Relationship between alexithymia, dissociation and personality in psychiatric outpatients.
The relationship between alexithymia and dissociation is not known. Both mechanisms ward off overwhelming affective states; hence, this report examines the relationship between dissociation, alexithymia, depressed mood and the five-factor model of personality in a sample of psychiatric outpatients. One hundred and sixteen outpatients were evaluated using the Toronto Alexithymia Scale (TAS), the Dissociative Experiences Scale (DES), NEO Five-Factor Inventory and visual analog scales assessing depression and anxiety. Data was analyzed using multivariate analysis of variance, logistic regression and linear regression techniques. Depressed mood accounted for the group differences between the global TAS and DES scores. Using DES both dimensionally and categorically with regression models, there was minimal contribution of DES or its subfactors to predict TAS. These data reaffirm previous findings that dissociation fundamentally differs from alexithymia. Dissociation involves a change of one's sense, of self, whereas alexithymia reflects a cognitive state of externally oriented thinking with an inability to identify and report discrete emotions.


Importance of High-Risk Human Papillomavirus Infection Detection in Female Renal Transplant Recipients in the First Year after Transplantation.
Most of human papillomavirus (HPV) infections are "cleared" by the immune system; however, in cases of immune system suppression, infections could lead to development of malignancies. The aim of this study was to find out the frequency of HR-HPV infection in early period after renal transplantation in recipients receiving immunosuppressive therapy and to follow the progression of the infection up to one year. 43 female renal transplant recipients and 79 healthy female individuals as a control group were enrolled in this investigation. For the detection of HPV infection, patients' samples (blood and vaginal swabs) were collected two weeks after transplantation with following collection of six months and one year. Different polymerase chain reactions for HR-HPV genomic sequences detection and ELISA kit for detection of anti-HPV IgG antibodies were used. In this study, we show that frequency rate of HR-HPV infection has increased in the first year after transplantation from early stage of immunosuppressive therapy (from 24% to 36%). Also an increase of HR-HPV load was detected over time, showing the highest median viral load at sixth month after transplantation. From the obtained data, it follows that it is very important to carefully monitor patients receiving immunosuppression therapy on progression of HR-HPV.


Management of Posterior Cruciate Ligament Tibial Avulsion Injuries: A Systematic Review.
Tibial-sided avulsion injuries of the posterior cruciate ligament (PCL) generally require surgical intervention. No consensus exists concerning the optimal surgical treatment approach for these injuries. To perform a systematic review investigating the open and arthroscopic surgical treatment modalities, outcomes, and complications of PCL tibial-sided bony avulsions. Systematic review; Level of evidence, 4. The authors performed a systematic review of the literature utilizing PubMed and EMBASE from 1975 to present outlining open versus arthroscopic surgical repair of PCL bony avulsion injuries and comparing subjective and objective postoperative patient-reported outcomes, including Tegner, IKDC (International Knee Documentation Committee), and Lysholm scoring systems, as well as rates of patient complications. The quest was performed in June 2016, and searched terms included posterior cruciate ligament, PCL, bony, avulsion(s), tibial-sided, open, and arthroscopic. Inclusion criteria included English-language studies involving surgical fixation strategies for PCL tibial-sided bony avulsions. Exclusion criteria included non-English language, case studies/case series, and subject matter not pertaining to PCL bony avulsions. Twenty-eight articles comprising 637 patients met the criteria and were included in the final review. PCL injuries with a tibial-sided avulsion were the result of motor vehicle accidents in 68.4% of patients, with 59.0% of these injuries resulting from motorcycle accidents. The arthroscopic group had better IKDC grade A scores (78.9%), indicating a normal knee postoperatively, as compared with the open group (65.9%). The postoperative Lysholm scores were similar between the groups, with a mean of 95.0 in the arthroscopic group and 92.8 in the open group. The arthroscopic group also reported 100% return to preinjury level of activity, compared with 86.2% in the open group. The most common complication in both groups was arthrofibrosis, which was reported more often in the arthroscopic group (0%-35%) versus the open treatment group (0%-25%). In patients with displaced tibial-sided PCL avulsion fractures treated operatively, surgical approaches render similar outcomes and risks. While the arthroscopic group had somewhat higher subjective and objective knee outcome scores, it demonstrated a slightly higher rate of arthrofibrosis. The clear advantage of the arthroscopic approach is that concomitant intra-articular injuries seen on preoperative magnetic resonance imaging, such as meniscal tears or osteochondral loose fragments, can be addressed at the time of the index operation.


Effects of fish movement assumptions on the design of a marine protected area to protect an overfished stock.
Marine Protected Areas (MPA) are important management tools shown to protect marine organisms, restore biomass, and increase fisheries yields. While MPAs have been successful in meeting these goals for many relatively sedentary species, highly mobile organisms may get few benefits from this type of spatial protection due to their frequent movement outside the protected area. The use of a large MPA can compensate for extensive movement, but testing this empirically is challenging, as it requires both large areas and sufficient time series to draw conclusions. To overcome this limitation, MPA models have been used to identify designs and predict potential outcomes, but these simulations are highly sensitive to the assumptions describing the organism's movements. Due to recent improvements in computational simulations, it is now possible to include very complex movement assumptions in MPA models (e.g. Individual Based Model). These have renewed interest in MPA simulations, which implicitly assume that increasing the detail in fish movement overcomes the sensitivity to the movement assumptions. Nevertheless, a systematic comparison of the designs and outcomes obtained under different movement assumptions has not been done. In this paper, we use an individual based model, interconnected to population and fishing fleet models, to explore the value of increasing the detail of the movement assumptions using four scenarios of increasing behavioral complexity: a) random, diffusive movement, b) aggregations, c) aggregations that respond to environmental forcing (e.g. sea surface temperature), and d) aggregations that respond to environmental forcing and are transported by currents. We then compare these models to determine how the assumptions affect MPA design, and therefore the effective protection of the stocks. Our results show that the optimal MPA size to maximize fisheries benefits increases as movement complexity increases from ~10% for the diffusive assumption to ~30% when full environment forcing was used. We also found that in cases of limited understanding of the movement dynamics of a species, simplified assumptions can be used to provide a guide for the minimum MPA size needed to effectively protect the stock. However, using oversimplified assumptions can produce suboptimal designs and lead to a density underestimation of ca. 30%; therefore, the main value of detailed movement dynamics is to provide more reliable MPA design and predicted outcomes. Large MPAs can be effective in recovering overfished stocks, protect pelagic fish and provide significant increases in fisheries yields. Our models provide a means to empirically test this spatial management tool, which theoretical evidence consistently suggests as an effective alternative to managing highly mobile pelagic stocks.


Dynamic CBCT Imaging using Prior Model-Free Spatiotemporal Implicit Neural Representation (PMF-STINR).
Dynamic cone-beam computed tomography (CBCT) can capture high-spatial-resolution, time-varying images for motion monitoring, patient setup, and adaptive planning of radiotherapy. However, dynamic CBCT reconstruction is an extremely ill-posed spatiotemporal inverse problem, as each CBCT volume in the dynamic sequence is only captured by one or a few X-ray projections. We developed a machine learning-based technique, prior-model-free spatiotemporal implicit neural representation (PMF-STINR), to reconstruct dynamic CBCTs from sequentially acquired X-ray projections. PMF-STINR employs a joint image reconstruction and registration approach to address the under-sampling challenge. Specifically, PMF-STINR uses spatial implicit neural representation to reconstruct a reference CBCT volume, and it applies temporal INR to represent the intra-scan dynamic motion with respect to the reference CBCT to yield dynamic CBCTs. PMF-STINR couples the temporal INR with a learning-based B-spline motion model to capture time-varying deformable motion during the reconstruction. Compared with previous methods, the spatial INR, the temporal INR, and the B-spline model of PMF-STINR are all learned on the fly during reconstruction in a one-shot fashion, without using any patient-specific prior knowledge or motion sorting/binning. PMF-STINR was evaluated via digital phantom simulations, physical phantom measurements, and a multi-institutional patient dataset featuring various imaging protocols (half-fan/full-fan, full sampling/sparse sampling, different energy and mAs settings, etc.). The results showed that the one-shot learning-based PMF-STINR can accurately and robustly reconstruct dynamic CBCTs and capture highly irregular motion with high temporal (~0.1s) resolution and sub-millimeter accuracy. It can be a promising tool for motion management by offering richer motion information than traditional 4D-CBCTs.


Effect of School Integrated Pest Management or Classroom Air Filter Purifiers on Asthma Symptoms in Students With Active Asthma: A Randomized Clinical Trial.
School and classroom allergens and particles are associated with asthma morbidity, but the benefit of environmental remediation is not known. To determine whether use of a school-wide integrated pest management (IPM) program or high-efficiency particulate air (HEPA) filter purifiers in the classrooms improve asthma symptoms in students with active asthma. Factorial randomized clinical trial of a school-wide IPM program and HEPA filter purifiers in the classrooms was conducted from 2015 to 2020 (School Inner-City Asthma Intervention Study). There were 236 students with active asthma attending 41 participating urban elementary schools located in the Northeastern US who were randomized to IPM by school and HEPA filter purifiers by classroom. The date of final follow-up was June 20, 2020. The school-wide IPM program consisted of application of rodenticide, sealing entry points, trap placement, targeted cleaning, and brief educational handouts for school staff. Infestation was assessed every 3 months, with additional treatments as needed. Control schools received no IPM, cleaning, or education. Classroom portable HEPA filter purifiers were deployed and the filters were changed every 3 months. Control classrooms received sham HEPA filters that looked and sounded like active HEPA filter purifiers. Randomization was done independently (split-plot design), with matching by the number of enrolled students to ensure a nearly exact 1:1 student ratio for each intervention with 118 students randomized to each group. Participants, investigators, and those assessing outcomes were blinded to the interventions. The primary outcome was the number of symptom-days with asthma during a 2-week period. Symptom-days were assessed every 2 months during the 10 months after randomization. Among the 236 students who were randomized (mean age, 8.1 [SD, 2.0] years; 113 [48%] female), all completed the trial. At baseline, the 2-week mean was 2.2 (SD, 3.9) symptom-days with asthma and 98% of the classrooms had detectable levels of mouse allergen. The results were pooled because there was no statistically significant difference between the 2 interventions (P = .18 for interaction). During a 2-week period, the mean was 1.5 symptom-days with asthma after use of the school-wide IPM program vs 1.9 symptom-days after no IPM across the school year (incidence rate ratio, 0.71 [95% CI, 0.38-1.33]), which was not statistically significantly different. During a 2-week period, the mean was 1.6 symptom-days with asthma after use of HEPA filter purifiers in the classrooms vs 1.8 symptom-days after use of sham HEPA filter purifiers across the school year (incidence rate ratio, 1.47 [95% CI, 0.79-2.75]), which was not statistically significantly different. There were no intervention-related adverse events. Among children with active asthma, use of a school-wide IPM program or classroom HEPA filter purifiers did not significantly reduce symptom-days with asthma. However, interpretation of the study findings may need to consider allergen levels, particle exposures, and asthma symptoms at baseline. ClinicalTrials.gov Identifier: NCT02291302.


