Beta oscillations correlate with the probability of perceiving rivalrous visual stimuli.
Under continuous lighting, moving stimuli such as ceiling fans and car wheels can sporadically appear to move in the reverse direction-this phenomenon is known as illusory motion reversal (IMR). We have previously suggested that IMR results from the spurious activation of motion detectors tuned for the opposite direction of motion, leading to a rivalry between two possible motion percepts. To determine if this hypothesis is supported by evidence from electrophysiology, we used EEG to directly compare neural signatures in IMR and binocular rivalry (BR), a well-studied form of rivalry. We find that both IMR and BR show large changes in power in the beta range (14-30 Hz) at the time of a perceptual switch. More importantly, during a stable perception, beta power correlates with the probability of a perception. Specifically, beta power associated with veridical motion perception (experienced the majority of the time) is higher than the power during illusory motion perception (experienced a minority of the time). The BR percepts, each 50% probable, are associated with an intermediate beta amplitude. We propose that the amplitude of synchronized beta activity reflects the size of currently active neural coalitions, with less likely percepts associated with smaller coalitions.


Epithelial myoepitheial carcinoma of minor salivary gland--low grade malignant tumor presenting with nodal metastasis.
Epithelial myoepithelial carcinoma (EMC) is a rare low grade malignant salivary gland neoplasm that most commonly occurs in the parotid gland but can also arise in minor salivary glands. We report a case of primary epithelial myoepithelial carcinoma of minor salivary gland in a 25 year old women who presented with swelling left cheek of one year duration and bilateral submandibular lymphadenopathy. A mass causing erosion of mandible, thyroid cartilage and masseter muscle was identified on CT scan. This was excised and histological examination revealed a mixture of ductal structures consisting of inner dark cells and outer clear cells seen in solid sheets. Immunohistochemical analysis showed the clear cells to be weakly positive for S100 and smooth muscle actin (SMA) and ductal cells to be positive for cytokeratin (CK) and epithelial membrane antigen (EMA). The characteristic morphological and immunohistochemical features aided in the diagnosis of epithelial myoepithelial carcinoma.


E2F1-induced long non-coding RNA MCF2L-AS1 modulates Cyclin D1 mRNA stability through ELAVL1 to induce Gefitinib resistance in non-small cell lung cancer.
Gefitinib is a widely used therapeutic drug for non-small cell lung cancer (NSCLC), and its acquired resistance has become one of the barriers to the successful use of the drugs to treat NSCLC patients. Long non-coding RNA (lncRNA) has an essential role in developing cancer drug resistance. Hence, this study aimed to investigate the effect and modulatory mechanisms of lncRNA MCF2L-AS1 in Gefitinib resistance in NSCLC. IBEAS-2B and A549 cells and human NSCLC tissues were used. A549/GR cell line was constructed by continuous exposure to Gefitinib. Cell viability, apoptosis, migration, colony formation, and protein expression studies were done in transfected cells. Interactions of MCF2L-AS1, ELAVL1, and Cyclin D1 (CCND1 was also investigated. In patients with Gefitinib-resistant NSCLC, MCF2L-AS1 and CCND1 were both up-regulated. Knockdown of MCF2L-AS1 reduced Gefitinib-resistant NSCLC cell progression, indicating that inhibition of MCF2L-AS1 restrained Gefitinib-resistant NSCLC. Mechanically, MCF2L-AS1 enhanced CCND1 mRNA stability via combining with ELAVL1, thereby elevating the resistance of NSCLC cells to Gefitinib. Moreover, E2F1 could transcriptionally up-regulate MCF2L-AS1. The results manifest that lncRNA MCF2L-AS1, as an oncogene of NSCLC, controls CCDN1 via ELAVL1 to drive the growth of NSCLC cells and Gefitinib resistance.


Sub-micromolar increase in [Ca(2+)](i) triggers delayed exocytosis of ATP in cultured astrocytes.
Astrocytes release a variety of transmitter molecules, which mediate communication between glial cells in the brain and modulate synaptic transmission. ATP is a major glia-derived transmitter, but the mechanisms and kinetics of ATP release from astrocytes remain largely unknown. Here, we combined epifluorescence and total internal reflection fluorescence microscopy to monitor individual quinacrine-loaded ATP-containing vesicles undergoing exocytosis in cultured astrocytes. In resting cells, vesicles exhibited three-dimensional motility, spontaneous docking and release at low rate. Extracellular ATP application induced a Ca(2+)-dependent increase in the rate of exocytosis, which persisted for several minutes. Using UV flash photolysis of caged Ca(2+), the threshold [Ca(2+)](i) for ATP exocytosis was found to be approximately 350 nM. Subthreshold [Ca(2+)](i) transients predominantly induced vesicle docking at plasma membrane without subsequent release. ATP exocytosis triggered either by purinergic stimulation or by Ca(2+) uncaging occurred after a substantial delay ranging from tens to hundreds of seconds, with only approximately 4% of release occurring during the first 30 s. The time course of the cargo release from vesicles had two peaks centered on <or=10 s and 60 s. These results demonstrate that: (1) [Ca(2+)](i) elevations in cultured astrocytes trigger docking and release of ATP-containing vesicles; (2) vesicle docking and release have different Ca(2+) thresholds; (3) ATP exocytosis is delayed by several minutes and highly asynchronous; (4) two populations of ATP-containing vesicles with distinct (fast and slow) time course of cargo release exist in cultured astrocytes.


Restoration of Proteostasis in the Endoplasmic Reticulum Reverses an Inflammation-Like Response to Cytoplasmic DNA in Caenorhabditis elegans.
Innate immune responses protect organisms against various insults, but may lead to tissue damage when aberrantly activated. In higher organisms, cytoplasmic DNA can trigger inflammatory responses that can lead to tissue degeneration. Simpler metazoan models could shed new mechanistic light on how inflammatory responses to cytoplasmic DNA lead to pathologies. Here, we show that in a DNase II-defective Caenorhabditis elegans strain, persistent cytoplasmic DNA leads to systemic tissue degeneration and loss of tissue functionality due to impaired proteostasis. These pathological outcomes can be therapeutically alleviated by restoring protein homeostasis, either via ectopic induction of the ER unfolded protein response or N-acetylglucosamine treatment. Our results establish C. elegans as an ancestral metazoan model for studying the outcomes of inflammation-like conditions caused by persistent cytoplasmic DNA and provide insight into potential therapies for human conditions involving chronic inflammation.


