systems the Gamma(As(III)) was reduced over 20%, showing a competition of arsenite for arsenate binding sites (or vice versa). All experimental data were quantified with a 2pK generalized diffused layer model considering two site types for both protons and anions binding using reaction stoichiometries, as follows: [table, see text].


Potent men undergoing radical prostatectomy: a prospective study measuring sexual health outcomes and the impact of erectile dysfunction treatments.
Radical prostatectomy (RP) can have a significant impact on sexual health. The purpose of this study was to measure changes in sexual health after RP, assess the impact of various treatments for erectile dysfunction, and define an appropriate endpoint for maintaining sexual health after surgery. One hundred sixteen men with good preoperative sexual health undergoing RP completed a validated anonymous survey preop and annually thereafter. Subgroup analysis was performed based on the use of erectile dysfunction (ED) treatments. Endpoints for evaluation included an erection adequate for intercourse and a return to baseline in sexual domain scores. Overall there was a significant reduction in scores after surgery for each of the sexual health questions and the function and bother domains. ED treatments providing an erection adequate for intercourse resulted in domain scores significantly higher than those in men unable to achieve such an endpoint, and comparable to those of men returning to good native erectile function, but still lower than preop. Even in men with good preoperative sexual health, with erections adequate for intercourse postop, the return to baseline rate was only 26% in sexual function and 40% in sexual bother. RP appears to have a significant impact on sexual health. Overall, ED treatments, when providing a functional erection, improve sexual health scores, even comparable to men returning to spontaneous erectile function. Although, men functioning well prior to surgery infrequently returned to their preoperative level of sexual health, even with return of native erectile function or the successful use of an ED treatment.


HOXA-AS2 enhances GBM cell malignancy by suppressing miR-2116-3p thereby upregulating SERPINA3.
Glioblastoma (GBM) is malignant, demanding more attention to the improvement of the diagnosis and therapy. LncRNAs have been implicated in the malignancy of GBM cells. HOXA-AS2, miR-2116-3p and SERPINA3 expression levels in GBM tissues and cell lines were detected by qRT-PCR. Western blotting was performed to detect the protein levels of Bax and Bcl-2. Dual-luciferase reporter assay was for detection of relationship among these factors, together with RIP and RNA pull-down. CCK-8, EdU, wound healing and transwell assays were for detection of the role of HOXA-AS2, miR-2116-3p and SERPINA3 in cell viability, proliferation, migration and invasion in GBM, respectively. HOXA-AS2 and SERPINA3 showed higher level in GBM tissues and cell lines. Low level of HOXA-AS2 attenuated GBM cell growth in vitro. Moreover, the anti-tumor impact of silenced HOXA-AS2 was restored by miR-2116-3p inhibitor, but its tumor-promotional effect could be reversed by silenced SERPINA3. HOXA-AS2 enhanced GBM cell malignancy through sponging miR-2116-3p and releasing SERPINA3, which might shed light on the diagnosis and therapy for GBM in the future.


Inability to verify parasagittal cerebral injury as a neuropathologic entity in the asphyxiated term neonate.
Localization of brain injury to parasagittal arterial border zones in the asphyxiated term neonate has been recently described as a frequent, clinically significant finding. However, pathologic examination of the brains of 79 term infants did not reveal a parasagittal distribution of damage. Coronal CT scans of 13 asphyxiated neonates with clinical findings of proximal hypotonia, and repeat scans 6-12 months later in seven patients, have not demonstrated watershed areas of decreased density. A larger series of prospectively identified, surviving neonates is needed to determine whether clinically relevant parasagittal injury may be present in this population.


Hollow-Core Negative Curvature Fiber with High Birefringence for Low Refractive Index Sensing Based on Surface Plasmon Resonance Effect.
In this paper, a hollow-core negative curvature fiber (HC-NCF) with high birefringence is proposed for low refractive index (RI) sensing based on surface plasmon resonance effect. In the design, the cladding region of the HC-NCF is composed of only one ring of eight silica tubes, and two of them are selectively filled with the gold wires. The influences of the gold wires-filled HC-NCF structure parameters on the propagation characteristic are investigated by the finite element method. Moreover, the sensing performances in the low RI range of 1.20-1.34 are evaluated by the traditional confinement loss method and novel birefringence analysis method, respectively. The simulation results show that for the confinement loss method, the obtained maximum sensitivity, resolution, and figure of merit of the gold wires-filled HC-NCF-based sensor are -5700 nm/RIU, 2.63 × 10-5 RIU, and 317 RIU-1, respectively. For the birefringence analysis method, the obtained maximum sensitivity, resolution, and birefringence of the gold wires-filled HC-NCF-based sensor are -6100 nm/RIU, 2.56 × 10-5 RIU, and 1.72 × 10-3, respectively. It is believed that the proposed gold wires-filled HC-NCF-based low RI sensor has important applications in the fields of biochemistry and medicine.


Regulation of biphasic drug release behavior by graphene oxide in polyvinyl pyrrolidone/poly(ε-caprolactone) core/sheath nanofiber mats.
One of the key issues for drug delivery systems is to develop a drug carrier with a time-programmed, biphasic release behavior. Using vancomycin hydrochloride (VAN) as a model drug, polyvinyl pyrrolidone (PVP) blended with graphene oxide (GO) sheets as the core matrix, and poly(ε-caprolactone) (PCL) as the sheath polymer, core/sheath PVP/PCL nanofiber mats were fabricated via a coaxial electrospinning process. We hypothesized that the addition of GO sheets would lead to their molecular interactions with VAN molecules, thereby adjusting the VAN release behavior. Field emission scanning electron microscopy and transmission electron microscopy of the fiber mats revealed their nanofibrous structure and clear core/sheath boundary. Raman analysis demonstrated the presence of GO sheets in the PVP/PCL nanofiber mats. Fourier transform infrared spectroscopy indicated the formation of hydrogen bonds between GO sheets and VAN molecules. In vitro studies showed that the PVP/PCL nanofiber mats were biocompatible, despite the addition of GO sheets, and exhibited typical biphasic drug release profiles, which were tailored by adjusting the content of GO sheets. Furthermore, an antimicrobial test showed different antimicrobial activities of the medicated nanofiber mats, depending on the GO content. Collectively, the results of the present study provide a simple approach to obtaining time-programmed drug release profiles.


Comparison of choroidal and retinal endothelial cells: characteristics and response to VEGF isoforms and anti-VEGF treatments.
Neovascular eye diseases such as wet age-related macular degeneration and proliferative diabetic retinopathy are two of the most common causes of irreversible visual loss. Although mediated by vascular endothelial growth factor (VEGF), the mechanisms of these diseases are not fully understood. Molecular inhibitors of VEGF including pegaptanib, ranibizumab and bevacizumab are used as treatments for these diseases. However, there have been very few direct comparisons between these agents, and as dose and treatment regimes differ their relative efficacies are hard to determine. In vitro comparisons tend to use cells from different sites or species, which show heterogeneity in their responses. The aim of this study was to compare the characteristics of primary cultures of isolated human choroidal endothelial cells (hCEC) and retinal endothelial cells (hREC), and their proliferation responses to stimulation with VEGF 121 and 165, and to compare the anti-proliferative effects of these three drugs. hCEC and hREC were positive for the cell markers VEGFR1, VEGFR2, CD31, CD34 and von Willebrand's factor (vWF), with greater expression of CD34 on the hREC compared to hCEC. Contrary to previous assumptions VEGF isoforms 121 and 165 were found to be equally potent in stimulating endothelial cell proliferation. However, hREC exhibited higher proliferation with either VEGF isoform compared to hCEC. The anti-VEGF treatments ranibizumab and bevacizumab were effective in decreasing proliferation of hCEC induced by the two VEGF isoforms, individually and in combination, with ranibizumab being moderately more effective, particularly in hREC. Pegaptanib was effective in controlling the proliferation of hCEC stimulated by VEGF 165, but was ineffective against the stimulatory effect of VEGF 121. There were found to be significant differences in microvascular endothelial cells from the retina and choroid, both in the expression of cell markers and their behaviour in response to growth factors and currently available anti-VEGF agents, highlighting the importance of targeting treatments to specific intraocular vascular beds and/or diseases.