Dual-mycorrhizal plants: their ecology and relevance.
Dual-mycorrhizal plants are capable of associating with fungi that form characteristic arbuscular mycorrhizal (AM) and ectomycorrhizal (EM) structures. Here, we address the following questions: (1) How many dual-mycorrhizal plant species are there? (2) What are the advantages for a plant to host two, rather than one, mycorrhizal types? (3) Which factors can provoke shifts in mycorrhizal dominance (i.e. mycorrhizal switching)? We identify a large number (89 genera within 32 families) of confirmed dual-mycorrhizal plants based on observing arbuscules or coils for AM status and Hartig net or similar structures for EM status within the same plant species. We then review the possible nutritional benefits and discuss the possible mechanisms leading to net costs and benefits. Cost and benefits of dual-mycorrhizal status appear to be context dependent, particularly with respect to the life stage of the host plant. Mycorrhizal switching occurs under a wide range of abiotic and biotic factors, including soil moisture and nutrient status. The relevance of dual-mycorrhizal plants in the ecological restoration of adverse sites where plants are not carbon limited is discussed. We conclude that dual-mycorrhizal plants are underutilized in ecophysiological-based experiments, yet are powerful model plant-fungal systems to better understand mycorrhizal symbioses without confounding host effects.


Metabasin approach for computing the master equation dynamics of systems with broken ergodicity.
We propose a technique for computing the master equation dynamics of systems with broken ergodicity. The technique involves a partitioning of the system into components, or metabasins, where the relaxation times within a metabasin are short compared to an observation time scale. In this manner, equilibrium statistical mechanics is assumed within each metabasin, and the intermetabasin dynamics are computed using a reduced set of master equations. The number of metabasins depends upon both the temperature of the system and its derivative with respect to time. With this technique, the integration time step of the master equations is governed by the observation time scale rather than the fastest transition time between basins. We illustrate the technique using a simple model landscape with seven basins and show validation against direct Euler integration. Finally, we demonstrate the use of the technique for a realistic glass-forming system (viz., selenium) where direct Euler integration is not computationally feasible.


Flow-conditioned HUVECs support clustered leukocyte adhesion by coexpressing ICAM-1 and E-selectin.
Endothelial sequestration of circulating monocytes is a key event in early atherosclerosis. Hemodynamics is proposed to regulate monocyte-endothelial cell interactions by direct cell activation and establishment of flow environments that are conducive or prohibitive to cell-cell interaction. We investigated fluid shear regulation of monocyte-endothelial cell adhesion in vitro using a disturbed laminar shear system that models in vivo hemodynamics characteristic of lesion-prone vascular regions. Human endothelial cell monolayers were flow conditioned for 6 h before evaluation of monocyte adhesion under static and dynamic flow conditions. Results revealed a distinctive clustered cell pattern of monocyte adhesion that strongly resembles in vivo leukocyte adhesion in early- and late-stage atherosclerosis. Clustered monocyte cell adhesion correlated with endothelial cells coexpressing intercellular adhesion molecule-1 (ICAM-1) and E-selectin as result of a flow-induced, selective upregulation of E-selectin expression in a subset of ICAM-1-expressing cells. Clustered monocyte cell adhesion assayed under static conditions exhibited a spatial variation in size and frequency of occurrence, which demonstrates differential regulation of endothelial cell adhesiveness by the local flow environment. Dynamic adhesion studies conducted with circulating monocytes resulted in clustered cell adhesion only within the disturbed flow region, where the monocyte rate of motion is sufficiently low for cell-cell interaction. These studies provide evidence and reveal mechanisms of local hemodynamic regulation of endothelial adhesiveness and endothelial monocyte interaction that lead to localized monocyte adhesion and potentially contribute to the focal origin of arterial diseases such as atherosclerosis.


Outcomes of primary phakic trabeculectomies without versus with 0.5- to 1-minute versus 3- to 5-minute mitomycin C.
To compare the intraocular pressure and hypotony outcomes of primary phakic trabeculectomies with no mitomycin C (MMC), shorter MMC, and longer MMC exposure. We evaluated primary phakic trabeculectomies with no MMC (36 eyes of 36 patients), 0.5- to 1-minute MMC (50 eyes of 50 patients), and 3- to 5-minute MMC (38 eyes of 38 patients) at the concentration of 0.5 mg/ml. Successful trabeculectomy was defined as an intraocular pressure of 21 mm Hg or less without development of a marked visual acuity loss associated with prolonged hypotony (intraocular pressure < 6 mm Hg over 3 months) and without the need for additional surgery to control intraocular pressure or treat postoperative complications. The three groups were similar in demographics, preoperative intraocular pressure, and medical dependency. However, the incidence of hypotony during the postoperative periods of 3 to 12 months was significantly higher in the 3- to 5-minute MMC group (P < .05, chi-square test). Severe visual acuity loss associated with hypotony was also more frequently found in the 3- to 5-minute MMC group than in the 0.5- to 1-minute (P = .009, chi-square test) group or the control group (P = .014, chi-square test). In addition, the success probabilities were significantly different among the three groups (P = .001, Kaplan-Meier survival analysis with log-rank test) and were the highest in the 0.5- to 1-minute MMC group and the lowest in the 3- to 5-minute MMC group. Shorter application (0.5 to 1 minute) of MMC appears to be optimal for the successful outcome of primary phakic trabeculectomy compared with no MMC or longer application of MMC at a concentration of 0.5 mg/ml.


Low oxygen in inspired air causes severe cerebrocortical hypoxia and cell death in the cerebral cortex of awake rats.
Type 1 respiratory failure (T1RF) is associated with secondary acute brain injury (sABI). The underlying mechanisms of sABI could include injury to brain cells mediated either by hypoxia or by lung injury-triggered inflammation. To elucidate to what extent T1RF causes hypoxia and a consequent hypoxic injury in the brain in the absence of lung injury, we exposed healthy, conscious Sprague-Dawley rats to 48 h long low partial pressure of O2 in inspired air (PiO2) (7.5-8 % O2 in N2, CO2 < 0.5 %, normal barometric pressure) and measured the partial pressure of oxygen in the premotor cortex (PtO2), cerebral blood flow (CBF), lactate concentrations, and cell death. Low PiO2 significantly affected PtO2, which was 52.3 (SD 2.1) mmHg when PiO2 was normal but declined to 6.4 (SD 3.8) mmHg when PiO2 was low for 1 h. This was accompanied by increased lactate concentrations in plasma, CSF, and premotor cortex. Low PiO2 elevated the number of dead cells in the cerebral cortex from 5.6 (SD 4.8) % (when PiO2 was normal) to 20.5 (SD 4.1) % and 32.37 (SD 6.5) % after 24 h and 48 h exposure to low PiO2, respectively. The Mann-Kendall test could not detect any monotonic increase or decrease in pial blood flow during the 48 h exposure to low PiO2. In summary, our findings suggest that exposure to low PiO2 caused a severe hypoxia in the cerebral cortex, which triggers a massive cell death. Since these conditions mimic T1RF, hypoxic injury could be an important underlying cause of T1RF-induced sABI.


A fuzzy image metric with application to fractal coding.
Image quality assessment is an important issue addressed in various image processing applications such as image/video compression and image reconstruction. The peak signal-to-noise ratio (PSNR) with the L(2)-metric is commonly used in objective image quality assessment. However, the measure does not agree very well with the human visual perception in many cases. A fuzzy image metric (FIM) is defined based on Sugeno's (1977) fuzzy integral. This new objective image metric, which is to some extent a proper evaluation from the viewpoint of the judgment procedure, is closely approximates the subjective mean opinion score (MOS) with a correlation coefficient of about 0.94, as compared to 0.82 obtained using the PSNR. Compared to the L(2)-metric, we demonstrate that a better performance can be achieved in fractal coding by using the proposed FIM.


Office evaluation and management of acute orthopedic trauma.
Virtually any injury that can be treated as an outpatient can be treated in a properly equipped and staffed orthopaedist's office, provided that it is accurately identified and evaluated initially. Anesthetic blocks, closed manipulations, some suturing, and immobilizations can all be done in the acute setting. Children and elderly patients are particularly suited to office treatment. Close follow-up is essential, and early rehabilitation can begin in the office setting.


BRCA1-Ku80 protein interaction enhances end-joining fidelity of chromosomal double-strand breaks in the G1 phase of the cell cycle.
Quality control of DNA double-strand break (DSB) repair is vital in preventing mutagenesis. Non-homologous end-joining (NHEJ), a repair process predominant in the G1 phase of the cell cycle, rejoins DSBs either accurately or with errors, but the mechanisms controlling its fidelity are poorly understood. Here we show that BRCA1, a tumor suppressor, enhances the fidelity of NHEJ-mediated DSB repair and prevents mutagenic deletional end-joining through interaction with canonical NHEJ machinery during G1. BRCA1 binds and stabilizes Ku80 at DSBs through its N-terminal region, promotes precise DSB rejoining, and increases cellular resistance to radiation-induced DNA damage in a G1 phase-specific manner. These results suggest that BRCA1, as a central player in genome integrity maintenance, ensures high fidelity repair of DSBs by not only promoting homologous recombination repair in G2/M phase but also facilitating fidelity of Ku80-dependent NHEJ repair, thus preventing deletional end-joining of chromosomal DSBs during G1.


Freeze-drying equipment.
Illustrated presentation of a sophisticated research freeze-drying apparatus, fitted with many controls including a program controller. With this machine, it is possible to remove samples from any part of the chamber, at any time, without interfering with the freeze-drying process. By this ability to sample, the apparatus makes it possible to study, during the freeze-drying process, the influence on the dried product of many parameters and to reproduce in the chamber the same drying conditions offered by the production-scale machines. The figures include one of a production-scale machine, and a patented device for automatic loading and unloading of the freezers and the freeze-dryers.