Hepcidin Response to Iron Therapy in Patients with Non-Dialysis Dependent CKD: An Analysis of the FIND-CKD Trial.
Hepcidin is the key regulator of iron homeostasis but data are limited regarding its temporal response to iron therapy, and response to intravenous versus oral iron. In the 56-week, open-label, multicenter, prospective, randomized FIND-CKD study, 626 anemic patients with non-dialysis dependent chronic kidney disease (ND-CKD) and iron deficiency not receiving an erythropoiesis stimulating agent were randomized (1:1:2) to intravenous ferric carboxymaltose (FCM), targeting higher (400-600μg/L) or lower (100-200μg/L) ferritin, or to oral iron. Serum hepcidin levels were measured centrally in a subset of 61 patients. Mean (SD) baseline hepcidin level was 4.0(3.5), 7.3(6.4) and 6.5(5.6) ng/mL in the high ferritin FCM (n = 17), low ferritin FCM (n = 16) and oral iron group (n = 28). The mean (SD) endpoint value (i.e. the last post-baseline value) was 26.0(9.1),15.7(7.7) and 16.3(11.0) ng/mL, respectively. The increase in hepcidin from baseline was significantly smaller with low ferritin FCM or oral iron vs high ferritin FCM at all time points up to week 52. Significant correlations were found between absolute hepcidin and ferritin values (r = 0.65, p<0.001) and between final post-baseline increases in both parameters (r = 0.70, p<0.001). The increase in hepcidin levels over the 12-month study generally mirrored the cumulative iron dose in each group. Hepcidin and transferrin saturation (TSAT) absolute values showed no correlation, although there was an association between final post-baseline increases (r = 0.42, p<0.001). Absolute values (r = 0.36, p = 0.004) and final post-baseline increases of hepcidin and hemoglobin (p = 0.30, p = 0.030) correlated weakly. Baseline hepcidin levels were not predictive of a hematopoietic response to iron therapy. In conclusion, hepcidin levels rose in response to either intravenous or oral iron therapy, but the speed and extent of the rise was greatest with intravenous iron targeting a higher ferritin level. However neither the baseline level nor the change in hepcidin was able to predict response to therapy in this cohort.


Biomechanical and biochemical properties of chicken calcaneal tendon under effect of age and nonforced active exercise.
This study investigated if nonforced active exercise alters the biomechanical and biochemical properties of calcaneal tendon during maturation. Chickens at 1, 5, and 8 months old were divided into two groups: caged and penned. Intact tendons were used for biomechanical analysis, but they were divided into tensile and compressive regions for quantification of hydroxyproline and glycosaminoglycans. The exercise increased tendon strength after the fifth month, energy absorption in the eighth month, and ultimate tensile stress in the first month. Age increased tendon strength and energy storage and reduced stiffness but did not alter stress. There was an increase in collagen content in the fifth month. Glycosaminoglycans showed a progressive decline in the tensile region. Thus, some biomechanical and biochemical changes depend on the maturation process itself and also are influenced by spontaneous exercise, showing that mechanical stimulation of low intensity may help to improve the quality of the tendon.


Investing in Whole Person Health: Working Toward an Integration of Physical, Behavioral, and Social Health.
North Carolina is developing a unique and innovative infrastructure to support integrated physical, behavioral, and social health care. Efforts by the North Carolina Department of Health and Human Services, the Foundation for Health Leadership & Innovation, Cone Health, Atrium Health, and the One Charlotte Health Alliance advance our understanding of how to best operationalize the design and payment of integrated services. Best practices such as the collaborative care and primary care behavioral health models reduce inefficiencies and disparities by bringing together teams of primary care and behavioral health care providers.


Competition for formation of nucleosomes on fragmented SV40 DNA: a hyperstable nucleosome forms on the termination region.
We have studied the relative abilities of different simian virus 40 (SV40) DNA segments to reconstitute into nucleosomes in vitro. The SV40 genome was separated into 15 discrete fragments by restriction endonuclease digestion and reconstituted with calf thymus core histones under conditions of varying histone-to-DNA ratios. Three fragments show very different abilities to form nucleosomes when low histone-to-DNA ratios require all fragments to compete for available histones. Two of these fragments, both from within protein-coding regions, are significantly underreconstituted. The third fragment, covering the SV40 termination region, competes much more effectively for histones than the other 14 fragments. The fragment containing the SV40 origin region formed nucleosomes with about average probability. Overall, the SV40 fragments differed by approximately an order of magnitude in their abilities to support nucleosome formation in vitro. The stability of the nucleosomes was measured by challenge with high concentrations of the destabilizing reagent heparin. The fragment that reconstituted most effectively also formed nucleosomes that were unusually stable to heparin challenge. These observations are intriguing since this fragment contains the sequences where replication of SV40 DNA commonly terminates and where early messenger RNA synthesis may terminate as well. The existence of unique hyperstable nucleosomes in this region suggests the interesting possibility that such nucleosomes may assist in termination events by assisting in the pausing of replication or transcription complexes.


Efficient Alkaline Water/Seawater Hydrogen Evolution by a Nanorod-Nanoparticle-Structured Ni-MoN Catalyst with Fast Water-Dissociation Kinetics.
Achieving efficient and durable nonprecious hydrogen evolution reaction (HER) catalysts for scaling up alkaline water/seawater electrolysis is desirable but remains a significant challenge. Here, a heterogeneous Ni-MoN catalyst consisting of Ni and MoN nanoparticles on amorphous MoN nanorods that can sustain large-current-density HER with outstanding performance is demonstrated. The hierarchical nanorod-nanoparticle structure, along with a large surface area and multidimensional boundaries/defects endows the catalyst with abundant active sites. The hydrophilic surface helps to achieve accelerated gas-release capabilities and is effective in preventing catalyst degradation during water electrolysis. Theoretical calculations further prove that the combination of Ni and MoN effectively modulates the electron redistribution at their interface and promotes the sluggish water-dissociation kinetics at the Mo sites. Consequently, this Ni-MoN catalyst requires low overpotentials of 61 and 136 mV to drive current densities of 100 and 1000 mA cm-2 , respectively, in 1 m KOH and remains stable during operation for 200 h at a constant current density of 100 or 500 mA cm-2 . This good HER catalyst also works well in alkaline seawater electrolyte and shows outstanding performance toward overall seawater electrolysis with ultralow cell voltages.