Incidence of cancer of the lung, stomach, breast, and cervix in the USSR: pattern and trends.
The most frequent fatal malignant tumors in the Soviet Union are cancers of the lung, stomach, breast, and cervix uteri. From incidence statistics and population estimates provided by the Department of Statistics of the Ministry of Health, age-adjusted incidence rates for the period 1971-87, using the World standard population, have been computed for the USSR as a whole and for each of the 15 Soviet republics. For six republics believed to have the highest quality of data and relatively homogeneous populations, time-trends are examined over the period. There is important geographical variation in the incidence of malignant tumors in the Soviet Union. The differences between high and low incidence areas are four-fold for cancer of the lung and stomach, three-fold for cancer of the breast and two-fold for cancer of the cervix. Overall in the six republics for which time-trends are examined, cancers of the lung and breast have increased, cancers of the stomach and cervix have decreased. There are some variations in specific age groups in some republics.


Effect of the larynx on ventilation and respiratory pattern in anesthetized rabbits.
The effects of the larynx on ventilation and pattern of breathing have been investigated in anesthetized, spontaneously breathing rabbits. Breathing was either via a tracheostomy or via a supralaryngeal tube in control condition, after laryngeal denervation and after subsequent bilateral midcervical vagotomy. Laryngeal resistance was measured in all experimental conditions when breathing was through the larynx. In control conditions the presence of the larynx in the breathing circuit, as compared to breathing through the tracheostomy, slightly but significantly lowered inspiratory and expiratory airflows, tidal volume, and minute ventilation and increased tracheal pressure. Inspiratory and expiratory durations were not significantly changed. Expiratory laryngeal resistance was higher than inspiratory. Laryngeal deafferentation did not significantly modify values of the respiratory variables. Subsequent motor denervation of the larynx enhanced the decrease in ventilatory parameters due to adding the larynx to the circuit and lengthened the respiratory cycle. Inspiratory laryngeal resistance increased sevenfold and expiratory resistance threefold. Subsequent midcervical vagotomy induced a further increase in inspiratory and expiratory durations and augmented tidal volume independent of the route of breathing, and also reduced laryngeal resistance previously increased by motor denervation. These results reveal the ventilatory effects of the larynx and show the importance of its patency in the pattern of breathing.


Lessons from neonatal β-cell epigenomic for diabetes prevention and treatment.
Pancreatic β-cell expansion and functional maturation during the birth-to-weaning period plays an essential role in the adaptation of plasma insulin levels to metabolic needs. These events are driven by epigenetic programs triggered by growth factors, hormones, and nutrients. These mechanisms operating in the neonatal period can be at least in part reactivated in adult life to increase the functional β-cell mass and face conditions of increased insulin demand such as obesity or pregnancy. In this review, we will highlight the importance of studying these signaling pathways and epigenetic programs to understand the causes of different forms of diabetes and to permit the design of novel therapeutic strategies to prevent and treat this metabolic disorder affecting hundreds of millions of people worldwide.


Significance of high-sensitivity cardiac troponin T in hypertrophic cardiomyopathy.
This study investigated the significance of the serum high-sensitivity cardiac troponin T (hs-cTnT) marker for prediction of adverse events in hypertrophic cardiomyopathy (HCM). Although serum cardiac troponins as sensitive and specific markers of myocardial injury have become well-established diagnostic and prognostic markers in acute coronary syndrome, the usefulness of hs-cTnT for prediction of cardiovascular events in patients with HCM is unclear. We performed clinical evaluation, including measurements of hs-cTnT in 183 consecutive patients with HCM. Of 183 HCM patients, 99 (54%) showed abnormal hs-cTnT values (>0.014 ng/ml). During a mean follow-up of 4.1 ± 2.0 years, 32 (32%) of the 99 patients in the abnormal hs-cTnT group, but only 6 (7%) of 84 patients with normal hs-cTnT values, experienced cardiovascular events: cardiovascular deaths, unplanned heart failure admissions, sustained ventricular tachycardia, embolic events, and progression to New York Heart Association functional class III or IV status (hazard ratio [HR]: 5.05, p < 0.001). Abnormal hs-cTnT value remained an independent predictor of these cardiovascular events after multivariate analysis (HR: 3.23, p = 0.012). Furthermore, in the abnormal hs-cTnT group, overall risk increased with an increase in hs-cTnT value (HR: 1.89/hs-cTnT 1 SD increase in the logarithmic scale, 95% confidence interval: 1.13 to 3.15; p = 0.015 [SD: 0.59]). In patients with HCM, an abnormal serum concentration of hs-cTnT is an independent predictor of adverse outcome, and a higher degree of abnormality in hs-cTnT value is associated with a greater risk of cardiovascular events.


[The importance of the determination of intraerythrocytic sodium for the differential diagnosis and the control of the progression of essential hypertension].
Intraerythrocytic sodium concentration in 432 patients with essential hypertension under antihypertensive therapy with various drugs was determined. Aim of this investigation was to detect the importance of such finding for diagnosis and control of essential hypertension. According results presented intraerythrocytic sodium should be investigated in beginning of each antihypertensive therapy and later in intervals of 6-8 months to control effectiveness of therapy.


Clinical effects of scaling and root planing in adults infected with Actinobacillus actinomycetemcomitans.
The periodontal pathogen Actinobacillus actinomycetemcomitans can frequently be isolated from subgingival plaque of adults with chronic inflammatory periodontal disease and individuals with plaque-induced gingivitis. Problems with the persistence of the organism after thorough debridement of root surfaces have been reported. In the present study clinical effects of the hygienic phase of periodontal therapy in ten adult patients with moderate or advanced periodontitis harbouring A. actinomycetemcomitans were analysed. Since proper analysis of highly correlated data within a given patient is crucial for appropriate interpretation, a major objective of this study was to compare the results of different models derived from logistic regression of clinical and microbiological factors on gain or loss of clinical attachment under different assumptions. Subgingival samples from every tooth present were obtained before and 6 weeks after thorough subgingival scaling, and selectively cultivated for the organism. A relevant gain of clinical attachment of 2 mm or more was observed at a total of 36% of periodontitis sites after scaling. Overall, loss of attachment of 2 mm or more was observed at 8% sites. Most loss occurred at sites with gingival enlargement (15%), whereas 3% periodontitis sites lost 2 mm or more. In multivariate analyses erroneously assuming either independence of data or correctly considering the correlated structure of observations attachment gain was mainly associated with deep probing depths at the outset. Presence or absence of A. actinomycetemcomitans before or after therapy was not included into the periodontitis models. Also, loss of attachment of 2 mm or more after subgingival scaling was not influenced by the organism. A direct comparison of the results obtained with both approaches of logistic regression may be helpful in the assessment of the influence of the magnitude of correlation of the data on the regression coefficients.