Time propagation of the Kadanoff-Baym equations for inhomogeneous systems.
We have developed a time-propagation scheme for the Kadanoff-Baym equations for general inhomogeneous systems. These equations describe the time evolution of the nonequilibrium Green function for interacting many-body systems in the presence of time-dependent external fields. The external fields are treated nonperturbatively whereas the many-body interactions are incorporated perturbatively using Phi-derivable self-energy approximations that guarantee the satisfaction of the macroscopic conservation laws of the system. These approximations are discussed in detail for the time-dependent Hartree-Fock, the second Born, and the GW approximation.


Standardized process used in the emergency department for pediatric oncology patients with fever and neutropenia improves time to the first dose of antibiotics.
This study aimed to evaluate the effect of a standardized process on time to the first dose of antibiotics in pediatric oncology patients presenting to the emergency department (ED) with fever and neutropenia (F-N). A standardized process and order set were created to be used on all pediatric febrile neutropenic patients who presented to the ED of a large academic children's hospital. The order set was used for patients with a known oncologic diagnosis, a fever greater than 38.3°C, and who were presumed or known to be neutropenic. A retrospective chart review was then performed for the 18 months before and the 6 months after implementation of the new process to evaluate if the time to the first dose of antibiotics was significantly reduced. A total of 130 occurrences of F-N were analyzed. This included 100 episodes before the implementation of the new process and 30 episodes afterward. The time to antibiotics being ordered was reduced by over half, with a median time of 72 minutes preprocess and 27 minutes postprocess implementation (P = 0.04). Median time from the arrival in the ED to the administration of the first dose of antibiotics was reduced by almost an hour, taking 154 minutes before the new process compared with 95 minutes after its implementation (P = 0.0001). The use of a standardized process that uses a standardized order set can reduce the time to the first dose of antibiotics in pediatric oncology patients with F-N.


Chlorinated Water Induced Aging of Pipe Grade Polypropylene Random Copolymers.
Polypropylene random copolymers (PP-R) are common materials for pressurized hot water pipes. In many pipe systems, potable water is disinfected by chlorine to prevent waterborne diseases. This paper deals with hot chlorinated water induced aging of two PP-R grades with varying morphology. One material had a conventional monoclinic α crystal form (PP-Rα), whereas the other was explicitly beta-nucleated resulting in a trigonal β crystal form with a fine spherulite structure (PP-Rβ). Micro-sized specimens with a thickness of 100 µm were used for aging experiments at 60 °C in chlorinated water with 5 mg/L free chlorine, and aging indicators were monitored for exposure times of up to 2000 h. On the other hand, superimposed mechanical-environmental tests were carried out by using cracked round bar specimens with a diameter of 14 mm to determine the fatigue crack growth (FCG) resistance of both PP-R grades at 60 °C in non-chlorinated and chlorinated water. PP-Rβ was found to outperform PP-Rα with an about 30% higher time-to-embrittlement value of 2000 h. Furthermore, PP-Rβ exhibited an enhanced FCG resistance in both non-chlorinated and chlorinated water. The effect of chlorine content on the deterioration of the FCG resistances was significantly more pronounced for PP-Rα.


Coagulation abnormalities following thermal injury.
Changes in coagulation may have a profound impact on outcomes following severe burns and the coagulation abnormalities after thermal injury are incompletely described. We postulated that thermal injury induces a systemic hypercoagulable state. With Institutional Review Board approval, five patients were consented for enrollment in this case series. After obtaining informed consent, blood was drawn on hospital days 1, 2, 3, 5, and 7 or until discharge if discharge was in less than 7 days. Standard coagulation testing was performed, as well as a battery of sophisticated specialized coagulation assays. Other data collected includes fluid resuscitation volumes, pharmacologic interventions, and general physiologic information. Results (n = 5) demonstrate that burns less than 6% total body surface area appear to have little effect on coagulation. Burns greater than 6% appear to induce a systemic hypercoagulable state with a phase and magnitude relationship proportional to total body surface area burned. Severe burns greater than 40% appear to induce a consumptive coagulopathy. Prothrombin fragment 1.2 may represent a useful screening test for a burn-induced hypercoagulable state.


Plasma concentrations of tricyclic antidepressants in clinical practice.
Plasma concentrations of four tricyclic antidepressant drugs were monitored in 180 patients. Plasma concentrations incongruent with dose suggested noncompliance at some time among 20% of the patients. Plasma concentrations correlated poorly with dose except with amitriptyline. Plasma concentration of drug and active metabolite, in the case of imipramine and amitriptyline, tended to be higher in ng/ml than the daily dose in mg; the converse was true for nortriptyline and desipramine. Most patients achieved "therapeutic"plasma concentrations at doses of 150 mg/day. However, "therapeutic" plasma concentrations did not correlate well with clinical response.


[C-fos topography in neocortical neurons of mice during fear conditioning].
Patterns of expression of c-Fos transcription factor in the motor (M1 and M2) and cingulate cortex (dorsal part, Cg1, RSA, and ventral part, PrL, Cg2, RSG) were analyzed after fear conditioning in 129 sv mice. Mice were exposed to the context and tone followed by electric footshock (footshock group, FG) or to context only (context group, CG). Control mice were taken from a home cage (HG). In the rostral part of the motor cortex the number of c-Fos-labeled neurons was the same in all the groups. It was increased in the rostrocaudal direction in FG and CG but not in HG mice. A higher level of c-Fos expression in FG (as compared to CG) was observed in the medial parts of the M1, in the caudal and medial parts of the M2, and in the dorsal but not ventral regions of the cingulate cortex. Thus, the rostrocaudal gradient of c-Fos expression was originally demonstrated in motor cortex of mice during learning.


Unsaturated and Benzannulated N-Heterocyclic Carbene Complexes of Titanium and Hafnium: Impact on Catalysts Structure and Performance in Copolymerization of Cyclohexene Oxide with CO2.
Tridentate, bis-phenolate N-heterocyclic carbenes (NHCs) are among the ligands giving the most selective and active group 4-based catalysts for the copolymerization of cyclohexene oxide (CHO) with CO2. In particular, ligands based on imidazolidin-2-ylidene (saturated NHC) moieties have given catalysts which exclusively form polycarbonate in moderate-to-high yields even under low CO2 pressure and at low copolymerization temperatures. Here, to evaluate the influence of the NHC moiety on the molecular structure of the catalyst and its performance in copolymerization, we extend this chemistry by synthesizing and characterizing titanium complexes bearing tridentate bis-phenolate imidazol-2-ylidene (unsaturated NHC) and benzimidazol-2-ylidene (benzannulated NHC) ligands. The electronic properties of the ligands and the nature of their bonds to titanium are studied using density functional theory (DFT) and natural bond orbital (NBO) analysis. The metal-NHC bond distances and bond strengths are governed by ligand-to-metal σ- and π-donation, whereas back-donation directly from the metal to the NHC ligand seems to be less important. The NHC π-acceptor orbitals are still involved in bonding, as they interact with THF and isopropoxide oxygen lone-pair donor orbitals. The new complexes are, when combined with [PPN]Cl co-catalyst, selective in polycarbonate formation. The highest activity, albeit lower than that of the previously reported Ti catalysts based on saturated NHC, was obtained with the benzannulated NHC-Ti catalyst. Attempts to synthesize unsaturated and benzannulated NHC analogues based on Hf invariably led, as in earlier work with Zr, to a mixture of products that include zwitterionic and homoleptic complexes. However, the benzannulated NHC-Hf complexes were obtained as the major products, allowing for isolation. Although these complexes selectively form polycarbonate, their catalytic performance is inferior to that of analogues based on saturated NHC.


Are laboratory tests useful for monitoring the activity of lupus nephritis? A 6-year prospective study in a cohort of 228 patients with lupus nephritis.
To evaluate the role of immunological tests for monitoring lupus nephritis (LN) activity. C3, C4, anti-dsDNA and anti-C1q antibodies were prospectively performed over 6 years in 228 patients with LN. In membranous LN only anti-C1q antibodies differentiated proteinuric flares from quiescent disease (p = 0.02). However, in this group 46% of flares occurred with a normal value of anti-C1q antibodies versus 20% in proliferative LN (p = 0.02). In patients with antiphospholipid antibodies (APL), 33% of flares occurred with normal levels of anti-C1q antibodies versus 14.5% in patients that were APL-negative (p = 0.02). In proliferative LN, anti-C1q antibodies showed a slightly better sensitivity and specificity (80.5 and 71% respectively) than other tests for the diagnosis of renal flares. All four tests had good negative predictive value (NPV). At univariate analysis anti-C1q was the best renal flare predictor (p<0.0005). At multivariate analysis, the association of anti-C1q with C3 and C4 provided the best performance (p<0.0005, p<0.005, p<0.005 respectively). Anti-C1q is slightly better than the other tests to confirm the clinical activity of LN, particularly in patients with proliferative LN and in the absence of APL. All four "specific" tests had a good NPV, suggesting that, in the presence of normal values of each, active LN is unlikely.


Dopaminergic regulation of neuronal excitability through modulation of Ih in layer V entorhinal cortex.
The entorhinal cortex (EC) is a significant component of the systems that underlie certain forms of memory formation and recall. Evidence has been emerging that the dopaminergic system in the EC facilitates these and other functions of the EC. The effects of dopamine (DA) on membrane properties and excitability of EC neurons, however, are not known. We used in vitro whole-cell patch-clamp recordings from layer V pyramidal neuronal somata and dendrites of the adult rat lateral EC to investigate the effects of DA on the excitability of these neurons. We found that brief application of DA caused a reduction in the excitability of layer V EC pyramidal neurons. This effect was attributable to voltage-dependent modification of membrane properties that can best be explained by an increase in a hyperpolarization-activated conductance. Furthermore, the effects of DA were blocked by pharmacological blockade of h-channels, but not by any of a number of other ion channels. These actions were produced by a D1 receptor-mediated increase of cAMP but were independent of protein kinase A. A portion of the actions of DA can be attributed to effects in the apical dendrites. The data suggest that DA can directly influence the membrane properties of layer V EC pyramidal neurons by modulation of h-channels. These actions may underlie some of the effects of DA on memory formation.