Frustration Tolerance in Youth With ADHD.
Objective: The objective of this study was to compare children with ADHD with children without ADHD on frustration tolerance and to examine the role of oppositional defiant disorder (ODD) in frustration tolerance within the sample. Method: Participants included 67 children ages 10 to 14 years-old with (n = 37) and without (n = 30) Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) ADHD who completed the Mirror Tracing Persistence Task (MTPT), a validated computerized behavioral measure of frustration tolerance. Results: Children with ADHD were more likely to quit this task than children without ADHD, demonstrating lower levels of frustration tolerance. There were no differences in frustration tolerance between children with ADHD + ODD and those with ADHD - ODD. Moreover, ODD did not moderate the relationship between ADHD and frustration tolerance. Conclusion: Our results suggest that low frustration tolerance is directly linked to ADHD and not better accounted for by ODD. This research highlights specific behavioral correlates of frustration in children with ADHD.


Examining the role of personal traumas in a nurse's work life.
In this monthly column, Aysha Mendes discusses the impact a nurse's personal traumas can have on his or her nursing practice, professional and personal experience of caring, and on patients and their families.


The Potential Proconvulsant Effects of Cannabis: a Scoping Review.
Cannabis' effect on seizure activity is an emerging topic that remains without consensus and merits further investigation. We therefore performed a scoping review to identify the available evidence and knowledge gaps within the existing literature on cannabis product exposures as a potential cause of seizures in humans. A scoping review was conducted in accordance with the PRISMA Extension for Scoping Reviews guidelines. The PubMed and Scopus databases were searched over a 20-year period from the date of the database query (12/21/2020). Inclusion criteria were (1) English language original research articles, (2) inclusion of human subjects, and (3) either investigation of seizures as a part of recreational cannabinoid use OR of exogenous cannabinoids as a cause of seizures. A total of 3104 unique articles were screened, of which 68 underwent full-text review, and 13 met inclusion/exclusion criteria. Ten of 11 studies evaluating acute cannabis exposures reported a higher seizure incidence than would be expected based on the prevalence of epilepsy in the general and pediatric populations (range 0.7-1.2% and 0.3-0.5% respectively). The remaining two studies demonstrated increased seizure frequency and/or seizure-related hospitalization in recreational cannabis users and those with cannabis use disorder. This scoping review demonstrates that a body of literature describing seizures in the setting of cannabis exposure exists, but it has several limitations. Ten identified studies showed a higher than expected incidence of seizures in populations exposed to cannabis products. Based on the Bradford Hill criteria, delta-9 tetrahydrocannabinol (THC) may be the causative xenobiotic for this phenomenon.


The use of 4,4,4-trifluorothreonine to stabilize extended peptide structures and mimic β-strands.
Pentapeptides having the sequence R-HN-Ala-Val-X-Val-Leu-OMe, where the central residue X is L-serine, L-threonine, (2S,3R)-L-CF3-threonine and (2S,3S)-L-CF3-threonine were prepared. The capacity of (2S,3S)- and (2S,3R)-CF3-threonine analogues to stabilize an extended structure when introduced in the central position of pentapeptides is demonstrated by NMR conformational studies and molecular dynamics simulations. CF3-threonine containing pentapeptides are more prone to mimic β-strands than their natural Ser and Thr pentapeptide analogues. The proof of concept that these fluorinated β-strand mimics are able to disrupt protein-protein interactions involving β-sheet structures is provided. The CF3-threonine containing pentapeptides interact with the amyloid peptide Aβ1-42 in order to reduce the protein-protein interactions mediating its aggregation process.


Use of bacteriophage MS2 as an internal control in viral reverse transcription-PCR assays.
Diagnostic systems based on reverse transcription (RT)-PCR are widely used for the detection of viral genomes in different human specimens. The application of internal controls (IC) to monitor each step of nucleic acid amplification is necessary to prevent false-negative results due to inhibition or human error. In this study, we designed various real-time RT-PCRs utilizing the coliphage MS2 replicase gene, which differ in detection format, amplicon size, and efficiency of amplification. These noncompetitive IC assays, using TaqMan, hybridization probe, or duplex scorpion probe techniques, were tested on the LightCycler and Rotorgene systems. In our approach, clinical specimens were spiked with the control virus to monitor the efficiency of extraction, reverse transcription, and amplification steps. The MS2 RT-PCR assays were applied for internal control when using a second target hepatitis C virus RNA in duplex PCR in blood donor screening. The 95% detection limit was calculated by probit analysis to 44.9 copies per PCR (range, 38.4 to 73.4). As demonstrated routinely, application of MS2 IC assays exhibits low variability and can be applied in various RT-PCR assays. MS2 phage lysates were obtained under standard laboratory conditions. The quantification of phage and template RNA was performed by plating assays to determine PFU or via real-time RT-PCR. High stability of the MS2 phage preparations stored at -20 degrees C, 4 degrees C, and room temperature was demonstrated.


Cancer education in Lithuania.
The aim of this article is to describe cancer education in Lithuania according to the data of 2013. In Lithuania, there are the following stages of education for physicians: basic education through integrated studies of medicine (six years), postgraduate education through residency studies (four to five years), and continuing professional development. In recent years, integrated studies of medicine have been the most popular specialty. Oncology is incorporated into the teaching courses in medicine programmes. In each university, an oncology course is mandatory during these studies. In Lithuania, there are two types of specialists related to oncology: medical oncologists and radiation oncologists. These oncologists complete multidisciplinary residency study programmes in the clinics. To receive a doctoral degree, specialists may join PhD programmes at any of the accredited universities. In recent years the number of dissertations in oncology has grown. Notably, oncology is chosen not only by students in the field of medicine. It also becomes the choice of those seeking a doctorate in the fields of nursing, public health, biochemistry, and physics. The professional development of oncologists is a lifelong commitment. In Lithuania, continuing specialist medical training is mandatory. This requirement is ensured with the process of licensing of medical practice. All Lithuanian study programmes are certificated by an independent public agency and are recognised by a number of other countries as well.