[Cranial complications in extension therapy of cervical fractures. Riechert's modification of extension therapy].
Cranial complications are reported in the treatment of cervical injury by Crutchfield skull caliper traction. The mechanical causes are discussed and a new skull caliper is demonstrated.


Carbon neutral hydrogen storage and release cycles based on dual-functional roles of formamides.
The development of alternative clean energy carriers is a key challenge for our society. Carbon-based hydrogen storage materials are well-suited to undergo reversible (de)hydrogenation reactions and the development of catalysts for the individual process steps is crucial. In the current state, noble metal-based catalysts still dominate this field. Here, a system for partially reversible and carbon-neutral hydrogen storage and release is reported. It is based on the dual-functional roles of formamides and uses a small molecule Fe-pincer complex as the catalyst, showing good stability and reusability with high productivity. Starting from formamides, quantitative production of CO-free hydrogen is achieved at high selectivity ( > 99.9%). This system works at modest temperatures of 90 °C, which can be easily supplied by the waste heat from e.g., proton-exchange membrane fuel cells. Employing such system, we achieve >70% H2 evolution efficiency and >99% H2 selectivity in 10 charge-discharge cycles, avoiding undesired carbon emission between cycles.


Increased prevalence of nodular thyroid disease in patients with Klinefelter syndrome.
Thyroid dysfunction in patients with Klinefelter syndrome (KS) remains an unresolved issue. Although low free thyroxine (FT4) levels within the normal range and normal thyroid stimulating hormone (TSH) levels have been reported, there is currently no data on nodular thyroid disease in this population. This study aims to evaluate the results of thyroid ultrasound (US) examinations in KS patients compared with healthy controls. A cohort of 122 KS and 85 age-matched healthy male controls underwent thyroid US screening and thyroid hormone analysis. According to US risk-stratification systems, nodules ≥1 cm were examined by fine needle aspiration (FNA). Thyroid US detected nodular thyroid disease in 31% of KS compared to 13% of controls. No statistical differences in the maximum diameter of the largest nodules and in moderate and highly suspicious nodules were found between patients and the control group. Six KS patients and two controls with nodules underwent FNA and were confirmed as cytologically benign. In line with published data, FT4 levels were found significantly near the lower limit of the normal range compared to controls, with no differences in TSH values between the two groups. Hashimoto's thyroiditis was diagnosed in 9% of patients with KS. We observed a significantly higher prevalence of nodular thyroid disease in KS compared to the control group. The increase in nodular thyroid disease is likely linked to low levels of FT4, inappropriate TSH secretion, and/or genetic instability.


Novel Questionnaires for Assessing Signs and Symptoms of Eosinophilic Esophagitis in Children.
Pediatric patients with eosinophilic esophagitis (EoE) experience heterogeneous symptoms and the patient's age may preclude reliable self-report of symptoms. The goal of this study was to develop a patient-reported outcome and an observer-reported outcome questionnaire to evaluate the signs and symptoms of EoE in pediatric patients (≥1 to <12 y of age) in a clinical trial setting. A concept-focused literature review, expert advice meetings, and concept elicitation interviews with pediatric EoE patients and their caregivers were conducted to identify disease-related signs and symptoms. Instructions, items, and response options were drafted. Cognitive debriefing interviews were conducted to evaluate children's and caregivers' ability to understand and respond to the questionnaires and to evaluate the comprehensiveness of the concepts measured. Results from the literature review, expert advice meetings (n = 6), and concept elicitation interviews (n = 24) informed the development of the Pediatric Eosinophilic Esophagitis Sign/Symptom Questionnaire intended for use by patients (PESQ-P) with EoE 8 years or older to younger than 12 years and an observer-reported outcome questionnaire planned for use by caregivers of patients (PESQ-C) 1 year old or older to younger than 12 years. Both questionnaires measure the same concepts; the PESQ-P assesses the frequency, duration, and/or severity of symptoms and the PESQ-C assesses the presence/absence of the signs/symptoms. The cognitive debriefing interviews (n = 17) demonstrated that participants were able to comprehend and complete the questionnaires as intended. This study provides evidence of the content validity of 2 novel questionnaires, PESQ-P and PESQ-C, designed to evaluate the symptom experience of pediatric EoE patients in a clinical trial setting.


Targeting Notch signaling with a Notch2/Notch3 antagonist (tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency.
The Notch pathway plays an important role in both stem cell biology and cancer. Dysregulation of Notch signaling has been reported in several human tumor types. In this report, we describe the development of an antibody, OMP-59R5 (tarextumab), which blocks both Notch2 and Notch3 signaling. We utilized patient-derived xenograft tumors to evaluate antitumor effect of OMP-59R5. Immunohistochemistry, RNA microarray, real-time PCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts. We found that anti-Notch2/3, either as a single agent or in combination with chemotherapeutic agents was efficacious in a broad spectrum of epithelial tumors, including breast, lung, ovarian, and pancreatic cancers. Notably, the sensitivity of anti-Notch2/3 in combination with gemcitabine in pancreatic tumors was associated with higher levels of Notch3 gene expression. The antitumor effect of anti-Notch2/3 in combination with gemcitabine plus nab-paclitaxel was greater than the combination effect with gemcitabine alone. OMP-59R5 inhibits both human and mouse Notch2 and Notch3 function and its antitumor activity was characterized by a dual mechanism of action in both tumor and stromal/vascular cells in xenograft experiments. In tumor cells, anti-Notch2/3 inhibited expression of Notch target genes and reduced tumor-initiating cell frequency. In the tumor stroma, OMP-59R5 consistently inhibited the expression of Notch3, HeyL, and Rgs5, characteristic of affecting pericyte function in tumor vasculature. These findings indicate that blockade of Notch2/3 signaling with this cross-reactive antagonist antibody may be an effective strategy for treatment of a variety of tumor types.


Influence of implantation side on the integration of dental implants. A study on miniature pigs.
'...significant differences in the bone-to-implant contact depending on the side of implantation.'


Lafora-like inclusion bodies in the CNS of aged dogs.
Forty randomly selected dogs, arranged into three groups according to age, were examined light and electron microscopically. Lafora-like inclusion bodies were found in all cases of aged dogs without neurological signs. They appeared as PAS positive, round bodies measuring up to 15 mu in diameter. Typically they had central cores and radiating peripheral lines. Electronmicroscopically, the inclusions consisted of irregularly clustered, short branching filaments measuring about 80--120 A in diameter or of electron-dense homogeneous or granular central cores with filamentous peripheral areas and located both in the perikarya and neuronal processes. The inclusions were disseminated all over the brain and spinal cord. The thalamic nuclei, a circumscribed area dorsal to the aqueduct, and the molecular layer of the superior colliculus were the most severely affected. The frequency of the inclusions showed age-dependency; the inclusions were not found in dogs younger than 2 years, but were extensive in all dogs of more than 8 years of age. The occurrence of the inclusions may therefore represent an age-dependent phenomenon. The relationship between the present findings and Lafora's disease is discussed.