Characterization of an optical multilayer hydrophone with constant frequency response in the range from 1 to 75 MHz.
The performance of an optical multilayer hydrophone for ultrasound measurements is investigated both in theoretical terms and experimentally. The optical measurement system comprises a thin high-finesse dielectric interference filter structure that is deposited onto a plane glass plate. An incident acoustic pressure wave deforms the layer system, and the induced variation of the optical reflectance is determined. Applying the concept of an optical off-axis detection scheme offers good sensitivity and a simple and low-cost setup. A primary interferometric calibration technique is applied to experimentally determine the pressure-voltage transfer function in the range from 1 to 75 MHz. Within the measurement uncertainty a constant transfer factor is obtained for the whole frequency range. Measurements of broadband ultrasound pulses are influenced neither by acoustic resonances of the very thin sensing element nor by diffraction phenomena that are known to cause waveform distortions in small probe hydrophone measurements. High temporal and spatial resolution is combined with high durability of the probe, which is why the optical multilayer hydrophone is well suited for use as a reference for secondary hydrophone calibration.


Rat liver endothelial cell glutamine transporter and glutaminase expression contrast with parenchymal cells.
Despite the central role of the liver in glutamine homeostasis in health and disease, little is known about the mechanism by which this amino acid is transported into sinusoidal endothelial cells, the second most abundant hepatic cell type. To address this issue, the transport of L-glutamine was functionally characterized in hepatic endothelial cells isolated from male rats. On the basis of functional analyses, including kinetics, cation substitution, and amino acid inhibition, it was determined that a Na+-dependent carrier distinct from system N in parenchymal cells, with properties of system ASC or B0, mediated the majority of glutamine transport in hepatic endothelial cells. These results were supported by Northern blot analyses that showed expression of the ATB0 transporter gene in endothelial but not parenchymal cells. Concurrently, it was determined that, whereas both cell types express glutamine synthetase, hepatic endothelial cells express the kidney-type glutaminase isozyme in contrast to the liver-type isozyme in parenchymal cells. This represents the first report of ATB0 and kidney-type glutaminase isozyme expression in the liver, observations that have implications for roles of specific cell types in hepatic glutamine homeostasis in health and disease.


[Arterial hypertension in menopausal women: Clinical, functional, and pharmaco-economical aspects].
The study was undertaken to define the specific features of daily variations of blood pressure (BP) and autonomic cardiac regulation (ACR), as well as the functional status of the myocardium and vascular endothelium in females with menopausal arterial hypertension (MPAH) and to assess the pharmacotherapeutic and economical aspects of the combined use of arifon retard and clinonorm. The study enrolled 30 reproductive females with mild and moderate arterial hypertension (AH) and 65 females with MPAH who were randomly divided into 2 groups according to the therapeutic model. MPAH was characterized by more unfavorable hemodynamic changes that AH in the presence of preserved fertile function: greater load on target organs, elevated BP, its inadequate nocturnal lowering, greater BP variations, the magnitude and rate of its morning elevation. In AH, the vasomotor function of the endothelium varies with the clinical form of the disease and with the functional status of the female reproductive system. By and large, in the group of patients with MPAH, the latter was characterized by a more significant decrease in endothelium-dependent vasodilation (EDVD). Arifon retard monotherapy has an adequate antihypertensive effect in female patients with MPAH, by ensuring 24-hour control of BP and affecting its chronostructure. A combination of arifon retard and climonorm has no cumulative effect on the level of BP and on the parameters of pressure-induced load; however, this is a pathogenetically grounded combination that potentiates the positive effects of a diuretic in significantly improving EDVD and ACR. The use of arifon retard in combination with climonorm in MPAH is the most cost-effective for public health care facilities and effective for patients. The course of MPAH is of certain peculiarity, which should be taken into account in choosing a therapeutic model for this category of patients.


Protective effect of Zataria multiflora Boiss. and its main compound, rosmarinic acid, against malathion induced oxidative stress and apoptosis in HepG2 cells.
Malathion (MT) is one of the most widely used organophosphorus insecticides which induces toxicity through oxidative stress induction, free radical production and acetylcholinesterase inhibition. In this work, HepG2 cells were used to determine the effect of Zataria multiflora methanolic extract (MEZM) and rosmarinic acid (RA) on MT-induced cytotoxicity, oxidative stress, and apoptosis. Total phenolic content (TPC) and total flavonoid content (TFC) were determined and plant was further standardized based on RA content using HPLC method. The cultured HepG2 cells were pretreated with MEZM (1 μg/ml) and RA (0.1 μg/ml) for 4 h and exposed to MT (100 μM). Cell viability, oxidative stress biomarkers, ROS production, and cell death were examined after 24 h. The amount of RA was determined 73.48 mg/g dried extract. IC50 values of MEZM and MT were 368.56 μg/ml and 99.43 μM, respectively. Pretreatment with MEZM and RA decreased the cytotoxicity, oxidative stress, and cell percentage in the late apoptosis and necrosis stages induced by MT. There was no significant difference between MEZM and RA effects. The present study showed the significant protective effects of MEZM against toxicity induced by MT in hepatocytes which can be attributed to the plant antioxidant constituents including RA.


Two storage hexamerins from the beet armyworm Spodoptera exigua: cloning, characterization and the effect of gene silencing on survival.
In insects, hemocyanin superfamily proteins accumulate apparently to serve as sources of amino acids during metamorphosis, reproduction and development. Storage hexamerins are important members of the hemocyanin superfamily. Although insects possess storage hexamerins, very little is known about the character and specific functions of hexamerin 1 and storage protein 1 in insect development. To gain insight into the function of storage proteins in insects, cDNAs for two storage proteins were cloned from the fat body of Spodoptera exigua. S. exigua hexamerin 1 (SeHex) cDNA contained an open reading frame of 2124 nucleotides encoding a protein of 707 amino acids with a predicted molecular weight of 82.12 kDa. S. exigua storage protein 1 (SeSP1) cDNA contained an open reading frame of 2256 bp encoding a protein of 751 amino acids with a predicted molecular weight of ~88.84 kDa. Northern blotting analyses revealed that SeHex mRNA is expressed in the fat body, cuticle, midgut and Malpighian tubules and SeSP1 in fat body, Malpighian tubules and tracheae. SeHex and SeSP1 mRNAs were expressed in fat body at different levels from first instar larvae to pupae, with expression was much lower from first instar larvae to first-day fifth instar larvae. SeHex transcript expression was high in fat body of wandering larvae (pre-pupae) and steadily decreased to the seventh pupal day. SeSP1 transcript expression was high in fat body of wandering larvae, 2-day-old fifth instar larvae and 2-, 4- and 7-day-old pupae. SeHex and SeSP1 mRNAs levels were expressed lower than control on the condition of starvation at 12 h. Of insects injected with SeHex and SeSP1 dsRNA, 38.7% and 24.3% survived to 204 h after treatment, respectively. This was significantly lower than in the controls groups. These findings provide new data on the tissue distribution, expression patterns and the function in starvation of storage proteins. RNA interference results revealed that storage protein genes are key in metamorphosis, reproduction and insect development. The results for SeHex and SeSP1 interference reveal that a potential method to control this pest is to disrupt the regulation of storage proteins.


[The comparative study of the of clinical effectiveness of the Candibiotic, Otipax, and Anauran ear drops for the treatment of acute external and middle ear otitis].
The objective of the present work was to study in vitro antimicrobial activity of the Candibiotic, ear drops used for the combined treatment of acute external ear otitis and acute otitis media Their anesthetic and anti-inflammatory action was compared with the effects of Otipax, and Anauran ear drops. The results of the study give a reason to recommend the application of Candibiotic ear drops as the highly effective medication for the endo-aural treatment of acute external ear otitis and acute otitis media.


Rate of Fentanyl Positivity Among Urine Drug Test Results Positive for Cocaine or Methamphetamine.
Drug overdose deaths continue to increase, despite the leveling off of prescription opioid use and policy changes limiting opioid prescribing. Illicit fentanyl is the leading cause of drug overdose death, and it is important to characterize the emerging combination of other illicit drugs with fentanyl, which increases the risk of overdose. To determine whether rates of the combination of nonprescribed fentanyl with cocaine or methamphetamine have changed in urine drug test (UDT) results through time. This cross-sectional study of UDT results from January 1, 2013, through September 30, 2018, included patient specimens submitted for UDTs by health care professionals as part of routine care. Patients were selected from health care practices across the United States, including substance use disorder treatment centers, pain management practices, primary care practices, behavioral health practices, obstetrics and gynecology practices, and multispecialty groups. The UDT analysis used liquid chromatography-tandem mass spectrometry to detect benzoylecgonine (cocaine metabolite), methamphetamine, fentanyl, and norfentanyl. Specimens from individuals reported to have been prescribed fentanyl were excluded. A convenience sample approach was used to randomly select 1 million unique patient UDT specimens from Millennium Health's UDT database for further analysis. Each specimen had associated cocaine, methamphetamine, and fentanyl UDT results. Medically necessary UDT to detect benzoylecgonine (cocaine metabolite), methamphetamine, fentanyl, and norfentanyl, ordered by a health care professional as part of routine patient care. Rates of nonprescribed fentanyl positivity among cocaine- or methamphetamine-positive UDT results, quantified through time. In a sampling of 1 million unique patients' UDT specimens analyzed for cocaine and fentanyl (median [interquartile range] age, 44 [19-69] years; 55.0% women), positivity rates for nonprescribed fentanyl among the cocaine-positive results increased significantly, from 0.9% (n = 84) (95% CI, 0.7%-1.1%) in 2013 to 17.6% (n = 427) (95% CI, 16.1%-19.1%) in 2018, a 1850% increase (τ = 0.78; z = 9.45; P < .001). In the same sampling of 1 million specimens, positivity rates for nonprescribed fentanyl among the methamphetamine-positive results also increased significantly, from 0.9% (n = 29) (95% CI, 0.6%-1.2%) in 2013 to 7.9% (n = 344) (95% CI, 7.1%-8.7%) in 2018, a 798% increase (τ = 0.72; z = 8.75; P < .001). An increasing number of UDT results positive for cocaine or methamphetamine were also positive for nonprescribed fentanyl. This provides additional insight into recently reported increases in cocaine- and methamphetamine-related overdoses. Stimulant users who may be opioid naive are at a heightened risk of overdose when exposed to fentanyl. Clinicians need to be aware that patients presenting for treatment of suspected drug overdose or substance use disorder may have been exposed, knowingly or unknowingly, to multiple substances, including the combination of stimulants and opioids.