Mammalian target of rapamycin (mTOR) inhibitors and combined chemotherapy in breast cancer: a meta-analysis of randomized controlled trials.
The mammalian target of rapamycin (mTOR) inhibitor, in combination with other chemotherapeutic drugs, has been used for treatment of breast cancer that develops resistance to endocrine therapy. However, the efficacy and safety need further evaluation. Here, we report a meta-analysis of randomized controlled trials (RCT) in breast cancer patients undergoing chemotherapy using steroid (exemestane) or nonsteroid (letrozole) aromatase inhibitors with or without mTOR inhibitors (everolimus). The overall response rate (ORR), progression-free survival (PFS), clinical benefi;t rate with 95% confidence interval (CI), and the major toxicities/adverse effects were analyzed. Data were extracted from twelve studies that meet the selection criteria. Among these, six studies that enrolled 3693 women received treatment of everolimus plus exemestane, or placebo with exemestane. The results showed that everolimus plus exemestane significantly increased the ORR relative risk (relative risk = 9.18, 95% CI = 5.21-16.15), PFS hazard ratio (hazard ratio = 0.44, 95% CI = 0.41-0.48), and clinical benefi;t rate (relative risk = 1.92, 95% CI 1.69-2.17) compared to placebo control, while the risks of stomatitis, rash, hyperglycemia, diarrhea, fatigue, anorexia and pneumonitis also increased. Three studies that enrolled 715 women who received everolimus as neoadjuvant therapy were analyzed. Compared to chemotherapy with placebo, chemotherapy plus everolimus did not increase the ORR relative risk (relative risk = 0.90, 95% CI = 0.77-1.05). Meanwhile, two other studies that enrolled 2104 women examined the efficacy of temsirolimus (or placebo control) plus letrozole. The results indicated that emsirolimus plus letrozole did not increase the ORR relative risk and clinical benefi;t rate (p > 0.05). Together, these data suggest that the combined mTOR inhibitor (everolimus) plus endocrine therapy (exemestane) is superior to endocrine therapy alone. As a neoadjuvant, everolimus did not increase the ORR, while temsirolimus plus letrozole treatment has limited effect on the ORR and the CBR of breast cancer patients.


Pearls in the management of submacular hematoma.
Subretinal hemorrhage (SRH), complicated by choroidal neovascularization such as age-related macular degeneration, often reduces central vision in middle-aged patients. Although the visual results of SRH removal by surgery seem to have improved recently, the efficacy has not yet been confirmed in a prospective, controlled fashion. Therefore, it cannot be stated with certainty that surgery for SRH is more beneficial than the natural course of the disease. However, we believe surgery is beneficial in selected patients. Herein, we describe our technique for the surgical removal of SRH. The development of safer, more effective techniques should further improve patient outcomes.


Voltammetric investigation of beta-estradiol.
Electrooxidation of beta-estradiol was investigated using a glassy carbon electrode (GCE) by cyclic voltammetry (CV), and differential pulse voltammetry (DPV). The statistical analysis of the linear relationships between concentration and peak current permits the quantitation of beta-estradiol by both CV and DPV in the concentration range of 4 x 10(-5)-10(-3) M with enough precision and accuracy. A mechanism was proposed about the electrooxidation of this substance. The methods were applied to a tablet form and a transdermal therapeutic system (TTS) of this drug. The results were statistically compared with those of official high performance liquid chromatography (HPLC) method and the differences were found as insignificant.


Therapeutic expression of an anti-death receptor 5 single-chain fixed-variable region prevents tumor growth in mice.
The clinical use of the single-chain fixed-variable (scFv) fragments of recombinant monoclonal antibodies as credible alternatives for classic therapeutic antibodies has two limitations: rapid blood clearance and inefficient local expression of functional molecules. In attempt to address these issues, we have developed a novel gene therapy protocol in which the anti-death receptor 5 (DR5) scFv fragments were either in vitro expressed in several tumor cell lines, or in vivo expressed in mice, using recombinant adeno-associated virus (rAAV)-mediated gene transfer. Viral transduction using the rAAV-S3C construct, which encodes a scFv molecule (S3C scFv) specific to DR5, led to stable expression in tumor cell lines and showed apoptosis-inducing activity in vitro, which could be inhibited by recombinant DR5 but not by DR4. A single i.m. injection of rAAV-S3C virus in nude mice resulted in stable expression of DR5-binding S3C scFv proteins in mouse sera for at least 240 days. Moreover, the expression of S3C scFv was associated with significant suppression of tumor growth and the increase of tumor cell apoptosis in previously established s.c. human lung LTEP-sml and liver Hep3B tumor xenografts.


[Cementless fixation of the endoprosthesis using trabecular, 3-dimensional interconnected surface structures].
While the principle of enlarging the surface area has been recognized and used in different ways for some time, there is often no schematic, detailed description or fundamental research. Taking a surface structure consisting of trabecular three-dimensional connecting elements, essential parameters are shown, making it clear that the flexible dynamic reaction of the effective "anchoring space" with a suitable specified shape (construction height, alignment, network) can be reproducibly shaped and used. This has led to a hip endoprosthesis with a graduated surface structure. The construction height of the trabecular structure varies, decreasing from proximal to distal.