[Distal bone metastases of transitional-cell carcinoma of the bladder. Apropos of a case].
To report a case of transitional cell carcinoma of the bladder metastatic to the right knee and review the literature. A 65-year-old patient who had refused to undergo surgery for a T2 N0 M0 bladder tumor in 1995 was admitted for poor general condition and a mass in the right knee. Biopsy confirmed bony metastasis of a carcinoma compatible with primary urothelial tumor of the bladder. Bony metastasis of transitional cell carcinoma of the bladder is relatively frequent and mainly to the spine. Distal bony lesions are rare and usually appear in the advanced stages of the disease.


Association between affective temperaments and severe coronary artery disease.
Affective temperaments are regarded as subclinical manifestations of major mood disorders and cumulating evidence suggest their role in cardiovascular (CV) pathology. We wished to analyze associations between affective temperaments and severe coronary artery disease (CAD), as assessed by coronary computed tomography angiography (CCTA). 225 consecutive patients referred to CCTA due to suspected CAD were included. Medical history and demographic parameters were recorded and all patients completed the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A). The severity and extent of CAD was evaluated by CCTA. Logistic regression analysis was used to identify predictors of severe CAD (≥70% luminal stenosis in ≥1 major coronary artery). According to multivariate logistic regression analysis, elevated hyperthymic affective temperament scores significantly decreased the odds of severe CAD (OR=0.92 CI: 0.84-1.00, p = 0.04), while independent positive associations were observed in case of dyslipidemia (OR=4.23 CI: 1.81-9.88, p = 0.001) and cyclothymic affective temperament scores (OR=1.12 CI: 1.02-1.23, p = 0.02). Furthermore, receiver operating curve (ROC) analysis was used to define ideal cutoff values. Hyperthymic temperament scores >11 (OR=0.41 CI: 0.19-0.90, p = 0.03), cyclothymic scores >7 (OR=3.23 CI: 1.35-7.76, p = 0.01) and irritable scores >6 (OR=2.79 CI: 1.17-6.69, p = 0.02) were also independently associated with severe CAD. Our study was limited by the cross-sectional design and the self-report nature of the questionnaires. Evaluation of affective temperaments might help to identify patients with elevated risk for severe CAD and subsequent need for coronary intervention.


Alterations with age in the biomechanical behavior of human ureteral wall: Microstructure-based modeling.
The human ureters have not been thoroughly explored from the biomechanics perspective, despite the wealth of such data for other soft-tissue types. This study was motivated by the need to use relevant biomechanical data from human ureters and microstructure-based material formulations for simulations of ureteral peristalsis and stenting. Our starting choice was the four-fiber family model that has proven its validity as a descriptor of the multiaxial response of cardiovascular tissues. The degree of model complexity, required for rigorous fits to passive quasi-static pressure-diameter-force data at several axial stretches, was systematically investigated. Ureteral segments from sixteen human autopsy subjects were evaluated. A diagonal and axial family model allowed equally-good fits as the full model for all age groups and ureteral regions; considerably better than those allowed by the phenomenological Fung-type model whose root-mean-square error of fitting was three-fold greater. This reduced model mimicked the structure seen in histologic sections, namely plentiful diagonal collagen fibers in the lamina propria and axial fibers in the muscle and adventitia. The paucity of elastin fibers and mixed muscle orientation justified the use of isotropic muscle-dominated matrix with small neo-Hookean parameter values. The significantly thicker lamina propria in the lower than the upper ureter of young subjects (312 ± 27 vs. 232 ± 26 μm; mean ± standard error) corroborated the significant regional differences in diagonal-fiber family parameter values. The significant muscle thickening with age (upper ureter: 373 ± 48 vs. 527 ± 67 μm; middle: 388 ± 29 vs. 575 ± 69 μm; lower: 440 ± 21 vs. 602 ± 71 μm) corroborated the significant age-related increase in axial-fiber family parameter values.


The human disease network in terms of dysfunctional regulatory mechanisms.
Elucidation of human disease similarities has emerged as an active research area, which is highly relevant to etiology, disease classification, and drug repositioning. In pioneer studies, disease similarity was commonly estimated according to clinical manifestation. Subsequently, scientists started to investigate disease similarity based on gene-phenotype knowledge, which were inevitably biased to well-studied diseases. In recent years, estimating disease similarity according to transcriptomic behavior significantly enhances the probability of finding novel disease relationships, while the currently available studies usually mine expression data through differential expression analysis that has been considered to have little chance of unraveling dysfunctional regulatory relationships, the causal pathogenesis of diseases. We developed a computational approach to measure human disease similarity based on expression data. Differential coexpression analysis, instead of differential expression analysis, was employed to calculate differential coexpression level of every gene for each disease, which was then summarized to the pathway level. Disease similarity was eventually calculated as the partial correlation coefficients of pathways' differential coexpression values between any two diseases. The significance of disease relationships were evaluated by permutation test. Based on mRNA expression data and a differential coexpression analysis based method, we built a human disease network involving 1326 significant Disease-Disease links among 108 diseases. Compared with disease relationships captured by differential expression analysis based method, our disease links shared known disease genes and drugs more significantly. Some novel disease relationships were discovered, for example, Obesity and cancer, Obesity and Psoriasis, lung adenocarcinoma and S. pneumonia, which had been commonly regarded as unrelated to each other, but recently found to share similar molecular mechanisms. Additionally, it was found that both the type of disease and the type of affected tissue influenced the degree of disease similarity. A sub-network including Allergic asthma, Type 2 diabetes and Chronic kidney disease was extracted to demonstrate the exploration of their common pathogenesis. The present study produces a global view of human diseasome for the first time from the viewpoint of regulation mechanisms, which therefore could provide insightful clues to etiology and pathogenesis, and help to perform drug repositioning and design novel therapeutic interventions.


Inhibition of protein kinase C by defensins, antibiotic peptides from human neutrophils.
Defensins, human neutrophil peptide (HNP) antibiotics, potently inhibited phospholipid/Ca2+ protein kinase (protein kinase C, PKC) and phosphorylation of endogenous proteins from rat brains catalyzed by the enzyme. Of the three defensin peptides, HNP-2 appeared to be more potent than HNP-1 and HNP-3. Kinetic studies indicated that defensins inhibited PKC noncompetitively with respect to phosphatidylserine (a phospholipid cofactor), Ca2+ (an activator), ATP (a phosphoryl donor) and histone H1 (a substrate protein) with Ki values ranging from 1.2 to 1.7 microM. Defensins, unlike polymyxin B (another peptide inhibitor of PKC), did not inhibit the binding of [3H]phorbol 12,13-dibutyrate to PKC; however, defensins, like polymyxin B, inhibited the PKC activity stimulated by 12-O-tetradecanoylphorbol-13-acetate. Defensins had little or no effect on myosin light chain kinase (a calmodulin/Ca2+-dependent protein kinase) and the holoenzyme or catalytic subunit of cyclic AMP-dependent protein kinase, indicating a specificity of action of defensins. It is suggested that defensins, among the most potent peptide inhibitors of PKC so far identified, may have profound effects on functions of neutrophils and other mammalian cells, in addition to their well-recognized antimicrobial activities.