Surface binding and uptake of polycationic ferritin by neonatal piglet intestinal epithelium.
Pieces of small intestine from newborn, I- and 6-day-old piglets were incubated in vitro and ligated segments were incubated in vivo with polycationic ferritin (PCF) to determine the distribution and possible role in protein uptake of anionic sites on membranes at the luminal surfaces of the epithelial cells. Most PCF binding to the absorptive cells occurred on the upper third or half of the villi and to some non-absorptive cells (tuft cells) throughout the length of the villi. Pieces of intestine which were fixed before incubation had PCF on microvilli and apical invaginations of absorptive cells, but none in the sub-apical tubules. When samples were incubated with PCF in vitro before fixation PCF was bound to the surfaces of microvilli of absorptive cells and to the membranes lining the apical invaginations, some sub-apical vesicles and some sub-apical tubules in all age-groups. In vivo experiments with longer incubation times resulted in a similar distribution, with increased amounts of PCF in the sub-apical tubules in samples from newborn and 1-day-old piglets only. In the newborn there were small vesicles containing PCF which had apparently moved further into the cells. At the same concentration (2 mg/ml) ferritin did not enter the sub-apical tubules; but it did enter and was taken up by the cells in the presence of 4% (w/v) serum albumin. It is concluded that the mechanism of protein uptake does not involve the microvillar membrane and that non-specific interaction with the invaginated plasma membrane, as a function of charge-density, leads to opening of the sub-apical tubular system to protein. Movement further into the cell depends on other factors.


Sociodemographic correlates of HIV drug resistance and access to drug resistance testing in British Columbia, Canada.
Sociodemographic correlates of engagement in human immunodeficiency virus (HIV) care are well studied, however the association with accessing drug resistance testing (DRT) and the development of drug resistance have not been characterized. Between 1996-2014, 11 801 HIV patients accessing therapy in British Columbia were observed longitudinally. A subset of 9456 patients had testable viral load; of these 8398 were linked to census data. Sociodemographic (census tract-level) and clinical (individual-level) correlates of DRT were assessed using multivariable General Estimating Equation logistic regression adjusted odds ratios (aOR). The mean number of tests per patient was 2.1 (Q1-Q3; 0-3). Separately, any drug resistance was determined using IAS-USA (2013) list for 5703 initially treatment naïve patients without baseline resistance; 5175 were census-linked (mean of 1.5 protease-reverse transcriptase sequences/patient, Q1-Q3; 0-2). Correlates of detecting drug resistance in this subset were analyzed using Cox PH regression adjusted hazard ratios (aHR). Our results indicate baseline CD4 <200 cells/μL (aOR: 1.5, 1.3-1.6), nRTI-only baseline regimens (aOR: 1.4, 1.3-1.6), and unknown (therapy initiation before routine pVL in BC) baseline pVL (aOR: 1.8, 1.5-2.1) were among individual-level clinical covariates strongly associated with having accessed DRT; while imperfect adherence (aHR: 2.2, 1.9-2.5), low baseline CD4 count (aHR: 1.9, 1.6-2.3), and high baseline pVL (aHR: 2.0, 1.6-2.6) were associated with a higher likelihood of developing drug resistance. A higher median income (aOR: 0.83, 0.77-0.89) and higher percentage of those with aboriginal ancestry (aOR: 0.85, 0.76-0.95) were census tract-level sociodemographic covariates associated with decreased access to DRT. Similarly, aboriginal ancestry (aHR: 1.2, 1.1-1.5) was associated with development of drug resistance. In conclusion, clinical covariates continue to be the strongest correlates of development of drug resistance and access to DRT for individuals. Regions of high median income and high aboriginal ancestry were weak census-level sociodemographic indicators of reduced DRT uptake, however high aboriginal ancestry was the only sociodemographic indicator for development of drug resistance.


Discovery of biomarkers for osteosarcoma by proteomics approaches.
Osteosarcomas are the most common malignant bone tumors, and the identification of useful tumor biomarkers and target proteins is required to predict the clinical outcome of patients and therapeutic response as well as to develop novel therapeutic strategies. Global protein expression studies, namely, proteomic studies, can offer important clues to understanding the tumor biology that cannot be obtained by other approaches. These studies, such as two-dimensional gel electrophoresis and mass spectrometry, have provided protein expression profiles of osteosarcoma that can be used to develop novel diagnostic and therapeutic biomarkers, as well as to understand biology of tumor progression and malignancy. In this paper, a brief description of the methodology will be provided followed by a few examples of the recent proteomic studies that have generated new information regarding osteosarcomas.


Tubulins from different higher plant species are immunologically nonidentical and bind colchicine differentially.
We have initiated immunological and drug-binding studies on the tubulins from different higher plant species. Antibodies were raised against electrophoretically separated rose (Rosa sp.) tubulin alpha- and beta-subunits and characterized by immunoblot autoradiographic assays. Each IgG preparation bound to its antigen and cross-reacted differentially with the respective tubulin subunits from an alga, sea urchin, rabbit, and cow. Antigenic determinants were shared more among the beta-subunits than among the alpha-subunits from these organisms. Tubulins were isolated from cultured cells of carrot (Daucus carota) and hibiscus (Hibiscus rosa-senensis). Immunoautoradiography and quantitation of cross-reactivity on blots showed nonidentity among homologous subunits from rose, carrot, hibiscus, and alga tubulins, with more antigenic differences among alpha-subunits than among beta-subunits. Comparative colchicine-binding assays showed that rose and hibiscus tubulins bound 33% and 65%, respectively, of the colchicine bound by carrot tubulin and that higher plant tubulins bound much less colchicine than bovine brain tubulin under identical conditions.


Anaphylatoxin inactivator of human plasma: its isolation and characterization as a carboxypeptidase.
The failure of human serum to give rise to anaphylatoxin activity could be attributed to the presence of a potent inactivator of anaphylatoxin in human serum. The inactivator was isolated and characterized as an alpha-globulin with a molecular weight of approximately 310,000. It was found to abolish the activity of both anaphylatoxins, which are derived respectively from the third and the fifth component of complement, and of bradykinin. Inactivation of C3-derived anaphylatoxin and of bradykinin was accompanied by release of C-terminal arginine from these peptides. The anaphylatoxin inactivator was shown to hydrolyze the synthetic substrates hippuryl-L-arginine and hippuryl-L-lysine and to be inhibited by ethylenediaminetetraacetate (EDTA) or phenanthroline. These observations indicate that the anaphylatoxin inactivator constitutes a metal-dependent enzyme resembling in specificity pancreatic carboxypeptidase B.


Simple and Fast Rolling Circle Amplification-Based Detection of Topoisomerase 1 Activity in Crude Biological Samples.
Isothermal amplification-based techniques such as the rolling circle amplification have been successfully employed for the detection of nucleic acids, protein amounts, or other relevant molecules. These methods have shown to be substantial alternatives to PCR or ELISA for clinical and research applications. Moreover, the detection of protein amount (by Western blot or immunohistochemistry) is often insufficient to provide information for cancer diagnosis, whereas the measurement of enzyme activity represents a valuable biomarker. Measurement of enzyme activity also allows for the diagnosis and potential treatment of pathogen-borne diseases. In all eukaryotes, topoisomerases are the key DNA-binding enzymes involved in the control of the DNA topological state during important cellular processes and are among the important biomarkers for cancer prognosis and treatment. Over the years, topoisomerases have been substantially investigated as a potential target of antiparasitic and anticancer drugs with libraries of natural and synthetic small-molecule compounds that are investigated every year. Here, the rolling circle amplification method, termed rolling circle enhanced enzyme activity detection (REEAD) assay that allows for the quantitative measurement of topoisomerase 1 (TOP1) activity in a simple, fast, and gel-free manner is presented.By cleaving and ligating a specially designed DNA substrate, TOP1 converts a DNA oligonucleotide into a closed circle, which becomes the template for rolling circle amplification, yielding ~103 tandem repeat rolling circle products. Depending on the nucleotide incorporation during the amplification, there is the possibility of different readout methods, from fluorescence to chemiluminescence to colorimetric. As each TOP1-mediated cleavage-ligation generates one closed DNA circle, the assay is highly sensitive and directly quantitative.


Molecular imaging of extracellular matrix proteins with targeted probes using magnetic resonance imaging.
The extracellular matrix (ECM) consists of proteins and carbohydrates that supports different biological structures and processes such as tissue development, elasticity, and preservation of organ structure. Diseases involving inflammation, fibrosis, tumor invasion, and injury are all attributed to the transition of the ECM from homeostasis to remodeling, which can significantly change the biochemical and biomechanical features of ECM components. While contrast agents have played an indispensable role in facilitating clinical diagnosis of diseases using magnetic resonance imaging (MRI), there is a strong need to develop novel biomarker-targeted imaging probes for in vivo visualization of biological processes and pathological alterations at a cellular and molecular level, for both early diagnosis and monitoring drug treatment. Herein, we will first review the pathological accumulation and characterization of ECM proteins recognized as important molecular features of diseases. Developments in MRI probes targeting ECM proteins such as collagen, fibronectin, and elastin via conjugation of existing contrast agents to targeting moieties and their applications to various diseases, are also reviewed. We have also reviewed our progress in the development of collagen-targeted protein MRI contrast agent with significant improvement in relaxivity and metal binding specificity, and their applications in early detection of fibrosis and metastatic cancer. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Biology-Inspired Nanomaterials > Peptide-Based Structures Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.


A proposed model of cerebrospinal fluid circulation: observations with radionuclide cisternography.
To determine the mechanisms of the tracer distribution at radionuclide cisternography (RC). Ten patients with venous vasculitis were studied with RC. Flow phantom studies were performed mimicking cerebrospinal fluid (CSF) circulation with and without a main outlet comparable to the pacchionian granulations. Nine of the 10 patients had normal findings on RC images, including a maximum uptake over the vertex at 24 hours. In all patients, a second maximum occurred in the lumbosacral area. The flow phantom studies showed no tracer accumulation at an open outlet corresponding to the pacchionian granulations. On the contrary, a maximum arose without such an outlet. A maximum always arose at the closed dead ends of the phantom, including the lumbosacral area. The commonly accepted flow model for CSF circulation needs to be revised. The pattern of the normal RC cannot be explained by a bulk flow transport of the tracer to an outlet at the pacchionian granulations but rather by a primary mixing caused by pulsatile flow with a secondary dilution by newly formed CSF from the ventricular system. We suggest that the main absorption of the CSF is through the central nervous system to the blood.