Mechanical resistance of peripheral nerve repair with biological glue and with conventional suture at different postoperative times.
Regardless of its type, the repair of a peripheral nerve must ideally permit early motion of the affected limb and resist disruption by the tensile forces generated throughout the healing process and regeneration. A comparative study of the mechanical resistance of the repair of the sciatic nerve with biological glue and conventional microsurgical suture over time was undertaken in 48 rats. Both right and left sciatic nerves were exposed simultaneously and repaired at random with the glue on one side and conventional suture on the opposite side. Mechanical resistance of the repair was evaluated in situ with a universal testing machine using a hooklike accessory applied proximally to the repair site, immediately and at 7, 14, and 28 days postoperatively. A load was applied at the rate of 2 mm/min till rupture. The resistance of both types of repair significantly increased up to day 14 ( P < 0.001), and the repair with the glue was significantly less resistant than repair with conventional suture immediately postoperatively ( P < 0.001) and on day 7 ( P = 0.03). Resistance became equivalent for the two types of repair on days 14 ( P = 0.67) and 28 ( P = 0.34). The change in resistance of both types of repair with time was in accordance with the power function numeric formula.


Correlative Fluorescence and Electron Microscopy in 3D-Scanning Electron Microscope Perspective.
The ability to correlate fluorescence microscopy (FM) and electron microscopy (EM) data obtained on biological (cell and tissue) specimens is essential to bridge the resolution gap between the data obtained by these different imaging techniques. In the past such correlations were limited to either EM navigation in two dimensions to the locations previously highlighted by fluorescence markers, or subsequent high-resolution acquisition of tomographic information using a TEM. We present a novel approach whereby a sample previously investigated by FM is embedded and subjected to sequential mechanical polishing and backscatter imaging by scanning electron microscope. The resulting three dimensional EM tomogram of the sample can be directly correlated to the FM data. © 2017 by John Wiley & Sons, Inc.


Anatomical study of arthroscopic surgery for lateral epicondylitis.
We conducted an anatomical study of arthroscopic surgery for lateral epicondylitis. Currently, the pathogenesis suggests that lateral epicondylitis is caused by extra-articular lesions or intra-articular lesions. We anatomically and histologically examined the relationship between extensor carpi radialis brevis (ECRB), articular capsules, and the lateral collateral ligament complex (LCLC). In addition, we examined the number and location of synovial fringes. This study will be useful for less-invasive treatment of lateral epicondylitis.


Temperature-induced water release and uptake in organic porous networks.
The behavior of water confined near nonpolar surfaces has important implications for a number of biological phenomena. In this type of confined environment the properties of "hydrophobicity" and "hydrophilicity" are closely related to the structure of the interfacial water, which in turn can depend on temperature in a very subtle way. Although the physical-chemical consequences of this fact have been theoretically addressed to a great extent, the underlying thermodynamic question is still widely discussed. Accordingly we performed thermogravimetric analysis and variable-temperature powder X-ray diffraction studies on representative hydrogen bonding organic pores occupied by water. The results indicate that a hydrophilic-to-hydrophobic transition of the inner surface of the pores occurs upon increasing temperature, which may be attributed to a strong influence of the dynamics and thermodynamics of local water molecules on the surface affinity of the pores. The relevance of our findings to the understanding of the phenomenon of water transport in natural pores is discussed.


Establishing reference interval for thyroid-stimulating hormone in children below two-year ages in Pakistani population.
Reference intervals (RIs) of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are age, assay and population specific. Currently, the age and assay-specific RIs for TSH are not available for children under two years of age. This study aimed to establish reference intervals for serum concentrations of TSH and FT4 in healthy children aged 1-24 months as per CLSI C28-A3 guidelines. This prospective cross-sectional study was conducted in children from 1 to 24 months visiting the clinical laboratory for serum vitamin D testing but without any recent illness, hospitalization, medication and history of maternal thyroid diseases from August 2018 to March 2019 were invited to participate in the study.Serum TSH and FT4 were measured on ADVIA Centaur (Siemens Diagnostics, US), using chemiluminescence immunoassay. Kolmogorov-Smirnov test assessed normality of the data and RIs based on central 95% of the population were established using the non-parametric approach. After excluding one subject with confirmed congenital hypothyroidism, a total of 131 children were included in the study. The median (IQR) age of the study subjects was 12 months (11), and majority 78 (59.5%) were boys. The RIs were established using non-parametric approach as the data was not normally distributed. Reference interval for TSH was 0.73-4.94 μIU/mL and for FT4 was 0.81-1.51 ng/dl. We established assay-specific RIs for serum TSH and FT4 in children aged 1-24 months in our population. The RIs were slightly lower from RIs developed on other platforms in different population.


Radiosensitization effect of hsa-miR-138-2-3p on human laryngeal cancer stem cells.
Treatments that target cancer stem cells play an important role in the controlling and eliminating of tumor initiation as well as in development, progression, and chemotherapy/radiotherapy resistance. In our previous study, we cultured and harvested human laryngeal cancer stem cells (CSCs) and applied microRNA biochips to screen differentially expressed miRNAs that were related to radiation tolerance in irradiated human laryngeal CSCs. According to the predicted genes and pathways of differential miRNAs target, down-regulated expression of hsa-miR-138-2-3p under radiation was thought to play a key role in enhancing the radio-sensitivity in human laryngeal squamous cancer stem cells. To investigate the radiational enhancement of hsa-miR-138-2-3p, we transfected hsa-miR-138-2-3p mimics that were synthesized based on the sequences of hsa-miR-138-2-3p in vitrointo human laryngeal CSCs (Hep-2, M2e, and TU212 cell lines) to make hsa-miR-138-2-3p overexpressed, and the tumorous specialities of CSCs, like cell proliferation, invasion, apoptosis, cell cycle arrest, and DNA damage were evaluated by CCK-8 assay, clone formation assay, invasion assay, flow cytometry, and comet assay. Furthermore, we explored the signal transduction pathways that regulated the cancer stem cell initiation, development, invasion, apoptosis and cell cycle arrest, which were controlled by hsa-miR-138-2-3p. Overexpressed hsa-miR-138-2-3p played a key role in many anti-cancer biological processes in human laryngeal CSCs: (1) it decreased laryngeal CSCs proliferation and invasion in response to radiotherapy; (2) it increased the proportion of early and late apoptosis in laryngeal CSCs after radiation, raised G1 phase arrest in laryngeal CSCs after radiation, and decreased the proportion of S stage cells of cell cycle that were related to radio-resistance in laryngeal CSCs; (3) it down-regulated the expression of β-catenin in Wnt signal pathway that was related to the tolerance of laryngeal CSCs to radiotherapy; (4) it down-regulated the expression of YAP1 in Hippo signal pathway that regulated cell proliferation, invasion and apoptosis; (5) it up-regulated the expression of p38 and JNK1 in MAPK signal pathway that was concerned to radio-sensitivity. In the present study, it was found that hsa-miR-138-2-3p regulated the Wnt/β-catenin pathways, the Hippo/YAP1 pathways, and the MAPK/p38/JNK1 pathways that were involved in cell proliferation, invasion, apoptosis, cell cycle arrest, radio-resistance and radio-sensitivity in laryngeal CSCs. These results will be useful for a better understanding of the cell biology of hsa-miR-138-2-3p in laryngeal CSCs, and for serving hsa-miR-138-2-3p as a promising biomarker and as a target for diagnosis and for novel anti-cancer therapies for laryngeal cancers.