Thoracic helical CT: influence of subsecond scan time and thin collimation on evaluation of peripheral pulmonary arteries.
The objective of this study was to analyze the influence of collimation on the identification of peripheral pulmonary arteries on helical CT scans. Three hundred sixty of 370 consecutive helical CT angiograms of the pulmonary circulation obtained during an 18-month investigation period were considered as technically acceptable for the detection of acute pulmonary embolism and were retrospectively analyzed. Patients in group A (n = 274) underwent CT with 2-mm collimation and pitch of 2; those in group B (n = 86) underwent CT with 3-mm collimation and pitch 1.7; a 0.75-s rotation time was systematically used. A total of 2160 segmental (six arterial zones per patient) and 2160 subsegmental (six arterial zones per patient) arterial zones were assessed. Whereas the percentage of segmental arteries was not significantly different between group A (86%) and group B (89%), the percentage of analyzable subsegmental arteries was greater in group A (65%) than in group B (43 %) (P<0.001). The causes of inadequately depicted subsegmental arterial zones were partial-volume effects (group A, n = 302; 52%; group B, n = 197; 67%; P<0.001), suboptimal enhancement (group A, n = 145; 25%; group B, n = 43; 15%; P<0.05), motion artifacts (group A, n = 113; 20%; group B, n = 30; 10%), and unincluded arteries (group A, n = 20; 3%; group B, n = 25; 8%). Helical CT with 2-mm collimation at 0.75 s per revolution enables marked improvement in the analysis of subsegmental arteries in routine clinical practice.


Emphysematous cholecystitis: pitfalls in its plain film diagnosis.
The clinical and radiographic findings of emphysematous cholecystitis are usually characteristic. However, on occasion the radiographic findings may be simulated by other processes. In such circumstances accurate diagnosis can usually be rapidly established by a variety of simple radiographic maneuvers and procedures. Five illustrative cases are presented herein and the pertinent literature is reviewed.


Isolation of specific peptides that home to dorsal root ganglion neurons in mice.
We isolated peptides that home to mouse dorsal root ganglion (DRG) from a phage library expressing random 7-mer peptides fused to a minor coat protein (pIII) of the M13 phage. An in vitro biopanning procedure yielded 113 phage plaques after five cycles of enrichment by incubation with isolated DRG neurons and two cycles of subtraction by exposure to irrelevant cell lines. Analyses of the sequences of this collection identified three peptide clones that occurred repeatedly during the biopanning procedure. Phage-antibody staining revealed that the three peptides bound to DRG neurons of different sizes. To determine if the peptides would recognize neuronal cells in vivo, we injected individual GST-peptide-fusion proteins into the subarachnoid space of mice and observed the appearance of immunoreactive GST in the cytosol of DRG neurons with a similar size distribution as that observed in vitro, indicating that the GST-peptide-fusion proteins were recognized and taken up by different DRG neurons in vivo. The identification of homing peptide sequences provides a powerful tool for future studies on DRG neuronal function in vitro and in vivo, and opens up the possibility of neuron-specific drug and gene delivery in the treatment of diseases affecting DRG neurons.


Pemafibrate, a PPAR alpha agonist, attenuates neointima formation after vascular injury in mice fed normal chow and a high-fat diet.
Recently, the prevention of cardiovascular events has become one of the most important aims of diabetes care. Peroxisome proliferator-activated receptor (PPAR) agonists have been reported to have vascular protective effects. Here, we examined whether pemafibrate, a selective PPAR alpha agonist, attenuated neointima formation after vascular injury and vascular smooth muscle cell (VSMC) proliferation. We performed endothelial denudation injury in mice treated with a high-fat diet (HFD) or normal chow. Orally administered pemafibrate significantly attenuated neointima formation after vascular injury in HFD and normal chow mice. Interestingly, pemafibrate increased the serum fibroblast growth factor 21 concentration and decreased serum insulin concentrations in HFD mice. In addition, body weight was slightly but significantly decreased by pemafibrate in HFD mice. Pemafibrate, but not bezafibrate, attenuated VSMC proliferation in vitro. The knockdown of PPAR alpha abolished the anti-VSMC proliferation effect of pemafibrate. BrdU assay results revealed that pemafibrate dose-dependently inhibited DNA synthesis in VSMCs. Flow cytometry analysis demonstrated that G1-to-S phase cell cycle transition was significantly inhibited by pemafibrate. Pemafibrate attenuated serum-induced cyclin D1 expression in VSMCs. However, apoptosis was not induced by pemafibrate as assessed by the TUNEL assay. Similar to the in vitro data, VSMC proliferation was also decreased by pemafibrate in mice. These data suggest that pemafibrate attenuates neointima formation after vascular injury and VSMC proliferation by inhibiting cell cycle progression.


Functional study of CHS gene family members in citrus revealed a novel CHS gene affecting the production of flavonoids.
Citrus flavonoids are considered as the important secondary metabolites because of their biological and pharmacological activities. Chalcone synthase (CHS) is a key enzyme that catalyses the first committed step in the flavonoid biosynthetic pathway. CHS genes have been isolated and characterized in many plants. Previous studies indicated that CHS is a gene superfamily. In citrus, the number of CHS members and their contribution to the production of flavonoids remains a mystery. In our previous study, the copies of CitCHS2 gene were found in different citrus species and the sequences are highly conserved, but the flavonoid content varied significantly among those species. From seventy-seven CHS and CHS-like gene sequences, ten CHS members were selected as candidates according to the features of their sequences. Among these candidates, expression was detected from only three genes. A predicted CHS sequence was identified as a novel CHS gene. The structure analysis showed that the gene structure of this novel CHS is very similar to other CHS genes. All three CHS genes were highly conserved and had a basic structure that included one intron and two exons, although they had different expression patterns in different tissues and developmental stages. These genes also presented different sensitivities to methyl jasmonate (MeJA) treatment. In transgenic plants, the expression of CHS genes was significantly correlated with the production of flavonoids. The three CHS genes contributed differently to the production of flavonoids. Our study indicated that CitCHS is a gene superfamily including at least three functional members. The expression levels of the CHS genes are highly correlated to the biosynthesis of flavonoids. The CHS enzyme is dynamically produced from several CHS genes, and the production of total flavonoids is regulated by the overall expression of CHS family genes.


Differential expression of DNA nonhomologous end-joining proteins Ku70 and Ku80 in melanoma progression.
Ku70 and Ku80 heterodimers function as regulatory subunits of the DNA-dependent protein kinase and play a very important role in the repairing of DNA double-strand breaks. Although Ku70 is proposed as a candidate for a tumor suppressor gene, not many data are available on Ku70 and Ku80 expression in human tumors. The main aim of this study was to investigate the expression of Ku70 and Ku80 in the ultraviolet-induced lesions-nevus cell nevi, lentigos maligna, and malignant melanomas. Nineteen nevus cell nevi, 23 lentigos maligna, 76 primary melanomas, and 31 melanoma metastases were stained immunohistochemically for the presence of Ku70 and Ku80 proteins. Ku70 and Ku80 expression was preserved in about 80% of nevi, 26% of lentigo maligna, 45% of primary melanomas, and 67% of melanoma metastases. Highly significant differences in Ku70 and Ku80 expression were found between nevi, lentigo maligna, and melanomas. In Cox regression, Ku70 and Ku80 were shown to be highly significant influences on patients' prognosis. Significant correlations between Ku70 and Ku80 expressions were found in nevi, lentigo maligna, and primary melanomas. These correlations were not more present in melanoma metastases. To summarize, earlier phases of melanoma progression seem to be connected with the loss of expression of Ku proteins. Metastatic spread is related to dysregulation of the Ku70 and Ku80 axis.