[Key enzymes of biosynthesis of amino acids of the glutamic series in the virus-cell system Anabaena variabilis + A-1].
The influence of cyanophage A-1 reproduction on glutamate dehydrogenase (GDG) and glutamine synthetase (GS) in A. variabilis cells was studied. It was determined that the both enzymes are intensified by 70% and 30%, accordingly. Isoenzymes of GDG and GS were isolated from native and infected cells of cyanobacteria, they had various physicochemical properties. It is concluded that cyanophage development causes the specific modification of cell enzymes.


Aging effects on extrapersonal (far-space) attention: cancellation and line bisection performance from 179 healthy adults.
Assessment of cognitive impairments is a vital part of clinical practice. Cancellation (visual search) and line bisection are commonly used tasks to assess visuospatial attention. Despite the fact visuospatial attention is engaged in both near (within reach) and far-space (out of reach), most studies have been conducted in near-space alone. Moreover, despite their use in clinical practice, it is unclear whether cancellation and bisection tasks are related. Here, we investigated the impact of aging on cancellation and line bisection performance in far-space in a large healthy sample. We provide preliminary age-graded norms for assessing visuospatial attention in far-space calculated from a sample of 179 healthy adults, between the ages of 18-94 (mean age = 49.29). Cancellation and line bisection were presented on a large screen in far-space and completed using a wireless remote. Aging was accompanied by longer task duration for both tasks, slower search speed and poorer quality of search. However, there was no significant effect of aging on line bisection error. There was a significant correlation between the two tasks in that longer task duration in line bisection was associated with slower search speed and poorer quality of search. Overall, participants presented a leftward bias during cancellation and line bisection akin to pseudoneglect. Moreover, we found that irrespective of age, search speed was faster in males than females. We offer novel evidence that performance on cancellation and line bisection tasks are related to one another in far-space, but are also sensitive to age-related decline, and even sex differences.


Spirituality: what is its role in pain medicine?
For many years, spirituality has been regarded as an integral aspect of patient care in fields closely allied to pain medicine such as palliative and supportive care. Despite this, it has received relatively little attention within the field of pain medicine itself. Reasons for this may include a lack of understanding of what spirituality means, doubtfulness of its relevance, an uncertainty about how it may be addressed, or a lack of awareness of how addressing spirituality may be of benefit. A review of the literature was conducted to determine the changing conceptual frameworks that have been applied to pain medicine, the emergence of the biopsychospiritual approach and what that means as well as evidence for the benefits of incorporation of this approach for the management of pain. Although the concept of spirituality is broad, there is now greater consensus on what is meant by this term. Many authors and consensus panels have explored the concept and formulated a conceptual framework and an approach that is inclusive, accessible, relevant, and applicable to people with a wide range of health conditions. In addition, there is accumulating evidence that interventions that address the issue of spirituality have benefits for physical and emotional health. Given the firm place that spirituality now holds within other fields and the mounting evidence for its relevance and benefit for people with pain, there is increasing evidence to support the inclusion of spiritual factors as an important component in the assessment and treatment of pain.


Macrofollicular variant of papillary carcinoma, a potential diagnostic pitfall: A report of two cases including a review of literature.
Macrofollicular variant of papillary thyroid carcinoma (MFVPTC) is one of the rarest histologic types of papillary carcinoma. This tumor may mimic an adenomatoid/colloid nodule or follicular neoplasm (macrofollicular type) both on histology and cytology. There are very few articles describing the cytologic features of MFVPTC. We report the cytologic findings of two surgically confirmed MFVPTC. The first case showed abundant thin colloid with moderate amount of follicular cells arranged in a honeycombed and syncytial pattern. Some but not all the follicular cells showed enlarged round to ovoid nuclei, overlapping nuclei, few nuclear grooves and rare intranuclear inclusions. The second case showed abundant thin colloid and predominantly benign appearing follicular cells with few overlapping nuclei, enlarged round to ovoid nuclei and rare nuclear grooves. No intranuclear inclusions were identified. A review of the literature was done and the cytologic findings of MFVPTC including our two cases were tabulated. The cytologic findings showed moderate to abundant thin with focally thick colloid in 75% of cases and sheet like arrangement of follicular cells in 76%. Although nuclear features such as chromatin clearing, overlapping and grooves were present in majority of cases, the quantity varied from rare to focal. Small to prominent nucleoli were present in all of the evaluable cases. Intranuclear inclusions were seen only in 45% of patients. Hence, the cytologic features of macrofollicular variant of papillary carcinoma though present can be subtle and intranuclear inclusions may not be present always.


Functional expression of a bacterial xylose isomerase in Saccharomyces cerevisiae.
In industrial fermentation processes, the yeast Saccharomyces cerevisiae is commonly used for ethanol production. However, it lacks the ability to ferment pentose sugars like d-xylose and l-arabinose. Heterologous expression of a xylose isomerase (XI) would enable yeast cells to metabolize xylose. However, many attempts to express a prokaryotic XI with high activity in S. cerevisiae have failed so far. We have screened nucleic acid databases for sequences encoding putative XIs and finally were able to clone and successfully express a highly active new kind of XI from the anaerobic bacterium Clostridium phytofermentans in S. cerevisiae. Heterologous expression of this enzyme confers on the yeast cells the ability to metabolize d-xylose and to use it as the sole carbon and energy source. The new enzyme has low sequence similarities to the XIs from Piromyces sp. strain E2 and Thermus thermophilus, which were the only two XIs previously functionally expressed in S. cerevisiae. The activity and kinetic parameters of the new enzyme are comparable to those of the Piromyces XI. Importantly, the new enzyme is far less inhibited by xylitol, which accrues as a side product during xylose fermentation. Furthermore, expression of the gene could be improved by adapting its codon usage to that of the highly expressed glycolytic genes of S. cerevisiae. Expression of the bacterial XI in an industrially employed yeast strain enabled it to grow on xylose and to ferment xylose to ethanol. Thus, our findings provide an excellent starting point for further improvement of xylose fermentation in industrial yeast strains.


Conservative management of a traumatic meniscal injury utilising osteopathy and exercise rehabilitation: A case report.
Meniscal injury is one of the most common knee soft tissue injuries, commonly affecting young athletes and an older, degenerative population. Treatment largely depends on the type and extent of the injury with arthroscopic repair or meniscectomy being mainstays. Although non-surgical approaches have been described, there is no published literature regarding a combination of indirect osteopathic techniques and rehabilitation in the management of these injuries. The current case report follows a 20-year-old male presenting with a 5-day history of acute knee pain, following trauma during an Australian Rules Football (AFL) match. An 8-week management plan of indirect osteopathic techniques and a tailored rehabilitation program was implemented. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Lower Extremity Functional Scale (LEFS) questionnaires were utilised to measure outcomes. After the 8-week treatment and rehabilitation program, the patient had exceeded the minimum detectable change score for all outcome measures. This case report suggests that osteopathic manipulative treatment and rehabilitation may be an alternative, non-surgical approach in the management of post-traumatic meniscal injuries.


Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone-sensitive prostate cancer.
Clinical outcomes may differ among patients presenting with primary (de novo) metastatic hormone-sensitive prostate cancer (mHSPC) versus secondary (metachronous) mHSPC occurring after local therapy. It is unknown what molecular features distinguish these potentially distinct presentations. A single-center retrospective study of mHSPC patients classified as primary mHSPC (n = 121) or secondary mHSPC (n = 106). A targeted set of genes was analyzed: BRCA2, PTEN, RB1, TP53, SPOP, CDK12, any two out of PTEN/RB1/TP53 alterations, and homologous recombination deficiency mutations. TP53 mutations were categorized as loss-of-function (LOF) versus dominant-negative (DN). The impacts of genetic features on progression-free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox proportional hazards regression. Median PFS was 15 and 30 months for men with primary and secondary mHSPC, respectively (hazard ratio: 0.57, 95% confidence interval: 0.41-0.78; p < .01). OS did not show a significant difference between groups. There were more men with Gleason 8-10 disease in the primary versus secondary mHSPC groups (83% vs. 68%; p < .01). In univariate and multivariate analyses, TP53 DN mutations showed a statistically significant association with OS for the entire mHSPC population. Conversely, SPOP mutations were associated with improved OS. Additionally, TP53 mutations (DN and LOF) were associated with worse OS for secondary mHSPC. A combination of PTEN/RB1/TP53 mutations was associated with worse OS and PFS for secondary mHSPC, while no genomic alteration affected outcomes for primary mHSPC. TP53 DN mutations, but not all TP53 alterations, were the strongest predictor of negative outcomes in men with mHSPC, while SPOP mutations were associated with improved outcomes. In subgroup analyses, specific alterations were prognostic of outcomes in secondary, but not primary, mHSPC.


Accuracy of an objective binocular automated phoropter for providing spectacle prescriptions.
Currently eye examinations are usually based on autorefraction followed by subjective refraction (SR) with a phoropter. An automated phoropter that can also perform autorefraction may facilitate the optometric workflow. The efficiency and feasibility of an objective autorefraction and correction system are assessed by comparing objective refractive measurements with SR on the same subjects and evaluating the visual acuity (VA) values obtained after the objective refractive measurement and correction. Objective autorefraction and correction was performed on 41 subjects using an automated binocular phoropter system. The auto-phoropter performs autorefraction by wavefront measurement and corrects the spherical and cylindrical errors with tunable fluidic lenses while the patient looks at a visual display inside the instrument. The instrument outputs are optometric constants of spherical and cylindrical aberrations. After measurement and automated correction of the refractive errors, the VA values were assessed by having the subjects look at an integrated Snellen chart. The objective measurement results were statistically compared with their SR. The correlations between SR and objective autorefraction and correction spherical equivalents (M) were 0.98 (0.97-0.99) and 0.96 (0.93-0.98), the vertical Jackson cross cylinder (J0) were 0.96 (0.92-0.98) and 0.95 (0.91-0.97), and the oblique Jackson cross cylinder (J45) were 0.73 (0.55-0.85) and 0.82 (0.69-0.90), for the right and left eyes, respectively, with the 95% confidence interval (CI) values in parentheses. 89.0% of the 82 eyes had at least 6/7.5 VA. A significant agreement between the SR and objective autorefraction and correction was observed. An all-objective refractive assessment with instantaneous verification may improve the precision of eye prescriptions and possibly reduce the procedure time.