Enantioselective catalysis with tropos ligands in chiral ionic liquids.
Enantioselective homogeneous rhodium-catalysed hydrogenation using tropoisomeric biphenylphosphine ligands was accomplished in readily available chiral ionic liquids and the catalytic system could be reused after extraction with scCO(2).


[Standardization in hematology and the use of the data in clinical laboratories].
Recently developed automated blood cell counters provide accurate and precise data on complete blood count (CBC). The results of nationwide surveys obtained using them are usually better than those obtained by biochemical tests. The precision of CBC counting has been improved owing to the efforts of laboratories and manufacturers. As for hemoglobinometry, the cyanmethemoglobin and oxyhemoglobin methods used in blood cell counters gave different results for fresh and artificial blood in control surveys. Now instead of the oxyhemoglobin method, the sodium lauryl sulfate-hemoglobin method is used to minimize the variation among different counters. The biggest problem at present is the lack of control blood which can be used for any blood cell counter. Another problem is the laboratory report sent to clinicians, which gives only numerical data. However, other comments and normal reference values should also be presented. Sufficient care may not be taken for normal reference values; they vary considerably among different laboratories. Also, most laboratories and manufacturers now use various conventional units for CBC, but the SI unit should be used for comparison of the data. In conclusion, nationwide unification of CBC values should be established in the near future with cooperative efforts by laboratories and manufacturers.


Diurnal variations in the catecholamine content in rat tissues. Effects of exogenous noradrenaline.
Endogenous noradrenaline (NA) content of the interscapular brown adipose tissue (IBAT), and of the hypothalamus, as well as adrenaline (A) and NA content of the adrenals were measured in the morning and in the evening in rats treated with saline (controls) or with NA (1.6 mg kg-1 pp). NA content in IBAT and in hypothalamus of control animals varies diurnally. NA content in IBAT was significantly higher in the evening than in the morning. In the hypothalamus, these variations were different of those found in the IBAT. Exogenous NA applied both in the morning and in the evening increases significantly NA content in IBAT both in the morning and in the evening, but more in the evening. Unlike IBAT, NA content of the hypothalamus after NA administration does not change essentially. In the adrenal gland of control rats, A content only is changed during the day, being markedly lower in the evening. After NA injection both A and NA are not changed significantly.


Complex segregation analysis of quantitative dermatoglyphic traits in five Indian populations.
Dermatoglyphics is widely used as a genetically determined trait in anthropogenetics although the genetic nature of its inheritance is still inconclusive, due to the lack of any established genetic model to resolve the existing inconsistencies in the literature. However, advanced statistical packages for complex segregation analyses are available and the aim of the present study is to determine the mode of dermatoglyphic trait inheritance in five different ethnic populations. Five hundred families (2435 individuals) of two generations were used for principal component analysis, familial correlation and segregation analysis (package MAN-5). The similarity of three factors suggests a common internal structure. Significant familial correlation (except spouse) indicates the involvement of a familial component in the variation of dermatoglyphic traits. Segregation analyses suggest the transmission of a genetic effect in the families which follows the Mendelian model and confirms a major gene effect on factor 1 and factor 2 with two co-dominant alleles. There is no evidence of a major gene effect or environmental effect on factor 3 (a-b ridge counts). The nature of transmission and trait variance (H2) strongly supports the existence of a common nature of dermatoglyphic trait inheritance in populations, irrespective of ethnic and geographic area. Major gene involvement in finger dermatoglyphics according to Mendelian models is confirmed.


Special tips for working with new patients.
The new patient's experience of your practice from th very first time he or she calls your office can influence the kind of relationship you will have as well as the patient's satisfaction and loyalty. This article suggests specific techniques hat turn new patients into loyal, established ones. It provides how-to-guidance about scheduling appointments for new patients, pronouncing and spelling new patients' names properly, screening new patients' phone calls for vital information, establishing the authority of the doctor, telling new patients what to expect, ending the first contact with new patients enthusiastically, and rolling out the red carpet at the first appointment. This article also offers strategies for following up with new patients and provides sample text for letters to send to new patients and for developing a new-patient get-acquainted checklist. Finally, this article includes strategies for turning new patients into strong referral sources.


64Cu-labeled minibody D2101 visualizes CDH17-positive gastric cancer xenografts with short waiting time.
We previously reported In-labeled anti-cadherin17 (CDH17) IgG visualized CDH17-positive gastric cancer xenografts. Unfortunately, a long waiting time was required to obtain high-contrast images due to long blood retention (blood half-life: 26 h). To accelerate blood clearance, we have developed anti-CDH17 minibody (D2101 minibody) and evaluated the pharmacokinetics in gastric cancer mouse models. Two different single chain Fvs (scFvs), D2101 mutant and D2111, were developed from each parental IgG. The binding ability to CDH17 and stability in plasma were evaluated. D2101 minibody, constructed based on D2101 mutant scFv, was labeled with Cu (Cu-D2101 minibody), and the in-vitro and in-vivo properties were evaluated by cell ELISA, biodistribution experiments, and PET imaging in mice bearing CDH17-positive AGS and CDH17-negative MKN74 tumors. D2101 mutant and D2111 scFvs showed similar affinities to CDH17. D2101 mutant scFv was more stable than D2111 scFv in plasma. No loss of binding affinity of the D2101 minibody by chelate conjugation and radiolabeling procedures was observed. The biodistribution of Cu-D2101 minibody showed high uptake in AGS tumors and low uptake in MKN74. The blood half-life of Cu-D2101 minibody was 6.5 h. Improved blood clearance of Cu-D2101 minibody provided high tumor-to-blood ratios compared with the previous results of parental IgG in AGS xenograft mice. PET studies showed consistent results with biodistribution studies. Cu-D2101 minibody exhibited higher tumor-to-blood ratios at earlier time points than those of the radiolabeled parental IgG. Cu-D2101 minibody has potential as an immunoimaging agent for CDH17-positive tumors.