Variations of lower-limb joint kinematics associated with the use of different ankle joint models.
Skeletal computational models relying on global optimisation are widely used alongside gait analysis for the estimate of joint kinematics, but the degrees of freedom (DOFs) and axes definitions to model the ankle complex are still debated. The aim of this paper is to establish whether ankle modelling choices would also critically affect the estimate of the other joints' kinematics. Gait and MRI data from fifteen juvenile participants were used to implement three ankle joint models (M1, one-DOF sagittal motion; M2, two-DOFs sagittal and frontal motions; M3, three-DOFs) as part of a full lower-limb skeletal model. Differences in lower-limb joint and foot progression angles calculated using global optimisation were evaluated both at individual and group level. Furthermore, the influence of these differences on the correlations between joints and on the calculations of the root mean square deviation (RMSD) were investigated. Inter-model variations at individual level reached up to 4.2°, 9.1°, and 15.0° for hip flexion, adduction, and rotation, respectively, and up to 6.5° for knee flexion. Despite the tibiotalar axis being the same for all models, up to 19.3° (9.1° on average) larger dorsiflexion was found at push-off with M2. A stronger correlation between foot progression and ankle and knee sagittal movements was found for M1. Finally, RMSD led to inconsistent ranking of the participants when using different models. In conclusion, the choice of the ankle joint model affects the estimates of proximal lower-limb joint kinematics, which should discourage comparisons across datasets built with different models.


Different demography of friends and strangers: an experiment on the impact of kinship and familiarity in Clethrionomys glareolus.
We examined demographic effects of familiarity and relatedness in the bank vole Clethrionomys glareolus (Schreber) in four 0.5-ha enclosures in Central Finland. In two enclosures were mature voles which had overwintered together and some of their mature off-spring (hereafter referred to as "Friends"), and in the other two individuals of the same species captured from different localities near the study area ("Strangers"). The experiment lasted from June to September. The populations of Friends reached densities twice as high as those of Strangers with a significantly higher rate of recruitment and survival of the young. This may have been due to mutual familiarity decreasing antagonism towards the juveniles. The conflicting results obtained from studies of Clethrionomys and Microtus are discussed. We believe that these genera represent behavioural adaptations to different habitats and ways of life. Most behavioural population regulation hypotheses are based on studies of Microtus. We conclude that these results should be applied with great caution to other rodent genera.


Variation of natural radionuclides in non-ferrous fayalite slags during a one-month production period.
The European Basic Safety Standards (EU-BSS) describes a set of NORM (Naturally Occurring Radioactive Material)-processing industries which produce residues known to be possibly enriched in NORs (Naturally Occurring Radionuclides). These residues can be used as a component in building materials aimed for public usage. The industrial processes, in which the residues are produced, are often complex and total monitoring can be challenging especially when the origin of the used raw materials varies. In this study the NORs present in non-ferrous fayalite slags of a secondary smelter facility, a NORM-processing industry according to the EU-BSS, were monitored daily during a one-month production period. In addition flue dust samples and feedstock samples, known to contain elevated levels of NORs, of the same period were measured. The survey involved the gamma-ray spectrometric analysis of the decay products from the 238U and 232Th decay chains, 235U and 40K using HPGe detectors. Secular equilibrium was observed for the slags, flue dust and feedstock samples in the 232Th decay chain, in contrast to the 238U decay chain. During the month in question the ratios of maximum over minimum activity concentration were 3.1 ± 0.5 for 40K, 4 ± 1 for 238U, 6 ± 1 for 226Ra, 13 ± 7 for 210Pb, 4.5 ± 0.6 for 228Ra and 4.7 ± 0.7 for 228Th for the slags. Even with the activity concentration of the feedstock material ranging up to 2.1 ± 0.3 kBq/kg for 238U, 1.6 ± 0.2 kBq for 226Ra, 22 ± 7 kBq/kg for 210Pb, 2.1 ± 0.2 kBq/kg for 228Ra and 2.0 ± 0.4 kBq/kg for 228Th, none of the slag samples exceeded the exemption/clearance levels of the EU-BSS and RP-122 part II, which can respectively provide guidance under equilibrium and in absence of equilibrium. As each NORM-processing industry has its own complexity and variability, the observed variations point out that one should approach one-time measurements or low frequency monitoring methods cautiously. Low frequency measurements should be optimised depending on the discharge of the batches. A follow up of the industrial process and its output can provide important insights to assure a limited public exposure upon application of these industrial residues. Finally a comparison is made with reported data on other metallurgical slags and the use of the slags in building materials is evaluated using the Activity Concentration Index (ACI) proposed by the EU-BSS.


Cruciform formation in a negatively supercoiled DNA may be kinetically forbidden under physiological conditions.
Cruciform formation in a pBR322 derivative containing a 68 base pair perfect palindromic sequence has been studied. In relaxed DNA the cruciform is unstable by about 17 kcal mole-1 in free energy. In a supercoiled DNA with a negative specific linking difference (superhelical density) of 0.03 or higher, however, the cruciform becomes the stable species. Nevertheless, even at native superhelical densities (typically around -0.06), cruciform formation is extremely slow, unless the DNA is subjected to conditions that destabilize base pairing. When precautions are taken to avoid artificial triggering of cruciform formation, the 68 bp perfect palindrome-containing plasmid isolated from cells is devoid of the cruciform. The rate of disappearance of the cruciform in linear DNA and the deletion of the palindromic sequence in vivo have also been examined.


[Influence of cytokine preparations on the in vitro resistance of bacteria to antibiotics].
Recombinant tumor necrosis factor-alpha and gamma-interferon were found in vitro to increase the sensitivity of bacteria to antibiotics both alone and in combination; alpha2-interferon decreased this sensitivity.


Association between cardiac tumors and tuberous sclerosis in the fetus and neonate.
A retrospective review was performed in 94 patients with > or =1 cardiac tumors seen on prenatal or neonatal echocardiography at 5 major referral centers. Tuberous sclerosis was present in 68 patients diagnosed with a cardiac tumor in utero or during the neonatal period, including 61 of 64 with multiple tumors.


The fMRI correlates of visuo-spatial abilities: sex differences and gender dysphoria.
The contribution of brain regions to visuospatial abilities according to sex differences and gender identity is inconsistently described. One potential explaining factor may be the different tasks employed requiring a variable load of working memory and other cognitive resources. Here we asked to 20 cis and 20 transgender participants to undergo functional Magnetic Resonance Imaging during performance of a judgement line of orientation test that was adapted to explore the basic visuospatial processing while minimizing the working memory load. We show that V1 activation may be viewed as a brain area with enhanced activation in males, regardless of participants' gender identity. On its turn, gender identity exclusively influences the visuospatial processing of extrastriate visual areas (V5) in women with gender dysphoria. They showed enhanced V5 activation and an increased functional connectivity between V5 and V1. Overall our neuroimaging results suggest that the basic visuospatial abilities are associated with different activations pattern of cortical visual areas depending on the sex assigned at birth and gender identity.