Natural evolution of desmoplastic fibroblastoma on magnetic resonance imaging: a case report.
Desmoplastic fibroblastoma (collagenous fibroma) is a recently described tumor thought to arise predominantly from subcutaneous tissue or skeletal muscle. The natural evolution of this tumor on magnetic resonance imaging has never been described, to the best of our knowledge. We herein report a case of desmoplastic fibroblastoma arising in the thigh and show the longitudinal magnetic resonance imaging findings. A 60-year-old Japanese man presented with swelling of the medial side of his right thigh, and he complained of nighttime pain and slight tenderness. Magnetic resonance imaging demonstrated a 4 × 4 cm mass in the right thigh. Open biopsy was performed. The mass was diagnosed histologically as a benign fibrous tumor, and we maintained follow-up without surgical therapy. After one year, magnetic resonance imaging showed an increase in tumor size to 4 × 5 cm, but the histologic findings were the same as those obtained one year earlier. Resection was performed with narrow surgical margins. Pathologic diagnosis was desmoplastic fibroblastoma. Two years after surgery, the patient is free from pain and shows no signs or symptoms of recurrence. The natural evolution of desmoplastic fibroblastoma is characterized by no changes in patterns on magnetic resonance imaging despite increasing size. This finding is clinically helpful for distinguishing desmoplastic fibroblastoma with increasing pain from the desmoid tumor.


Substandard Cisplatin Found While Screening the Quality of Anticancer Drugs From Addis Ababa, Ethiopia.
A postmarket evaluation of chemotherapy dosage forms in Ethiopia was conducted to test the accuracy of the chemoPAD, a paper analytical device for drug quality screening. In September of 2018 in Addis Ababa, Ethiopia, 41 anticancer drug dosage forms (representing 4 active ingredients, 5 brands, and 7 lot numbers) were collected and were rapidly screened for quality using a chemotherapy paper analytical device (chemoPAD). Confirmatory analysis via high performance liquid chromatography was conducted. The chemoPAD showed that the correct active pharmaceutical ingredient was present in doxorubicin, methotrexate, and oxaliplatin injectable dosage forms. However, 11 of 20 cisplatin samples failed the screening test. Confirmatory assay by high-performance liquid chromatography showed that all 20 cisplatin samples-comprising three lot numbers of a product stated to be Cisteen-were substandard, containing on average 54% ± 6% of the stated cisplatin content. Inductively coupled plasma optical emission spectroscopy analysis of five representative samples found 57% to 71% of the platinum that should have been present. The sensitivity of the chemoPAD for detection of falsified products could not be measured (as none were present in these samples), but the selectivity was 100% (no false positives). The sensitivity for detection of substandard products was 55%, and the selectivity was 100% (no false positives). Although instrumental analysis by pharmacopeia methods must remain the gold standard for assessing overall drug quality, these methods are time consuming and patients could be exposed to a bad-quality drug while clinical workers wait for testing to be performed. The chemoPAD technology could allow clinicians to check at the point of use for serious problems in the quality of chemotherapy drugs on a weekly or monthly schedule.


Maximally selected chi-square statistics for ordinal variables.
The association between a binary variable Y and a variable X having an at least ordinal measurement scale might be examined by selecting a cutpoint in the range of X and then performing an association test for the obtained 2 x 2 contingency table using the chi-square statistic. The distribution of the maximally selected chi-square statistic (i.e. the maximal chi-square statistic over all possible cutpoints) under the null-hypothesis of no association between X and Y is different from the known chi-square distribution. In the last decades, this topic has been extensively studied for continuous X variables, but not for non-continuous variables of at least ordinal measurement scale (which include e.g. classical ordinal or discretized continuous variables). In this paper, we suggest an exact method to determine the finite-sample distribution of maximally selected chi-square statistics in this context. This novel approach can be seen as a method to measure the association between a binary variable and variables having an at least ordinal scale of different types (ordinal, discretized continuous, etc). As an illustration, this method is applied to a new data set describing pregnancy and birth for 811 babies.


PDE3 and PDE4 isozyme-selective inhibitors are both required for synergistic activation of brown adipose tissue.
Brown adipose tissue (BAT) is a highly thermogenic organ that converts lipids and glucose into heat. Many of the metabolic and gene transcriptional hallmarks of BAT activation, namely increased lipolysis, uncoupling protein-1 (UCP1) mRNA, and glucose uptake, are regulated by the adrenergic second messenger, cAMP. Cyclic nucleotide phosphodiesterases (PDEs) catalyze the breakdown of cAMP, thereby regulating the magnitude and duration of this signaling molecule. In the absence of adrenergic stimulus, we found that it required a combination of a PDE3 and a PDE4 inhibitor to fully induce UCP1 mRNA and lipolysis in brown adipocytes, whereas neither PDE inhibitor alone had any substantial effect under basal conditions. Under submaximal β-adrenoceptor stimulation of brown adipocytes, a PDE3 inhibitor alone could potentiate induction of UCP1 mRNA, whereas a PDE4 inhibitor alone could augment lipolysis, indicating differential roles for each of these two PDEs. Neither induction of UCP1 nor lipolysis was altered by inhibition of PDE1, PDE2, or PDE8A. Finally, when injected into mice, the combination of PDE3 and PDE4 inhibitors stimulated glucose uptake in BAT under thermoneutral and fasted conditions, a response that was further potentiated by the global ablation of PDE8A. Taken together, these data reveal that multiple PDEs work in concert to regulate three of the important pathways leading to BAT activation, a finding that may provide an improved conceptual basis for the development of therapies for obesity-related diseases.


Characteristics of injection drug users who participate in drug dealing: implications for drug policy.
So-called "balanced" drug policy couples enforcement initiatives targeting drug dealers with health-focused interventions serving addicted individuals. There are few evaluations of this approach, and little is known about how these two populations may overlap. We evaluated factors associated with drug dealing among injection drug users (IDUs) in Vancouver, Canada, and examined self-reported drug-dealing roles and reasons for dealing. Among 412 IDUs seen from March through December 2005, 68 (17%) had dealt drugs during the previous six months. Variables independently associated with drug dealing included: recent incarceration (adjusted odds ratio [AOR] = 2.9; 95%CI: 1.4-6.0); frequent heroin injection (AOR = 2.5; 95%CI: 1.4-4.6); frequent cocaine injection (AOR = 2.0; 95%CI: 1.1-3.8); and recent overdose (AOR = 2.7; 95%CI: 1.0-7.3). The most common drug-dealing roles were direct selling (82%), middling (35%), and steering (19%), while the most common reasons for dealing included obtaining drugs (49%) and money (36%). Drug dealing among IDUs was predicted by several markers of higher intensity addiction, and drug-dealing IDUs tended to occupy the most dangerous positions in the drug-dealing hierarchy. These findings suggest that elements of "balanced" drug policies may undermine each other and indicate the need for alternative interventions.


A novel activation pathway for mature thymocytes. Costimulation of CD2 (T,p50) and CD28 (T,p44) induces autocrine interleukin 2/interleukin 2 receptor-mediated cell proliferation.
Prior studies have shown that thymocytes, unlike peripheral T cells, do not proliferate in response to mitogenic combinations of anti-CD2 mAbs. The present study demonstrated that stimulation by a mitogenic anti-CD2 combination (9-1 plus 9.6) with anti-CD28 induced vigorous thymocyte proliferation in the absence of exogenous IL-2. This thymocyte proliferation was IL-2 dependent as shown by the complete inhibition using anti-IL-2-R mAbs. Induction of IL-2-R transcripts was detected in thymocytes stimulated by the anti-CD2 antibody combination alone or the anti-CD2 combination plus anti-CD28 antibody. However, induction of IL-2 transcripts was observed only in thymocytes triggered jointly by the anti-CD2 combination plus anti-CD28 antibodies. The double-negative (CD4-8-) or CD1+ thymocytes isolated by sorting or by panning were unresponsive to CD2/CD28 triggering. The same mitogenic signal could induce vigorous proliferation of thymocytes with a mature phenotype, i.e., CD3+CD4+ or CD3+CD8+ thymocytes. Immunofluorescence studies demonstrated that the majority of CD3+ thymocytes were CD28+, and most of the CD28+ cells were located in the medullary compartment of thymus. These results indicated that the T cell lineage surface molecules CD28 and CD2 are involved in the regulation of expansion and further differentiation of mature thymocytes.


A doubly responsive probe for the detection of Cys4-tagged proteins.
Recombinant proteins bearing a tag are crucial tools for assessing protein location or function. Small tags such as Cys4 tag (tetracysteine; Cys-Cys-X-X-Cys-Cys) are less likely disrupt protein function in the living cell than green fluorescent protein. Herein we report the first example of the design and synthesis of a dual fluorescence and hyperpolarized (129)Xe NMR-based sensor of Cys4-tagged proteins. This sensor becomes fluorescent when bound to such Cys4-tagged peptides, and the (129)Xe NMR spectrum exhibits a specific signal, characteristic of the biosensor-peptide association.


Baseline prevalence and longitudinal evolution of non-motor symptoms in early Parkinson's disease: the PPMI cohort.
To examine the baseline prevalence and longitudinal evolution in non-motor symptoms (NMS) in a prospective cohort of, at baseline, patients with de novo Parkinson's disease (PD) compared with healthy controls (HC). Parkinson's Progression Markers Initiative (PPMI) is a longitudinal, ongoing, controlled study of de novo PD participants and HC. NMS were rated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I score and other validated NMS scales at baseline and after 2 years. Biological variables included cerebrospinal fluid (CSF) markers and dopamine transporter imaging. 423 PD subjects and 196 HC were enrolled and followed for 2 years. MDS-UPDRS Part I total mean (SD) scores increased from baseline 5.6 (4.1) to 7.7 (5.0) at year 2 in PD subjects (p<0.001) versus from 2.9 (3.0) to 3.2 (3.0) in HC (p=0.38), with a significant difference between the groups (p<0.001). In the multivariate analysis, higher baseline NMS score was associated with female sex (p=0.008), higher baseline MDS-UPDRS Part II scores (p<0.001) and more severe motor phenotype (p=0.007). Longitudinal increase in NMS severity was associated with the older age (0.008) and lower CSF Aβ1-42 (0.005) at baseline. There was no association with the dose or class of dopaminergic therapy. This study of NMS in early PD identified clinical and biological variables associated with both baseline burden and predictors of progression. The association of a greater longitudinal increase in NMS with lower baseline Aβ1-42 level is an important finding that will have to be replicated in other cohorts. ClinicalTrials.gov identifier: NCT01141023.