An observational study of providing structure as a psychiatric nursing intervention.
To observe the actions of psychiatric nurses when providing structure and identify results in order to better understand providing structure as a complex nursing intervention. Participant observation data were collected on a dual diagnosis ward and a crisis intervention ward in a mental healthcare organization. A total of 52 events were selected that involved providing structure. Three phases in the processing of providing structure were identified: the start of the interaction, the interaction phase, and the end of the interaction. For each phase in the intervention, both critical nurse and patient responses were coded. The results of this observational study contribute to a formalization of the nursing intervention "providing structure" in the Nursing Interventions Classification.


Antiretroviral treatment in HIV-infected children who require a rifamycin-containing regimen for tuberculosis.
In high prevalence settings, tuberculosis and HIV dual infection and co-treatment is frequent. Rifamycins, especially rifampicin, in combination with isoniazid, ethambutol and pyrazinamide are key components of short-course antituberculosis therapy. Areas covered: We reviewed available data, for which articles were identified by a Pubmed search, on rifamycin-antiretroviral interactions in HIV-infected children. Rifamycins have potent inducing effects on phase I and II drug metabolising enzymes and transporters. Antiretroviral medications are often metabolised by the enzymes induced by rifamycins or may suppress specific enzyme activity leading to drug-drug interactions with rifamycins. These may cause significant alterations in their phamacokinetic and pharmacodynamic properties, and sometimes that of the rifamycin. Recommended strategies to adapt to these interactions include avoidance and dose adjustment. Expert opinion: Despite the importance and frequency of tuberculosis as an opportunistic disease in HIV-infected children, current data on the management of co-treated children is based on few studies. We need new strategies to rapidly assess the use of rifamycins, new anti-tuberculosis drugs and antiretroviral drugs together as information on safety and dosing of individual drugs becomes available.


Comprehensive imaging in patients with suspected pulmonary arterial hypertension.
Currently, several imaging techniques are being used for a comprehensive evaluation of patients with suspected pulmonary hypertension (PH), in order to provide information that may clarify the presence and identify the aetiology of this complex pathology. The current paper is focused on recent updates regarding the importance of comprehensive imaging techniques for patients with suspected PH. Transthoracic echocardiography that can mainly detect right ventricle pressure overload and dysfunction is the cornerstone of imaging evaluation, while right heart catheterisation remains the gold standard assessment method. Chest radiography that may exclude pleuroparenchymal lung diseases, CT, the primary imaging modality for the assessment of lung parenchyma and CT pulmonary angiography, that allows for the non-invasive assessment of the pulmonary arteries, are equally important. Imaging techniques like dual-energy CT, single photon emission CT and ventilation perfusion scan may provide accurate diagnostic information for patients with chronic thromboembolic PH. Cardiac MRI provides the most accurate three-dimensional characterisation of the right ventricle. Accurate use of diagnostic imaging algorithms allows early detection of the disease, with the constant goal of improved PH patients prognosis.


Hemoprotein-Catalyzed Cyclopropanation En Route to the Chiral Cyclopropanol Fragment of Grazoprevir.
Reactions that were once the exclusive province of synthetic catalysts can increasingly be addressed using biocatalysis. Through discovery of unnatural enzyme reactions, biochemists have significantly expanded the reach of enzymatic catalysis to include carbene transfer chemistries including olefin cyclopropanation. Here we describe hemoprotein cyclopropanation catalysts derived from thermophilic bacterial globins that react with diazoacetone and an unactivated olefin substrate to furnish a cyclopropyl ketone, a previously unreported reaction for enzyme catalysts. We further demonstrate that the resulting cyclopropyl ketone can be converted to a key cyclopropanol intermediate that occurs en route to the anti-hepatitis C drug grazoprevir.


Breastfeeding, overweight status, and inflammation.
Research documents a host of health benefits of breastfeeding for infants and children, including long-term health conditions arising from inflammation. Here, we provide new evidence about this association, focusing on the link between breastfeeding in infancy and inflammation in early adulthood. Our study is based on the National Longitudinal Study of Adolescent to Adult Health (Add Health) which allows us investigate a potentially important mediating pathway - overweight status from early adolescence into young adulthood. Results from pathway analyses in a structural equation modeling framework indicate that, in addition to a direct pathway linking breastfeeding and inflammation, an indirect pathway through overweight status across adolescence into young adulthood partially explains the association between breastfeeding and inflammation. Overweight status, moreover, links breastfeeding to inflammation not only through proximal timing of overweight status, but also through an indirect cascading process of overweight status over the life course that is evident in adolescence. Overall, this study highlights the importance of considering breastfeeding, overweight status and inflammation as dynamic life course processes that contribute to development of health inequalities.