Decreased stage migration rate of early gastric cancer with a new reconstruction algorithm using dual-energy CT images: a preliminary study.
To evaluate the potential value of advanced monoenergetic images (AMEIs) on early gastric cancer (EGC) using dual-energy CT (DECT). 31 EGC patients (19 men, 12 women; age range, 38-81 years; mean age, 57.19 years) were retrospectively enrolled in this study. Conventionally reconstructed polyenergetic images (PEIs) at 120 kV and virtual monoenergetic images (MEIs) and AMEIs at six different kiloelectron volt (keV) levels (from 40 to 90 keV) were evaluated from the 100 and Sn 140 kV dual energy image data, respectively. The visibility and stage migration of EGC for all three image data sets were evaluated and statistically analyzed. The objective and subjective image qualities were also evaluated. AMEIs at 40 keV showed the best visibility (80.7 %) and the lowest stage migration (35.5 %) for EGC. The stage migration for AMEIs at 40 keV was significantly lower than that for PEIs (p = 0.026). AMEIs at 40 keV had statistically higher CNR in the arterial and portal phases, gastric-specific diagnostic performance and visual sharpness compared with other AMEIs, MEIs and PEIs (all p < 0.05). AMEIs at 40 keV with MPR increase the CNR of EGC and thus potentially lower the stage migration of EGC. • AMEIs benefits from the recombination of low-keV images and medium energies. • AMEIs could receive better CNR results than MEIs. • AMEIs at 40 keV potentially lower the stage migration of EGC.


The effects of palatinose on attention and cerebral blood flow in healthy adults: A randomized double-blind placebo-controlled crossover study.
The primary energy source for the brain is glucose, and a continuous supply is required for the brain to work longer. This study aimed to verify the effects of palatinose on attention and cerebral blood flow in healthy adults. This randomized, double-blind, placebo-controlled crossover study included 64 healthy Japanese adults. Participants performed the Digit Vigilance Task (DVT) 60 min pre-ingestion (14:00) and 0 (15:00), 60 (16:00), 120 (17:00), and 180 (18:00) min after ingestion of 10 g of either palatinose or glucose. Cerebral blood flow was measured using a wearable 2CH functional near-infrared spectrometer (fNIRS) during each DVT. The participants underwent the Uchida-Kraepelin (UK) test between each DVT to control for fatigue. DVT reaction times with palatinose intake were significantly shorter than those with glucose intake at 16:00, 17:00, and 18:00 (p = 0.0015, p < 0.001, and p < 0.001, respectively). The change in cerebral blood flow as a function of total hemoglobin level was significantly higher in the palatinose group than in the glucose group (p = 0.018). Regarding the post-UK mood questionnaire, "physically fatigued" and "annoyed" were significantly lower in the palatinose intake group compared to the glucose intake group at 17:00 (p = 0.0445 and p = 0.0318, respectively). Furthermore, "physically fatigued" was significantly lower, and "seriously" was higher in the palatinose intake compared to the glucose intake group at 18:00 (p = 0.00652 and p < 0.001, respectively). These findings suggest that 10 g of palatinose has favorable effects on attention and cerebral blood flow. UMIN000046182.


Vulvovaginal candidiasis and bacterial vaginosis.
Vulvovaginal candidiasis (VVC) and bacterial vaginosis (BV) are frequently encountered in clinical practice. Recent advances have furthered understanding of pathophysiology. Proper diagnosis, based on appropriate office and, in complicated cases, laboratory tests is the key to rational selection of therapy. For women who have routine uncomplicated episodes of VVC or BV, a variety of effective treatment options exists. Recurrent disease remains a challenge for these conditions but can often be managed successfully.


Diagnostic performance of [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography in cyst infection in patients with autosomal dominant polycystic kidney disease.
Cyst infection is a common complication of autosomal dominant polycystic kidney disease (ADPKD). Diagnosis is challenging with standard imaging techniques. We aimed to evaluate the diagnostic performance of [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography (18-FDG PET-CT) for the diagnosis of cyst infections among ADPKD patients, in comparison with computed tomography (CT) and magnetic resonance imaging (MRI). All APKD patients who underwent 18-FDG PET-CT for suspected cyst infection between 2006 and 2013 in a French teaching hospital were included. Diagnosis of cyst infection was retained a posteriori on an index of clinical suspicion. 18-FDG PET-CT findings were was considered to be positive in cases of cyst wall hypermetabolism. CT or MRI findings were were considered to be positive in cases of cyst wall thickening (and enhancement if contrast medium was injected) and infiltration of the adjacent fat. A control group of ADPKD patients with 18-FDG PET-CT performed for other reasons was included. Thirty-two 18-FDG PET-CT scans were performed in 24 ADPKD patients with suspected cyst infection. A diagnosis of cyst infection was retained in 18 of 32 cases: 14 with positive 18-FDG PET-CT findings, and four false negatives. There were no false positives and no hypermetabolism of cyst walls in nine ADPKD control patients. 18-FDG PET-CT had a sensitivity of 77%, a specificity of 100%, and a negative predictive value of 77%. 18-FDG PET-CT allowed a differential diagnosis in three patients. In contrast, CT had a sensitivity of 7% and a negative predictive value of 35% (p <0.001 vs. 18-FDG PET-CT). Only eight MRI scans were performed. The diagnostic performance of 18-FDG PET-CT is superior to that of CT in cyst infections, for comparable radiation doses and with no injection of nephrotoxic contrast medium, in ADPKD patients.


Ofloxacin in juvenile non-human primates and rats. Arthropathia and drug plasma concentrations.
Arthropathia in juvenile animals is the most important toxic effect induced by quinolones. We conducted pharmacokinetic and morphological studies with ofloxacin on non-human primates (Callithrix jacchus, Marmosets) and rats. In the marmoset, electron microscopy and the application of immuno-morphological methods proved to be suitable for the detection of specific alterations in cartilage (e.g. loss of proteoglycans and altered chondrocytes). Subsequently performed electron microscopic examinations in rats showed similar specific alterations of the femur cartilage surface after multiple oral applications of 600 mg ofloxacin/kg body wt. These results were correlated with pharmacokinetic data obtained for the same species. After single oral application of 100, 300 or 600 mg ofloxacin/kg body wt to 5 week-old rats peak plasma levels were achieved 15-45 min after administration indicating a rapid absorption of the drug. The following peak concentrations were measured for the three doses applied (mean +/- SD): 8.9 +/- 2.1, 22.6 +/- 7.5 mg/l and 33.5 +/- 9.8 mg/l, respectively. After 360 min the concentrations were 1.1 +/- 0.4, 5.9 +/- 2.5 and 15.9 +/- 5.1 mg/l, respectively. After subcutaneous injection of 100 mg ofloxacin/kg body wt the mean peak concentration was 27.7 +/- 2.6 mg/l after 45 min (0.5 +/- 0.2 mg/l after 360 min). In the marmoset higher plasma concentrations were measured with comparable doses. One, 3, and 6 h after the last of nine administrations of 200 mg ofloxacin/kg body wt, the mean (+/- SD) plasma concentrations were: 42.7 +/- 16.7, 40.6 +/- 9.5, and 26.5 +/- 3.6 mg ofloxacin/l plasma. Typical alterations of the joint cartilage of juvenile rats (e.g. opened chondrocyte cavities, swelling of rough endoplasmic reticulum and mitochondrial swelling in the chondrocytes) were induced by oral administration of ofloxacin at doses that were approximately 100 times higher than therapeutic ones, but led to peak plasma concentrations which were only approximately 10 times above the therapeutic level.