Klotho-HIV and Oxidative Stress: The Role of Klotho in Cardiovascular Disease Under HIV Infection-A Review.
Combined antiretroviral therapy has improved quality and life expectancy of people living with human immunodeficiency virus (HIV). However, this therapy increases oxidative stress (OS), which in turn causes alterations in lipid and carbon metabolism, kidney disease, liver cirrhosis, and increased risk of cardiovascular disease. The Klotho gene has been implicated in cardiovascular risk increase. Klotho protein expression at X level decreases the risk of heart disease. HIV-positive people usually present low plasma levels of Klotho; thus, contributing to some extent to an increase in cardiovascular risk for these types of patients, mostly by favoring atherosclerosis. Therefore, our aim is to provide an overview of the effect of OS on Klotho protein and its consequent cardiometabolic alterations in HIV-positive patients on antiretroviral therapy.


DXA measurements in Rett syndrome reveal small bones with low bone mass.
Low bone mass is reported in growth-retarded patients harboring mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene causing Rett syndrome (RTT). We present the first study addressing both bone mineral density (BMD) and bone size in RTT. Our object was to determine whether patients with RTT do have low BMD when correcting for smaller bones by examination with dual-energy X-ray absorptiometry (DXA). We compared areal BMD (aBMD(spine) and aBMD(total hip) ) and volumetric bone mineral apparent density (vBMAD(spine) and vBMAD(neck) ) in 61 patients and 122 matched healthy controls. Further, spine and hip aBMD and vBMAD of patients were associated with clinical risk factors of low BMD, low-energy fractures, MECP2 mutation groups, and X chromosome inactivation (XCI). Patients with RTT had reduced bone size on the order of 10% and showed lower values of spine and hip aBMD and vBMAD (p < .001) adjusted for age, pubertal status, and body mass index (BMI). aBMD(spine) , vBMAD(spine) , and aBMD(total hip) were associated with low-energy fractures (p < .05). Walking was significantly associated to aBMD(total hip) and vBMAD(neck) adjusted for age and body mass index (BMI). Further, vBMAD(neck) was significantly associated to a diagnosis of epilepsy, antiepileptic treatment, and MECP2 mutation group, but none of the associations with vBMAD(neck) remained clinically significant in a multiple adjusted model including age and BMI. Neither aBMD(spine) , vBMAD(spine) , nor aBMD(total hip) were significantly associated with epilepsy, antiepileptic treatment, MECP2 mutation group, XCI, or vitamin D status. Low bone mass and small bones are evident in RTT, indicating an apparent low-bone-formation phenotype.


Experiences with pregnancy of adolescents with disabilities from the perspectives of the school social workers who serve them.
Adolescents with disabilities are more likely than adolescents without disabilities to become pregnant, although very little is known about the lived contexts of their sexual and pregnancy experiences. Such youths are often deprived of sexual health information across a range of potential sources, although school social workers are in a unique position to provide them services. Thirteen school social workers working primarily with adolescents with disabilities were interviewed using a phenomenological study design to offer their perspectives concerning the sexual and pregnancy experiences of such youths. Inductive content analysis revealed that school social workers provided services for pregnant and parenting adolescents with a range of disabilities in areas that included making decisions about sex, deciphering whether they were pregnant, and making decisions once they were pregnant. These experiences were complicated by cognitive impairments; emotional struggles; desires to fit in with peers; histories of sexual abuse; and issues with communication, self-esteem, and impulsivity. School social workers play an integral role in preventing pregnancy and supporting adolescents with disabilities who are pregnant. Recommendations pertaining to the provision of sexual health services for adolescents with disabilities are provided.


Hispolon suppresses metastasis via autophagic degradation of cathepsin S in cervical cancer cells.
Hispolon, a phenolic compound isolated from Phellinus igniarius, induces apoptosis and anti-tumor effects in cancers. However, the molecular mechanism involved in hispolon-mediated tumor-suppressing activities observed in cervical cancer is poorly characterized. Here, we demonstrated that treatment with hispolon inhibited cell metastasis in two cervical cancer cell lines. In addition, the downregulation of the lysosomal protease Cathepsin S (CTSS) was critical for hispolon-mediated suppression of tumor cell metastasis in both in vitro and in vivo models. Moreover, hispolon induced autophagy, which increased LC3 conversion and acidic vesicular organelle formation. Mechanistically, hispolon inhibited the cell motility of cervical cells through the extracellular signal-regulated kinase (ERK) pathway, and blocking of the ERK pathway reversed autophagy-mediated cell motility and CTSS inhibition. Our results indicate that autophagy is essential for decreasing CTSS activity to inhibit tumor metastasis by hispolon treatment in cervical cancer; this finding provides a new perspective on molecular regulation.


Mitochondria are associated with microtubules and not with intermediate filaments in cultured fibroblasts.
Triple-immunofluorescence experiments with antibodies to cytochrome c oxidase, tubulin, and vimentin have been used to immunolabel the mitochondria, microtubules, and intermediate filaments inside the same cultured fibroblasts. In particular, fibroblasts were immunolabeled after they had either been transformed by infection with Rous sarcoma virus or given long-term treatment with cycloheximide. These treatments induced redistribution of the intermediate filaments into a perinuclear arrangement, segregated away from the microtubules, which remained extended to the cell periphery. In such cells, many labeled mitochondria were observed to be codistributed with the peripherally located microtubules. From these results, we infer that an association, probably involving some type of chemical linkage(s), between mitochondria and microtubules exists in these cells that is independent of the intermediate filaments.


Temperature dependent structural properties and bending rigidity of pristine and defective hexagonal boron nitride.
Structural and thermodynamical properties of monolayer pristine and defective boron nitride sheets (h-BN) have been investigated in a wide temperature range by carrying out atomistic simulations using a tuned Tersoff-type inter-atomic empirical potential. The temperature dependence of lattice parameter, radial distribution function, specific heat at constant volume, linear thermal expansion coefficient and the height correlation function of the thermally excited ripples on pristine as well as defective h-BN sheet have been investigated. Specific heat shows considerable increase beyond the Dulong-Petit limit at high temperatures, which is interpreted as a signature of strong anharmonicity present in h-BN. Analysis of the height fluctuations, ⟨h2⟩, shows that the bending rigidity and variance of height fluctuations are strongly temperature dependent and this is explained using the continuum theory of membranes. A detailed study of the height-height correlation function shows deviation from the prediction of harmonic theory of membranes as a consequence of the strong anharmonicity in h-BN. It is also seen that the variance of the height fluctuations increases with defect concentration.


How fern and fern allies respond to heterogeneous habitat - a case in Yuanjiang dry-hot valley.
The Yuanjiang dry-hot valley features hot and dry climate, low vegetation and soil degradation. It had lush vegetation in the past, but has become degraded in recent decades. Understanding the interrelationship between species and the habitat is necessary to explain this change. In this study, a link between fern and fern allies - a group that is hypersensitive to environmental factors and their circumstances is constructed. Intensive transects and plots were designed to be proxies for extant fern and fern allies, and their habitats. Fifty years of meteorological records of precipitation and temperature along altitude and river running direction (latitudinal) were employed. Alpha and beta diversity are used to access diversity. Species_estimated, Singletons, Uniques, ACE, ICE, and Chao2, which associate to abundance and rarity, are subscribed to the correlation between fern and fern allies, and their ecosystem. Eight species, Selaginella pseudopaleifera, Aleuritopteris squamosa, Adiantum malesianum, Pteris vittata, Davallia trichomanoides, Sinephropteris delavayi, Selaginella jugorum, and Lygodium japonicum are used as indicators of a typical xeric and sun-drying habitat. The results indicate (1) accompanied by dramatically shrinking habitats, fern and fern allies are in very low diversity and abundance, whereas the rarity is relatively high; (2) for fern and fern allies, environmental factors are positive when altitude goes up; and (3) eight indicator species are latitudinally correlated with fern and fern allies along the river running direction.


An integrative view of phylogenetic comparative methods: connections to population genetics, community ecology, and paleobiology.
Recent innovations in phylogenetic comparative methods (PCMs) have spurred a renaissance of research into the causes and consequences of large-scale patterns of biodiversity. In this paper, we review these advances. We also highlight the potential of comparative methods to integrate across fields and focus on three examples where such integration might be particularly valuable: quantitative genetics, community ecology, and paleobiology. We argue that PCMs will continue to be a key set of tools in evolutionary biology, shedding new light on how evolutionary processes have shaped patterns of biodiversity through deep time.


Conjugated linoleic acid and disease prevention: a review of current knowledge.
Conjugated linoleic acid (CLA), a derivative of a fatty acid linoleic acid (LA), has been reported to decrease tumorigenesis in animals. CLA is unique because unlike most antioxidants which are components of plant products, it is present in food from animal sources such as dairy foods and meats. CLA concentrations in dairy products typically range from 2.9 to 8.92 mg/g fat of which the 9-cis, 11-trans isomer makes up to 73% to 93% of the total CLA. Low concentrations of CLA are found in human blood and tissues. In vitro results suggest that CLA is cytotoxic to MCF-7 cells and it inhibits the proliferation of human malignant melanoma and colorectal cancer cells. In animal studies, CLA has inhibited the development of mouse epidermal tumors, mouse forestomach cancer and rat mammary cancer. Hamsters fed CLA collectively had significantly reduced levels of plasma total cholesterol, non-high-density lipoprotein cholesterol, (combined very-low and low-density lipoprotein) and triglycerides with no effect on high-density lipoprotein cholesterol, as compared to controls. Dietary CLA modulated certain aspects of the immune defense but had no obvious effect on the growth of an established, aggressive mammary tumor in mice. It is now thought that CLA itself may not have anti-oxidant capabilities but may produce substances which protect cells from the detrimental effects of peroxides. There is, however, insufficient evidence from human epidemiological data, and very few of the animal studies have shown a dose-response relationship with the quantity of CLA feed and the extent of tumor growth. Further research with tumor models is needed to test the efficacy and utility of CLA in cancer and other disease prevention and form the basis of evaluating its effect in humans by observational studies and clinical trials.