Gallium-68-labeled fibroblast activation protein inhibitor PET in gastrointestinal cancer: insights into diagnosis and management.
Gallium-68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) is an emerging promising tumor tracer. This study aims to evaluate the diagnostic efficiency of 68Ga-FAPI PET in gastrointestinal cancer, and to determine its potential impact on clinical management. Patients with malignancies were prospectively enrolled in a clinical trial to evaluate the diagnostic value of 68Ga-FAPI PET. One hundred twenty patients with gastrointestinal malignancies (121 68Ga-FAPI PET scans) between June 2020 and May 2021 were retrospectively analyzed. Initial staging of untreated patients and restaging of treated patients were evaluated. The treatment scheme promoted by imaging was determined according to NCCN guidelines. Final diagnosis and treatment reference standards were determined by a dedicated multidisciplinary team. The diagnostic performance and treatment guidance of 68Ga-FAPI PET were compared with those of conventional imaging (CI) and 18F-FDG PET. The diagnostic accuracy of 68Ga-FAPI PET was much higher than that of CI and 18F-FDG PET (95.0% vs. 65.1% and 69.0%, respectively, both p < 0.001). 68Ga-FAPI PET revised diagnosis in 30.3% and 26.2% of patients compared with CI and 18F-FDG PET. The accordance rate of 68Ga-FAPI PET-guided treatment in comparison with the reference standard was significantly higher than that of CI and 18F-FDG PET (96.7% vs. 75.2% and 76.2%, respectively, both p < 0.001). 68Ga-FAPI PET changed treatment in 22.9% and 23.8% of patients compared with CI and 18F-FDG PET. 68Ga-FAPI PET showed remarkable diagnostic performance in gastrointestinal cancer, resulting in more accurate staging and guidance for timely treatment revision, thereby having a critical impact on clinical management. NCT04554719. Registered September 8, 2020-retrospectively registered, http://clinicaltrails.gov/show/NCT04554719.


A novel human hepatoma cell line, FLC-4, exhibits highly enhanced liver differentiation functions through the three-dimensional cell shape.
We characterized three-dimensional human hepatoma cell lines, functional liver cell (FLC) cell lines, to establish a highly differentiated hepatoma cell line. We investigated the effect of extracellular matrix and cell morphology on liver-specific gene expression in FLC cells. The hepatocyte nuclear factor-4α (HNF-4α) and other liver-specific gene expressions were enhanced in spherical FLC-4 cells on EHS-gel, but other human hepatoma cells such as HepG2 did not show the enhancement. Importantly, the liver-specific gene expression levels in spherical FLC-4 cells cultured on EHS-gel were comparable to those of human liver and were much higher than those of other human hepatoma cell lines. The major matrix components and growth factors in EHS-gel did not affect cell shape and liver functions. To exclude any effect of the extracellular matrix, we made spherical FLC-4 cells by actin filament disruption. The actin-disrupted spherical cells also showed an enhanced liver-specific gene expression. We concluded that three-dimensional cell shape per se is one of the most important determinants of liver differentiation functions in FLC-4 cells. Cell morphology-dependent induction of liver-specific gene expression was mediated through microtubule organization. In conclusion, differentiation of FLC-4 human hepatoma cell line can be enhanced to a human liver-like level through the three-dimensional cell shape in a microtubule-dependent manner.


Effects on the development of Dipylidium caninum and on the host reaction to this parasite in the adult flea (Ctenocephalides felis felis).
Temperature was found to be a major factor affecting the development of Dipylidium caninum and the presence of a host reaction of adult Ctenocephalides felis felis to D. caninum. Adult fleas reared at 30-32 degrees C contained fully developed metacestodes when they emerged from their cocoons. However at lower temperatures, D. caninum could not complete development until the flea hosts had spent some time on their mammalian hosts. It was the surface temperature of the mammals (31-36 degrees C) and not the fleas' blood meals which resulted in the metacestodes completing their development. This development of D. caninum was therefore independent of the flea development. At 20 degrees C, a larger and more prolonged host reaction was mounted than at higher temperatures. The larval flea diet had a small effect on the subsequent cestode development and the adult fleas' reaction to it.


Impaired Gastric Hormone Regulation of Osteoblasts and Lysyl Oxidase Drives Bone Disease in Diabetes Mellitus.
Diabetic bone disease is a complication of type I and type II diabetes, both of which are increasing in the United States and elsewhere. Increased hip and foot fracture rates do not correlate well with changes in bone mineral density (BMD), whereas studies support the importance of collagen structure to bone strength. Extracellular lysyl oxidase (LOX) catalyzes the oxidative deamination of hydroxylysine and lysine residues in collagens resulting in aldehydes that subsequently form critically important biosynthetic crosslinks that stabilize functional collagens. Although LOX-dependent biosynthetic crosslinks in bone collagen are deficient in diabetic bone, the expression and regulation of bone LOXs in diabetes have not been comprehensively studied. Here, we found that LOX is profoundly downregulated in bone in diabetes. Moreover, we have identified a novel metabolic regulatory relationship that is dysregulated in diabetes using mouse models. Data indicate that the incretin (gastric hormone) known as glucose-dependent insulinotropic polypeptide (GIP) that is anabolic to osteoblasts strongly upregulates LOX, and that this regulation is disrupted in the streptozotocin-induced model of diabetes in mice. In vivo and in vitro studies support that diabetes results in elevated circulating peripheral dopamine, likely also derived from the gut, and is responsible for blocking GIP signaling and LOX levels in osteoblasts. Moreover, peripheral administration of the dopamine D2 receptor antagonist amisulpride to diabetic mice restored trabecular bone structure to near normal and partially reversed downregulation of LOX. Taken together our data identifies a novel metabolic relationship between the gut-derived hormone GIP and bone-derived LOX, and points to the importance of LOX dysregulation in the pathology of diabetic bone disease. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.


Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection.
Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches; however, what role the BM microenvironment plays in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single-cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over substantially faster than at steady-state and HSC function is drastically affected. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and-coupled with reactive oxygen species quenching-enables partial rescuing of HSC function.


Positive appearance and functionality reflections can improve body satisfaction but do not protect against idealised media exposure.
We tested the effectiveness of a positive appearance or functionality reflective writing task on women's body satisfaction and whether these writing task reflections offered any protective advantage when exposed to idealised imagery. Young adult women (N=230; Mage=23years) wrote about positive elements of either their appearance or their body's functionality, and then were exposed to images of scenery, or thin and attractive models presented in posed or active form. Direction and amount of social comparison were also examined. Women reported immediate gains in both appearance and physical functionality satisfaction regardless of reflection type. However, neither reflection was protective against decreased satisfaction after exposure to idealised images. Greater upward comparison on either appearance or physical functionality domains was related to poorer outcomes. Our reflection task has potential to shift body focus but future research could examine multiple sessions and reflections on a broader range of self-relevant domains.