Nicotine Pharmacokinetics in Rat Brain and Blood by Simultaneous Microdialysis, Stable-Isotope Labeling, and UHPLC-HRMS: Determination of Nicotine Metabolites.
The disposition and metabolism of nicotine in the brain is an important determinant of its exposure. We have developed a novel method for the dynamic determination of nicotine and its metabolites in rat brain and blood by simultaneous microdialysis sampling, stable-isotope labeling, and ultra high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) assaying. Microdialysis probes were inserted into both the right striatum and jugular vein of Sprague-Dawley rats. The collections of dialystes after nicotine intraperitoneal injection were analyzed by the optimized UHPLC-HRMS. Nicotine-pyridyl- d4 was used as a metabolic tracer, and several stably labeled isotopes were applied to calibrate the in vivo recoveries of retrodialysis. The quadrupole-Orbitrap HRMS provided reliable characterization of the nicotine derivatives with less than 3.5 ppm mass measurement accuracy. Good precision and accuracy were obtained for different analytes within the predefined limits of acceptability and the range of the standard curve. Nicotine and its 11 metabolites were identified in most microdialysis samples from the blood and brain tissue samples. Besides cotinine as the main metabolic product of nicotine, trans-3'-hydroxy-cotinine, nicotine- N-oxide, and norcotinine were proven to be the second most abundant metabolites. The other seven nicotine products, including 4-oxo-4-(3-pyridyl)-butanoic acid, 4-hydroxy-4-(3-pyridyl)-butanoic acid, cotinine- N-oxide, nicotine- N-glucuronide, cotinine- N-glucuronide, and trans-3'- hydroxy-cotinine- O-glucuronide, which have not been determined previously in animal brain, were present in minor amounts. The pharmacokinetic profile of nicotine metabolites indicated that the metabolic characteristic of nicotine in the brain was relatively different from that in the blood. The present work would provide comprehensive evidence for clarifying the differences between nicotine metabolism in the brain and peripheral system.


Relationship between in vitro growth of bovine oocytes and steroidogenesis of granulosa cells cultured in medium supplemented with bone morphogenetic protein-4 and follicle stimulating hormone.
Bone morphogenetic protein-4 (BMP-4) and FSH play important regulatory roles in follicular growth and steroidogenesis in vivo. The purpose of this study was to investigate the effects of BMP-4 and FSH on in vitro growth (IVG) and steroidogenesis of bovine oocyte-cumulus-granulosa complexes (OCGCs). We cultured OCGCs collected from early antral follicles (0.5-1 mm) in medium without BMP-4 and FSH for 4 days and investigated the appearance of OCGCs and their steroidogenesis. During the first 4 days of IVG, morphologically normal OCGCs produced more estradiol-17β (E2), but less progesterone (P4). Morphologically normal OCGCs were subjected to an additional culture in medium supplemented with BMP-4 (0, 10, and 50 ng/mL) and FSH (0 and 0.5 ng/mL) until day 12. We examined the viability and steroidogenesis of OCGCs after 8 and 12 days of culture. Oocyte growth, characteristics of granulosa cells, and the maturational competence of oocytes were also investigated. On day 8, the viability of OCGCs cultured without FSH was higher in the 10 ng/mL BMP-4 group than in the 50 ng/mL BMP-4 group (P < 0.05). No significant difference was observed in the viability of groups cultured with FSH, regardless of the addition of BMP-4, and FSH improved the viability of 50 ng/mL BMP-4 group similar to 10 ng/mL BMP-4 group. The total number of granulosa cells was larger in 10 ng/mL BMP-4 group cultured with FSH than in 50 ng/mL BMP-4 group cultured with FSH on day 8 (P < 0.05). E2 production decreased from days 8-12, and P4 production increased throughout IVG culture, regardless of the addition of BMP-4 and FSH (P < 0.05). No significant differences in E2 production were observed between groups from days 4-8, regardless of whether BMP-4 was added without FSH; however, E2 production in the group cultured with 50 ng/mL BMP-4 was suppressed by FSH. BMP-4 suppressed E2 production from days 8-12, regardless of whether FSH was added. The group cultured with 10 ng/mL BMP-4 without FSH showed the lowest P4 production among all groups for all culture periods. OCGCs that produced mature oocytes tended to secrete more E2 and less P4 than OCGCs that produced immature oocytes. In conclusion, until day 8 of the IVG culture, P4 production by OCGCs was suppressed by the addition of 10 ng/mL BMP-4 in the absence of FSH, without inhibiting E2 production. These conditions appear to mimic growing follicles until day 8 and mimic degenerating follicles from days 8-12 of culture.


Genetic regulation of the antibody response to H-2Db alloantigens in mice. IV. Antigens that activate helper T cells for IgG, coded for by the non-H-2 genome.
When B10.A(5R) mice are immunized with congenic C57BL/10 cells only 2-ME-sensitive antibodies (IgM type) are found directed against H-2Db. To obtain 2-ME-resistant antibodies (IgG type) 5R mice must be immunized with noncongenic cells (e.g., A.BY); in this case non-H-2 cell surface antigens will activate helper T cells to induce anti-Db IgG antibody production by B cells. An attempt was made to define helper antigens that activate helper T cells. Neither N-2 antigens of seven H-2Db recombinant strains nor a limited set of non-H-2 cell surface antigens were able to serve as helper antigens. By using individual backcross mice as antigen, one helper antigen was found on the background of strain A under the conditions used, whereas other backgrounds may carry more than one antigen. The helper antigen is dominantly expressed in F1 mice and has to be presented on the same cell as H-2Db to induce the switch from IgM to IgG.


Intravitreal bevacizumab with or without mitomycin C trabeculectomy in the treatment of neovascular glaucoma.
To demonstrate the role of intravitreal bevacizumab in regression of iris neovascularization, and intraocular pressure (IOP) control in neovascular glaucoma. A retrospective random case series study was performed. Twenty eyes of 20 patients who presented with neovascular glaucoma were treated with intravitreal bevacizumab 2.5 mg in 0.1 mL. Retinal photocoagulation was performed for all cases as soon as possible after intravitreal injection and subscleral trabeculectomy with mitomycin C 0.4 mg/mL for 3 minutes for cases having peripheral anterior synechiae. Cases were followed up for 12 months when regression of iris neovessels, IOP control, improvement in visual acuity, and success of filtering surgery were recorded. All cases showed complete regression of iris neovessels at 2 months after injection; recurrence of iris neovessels was observed in 4 cases (20%) at 4 months and in 14 cases (70%) at 8 months follow-up. The mean IOP dropped from 41.45 ± 5.89 mmHg preoperatively, to 19.3 ± 5.5 mmHg and 17.75 ± 3.74 mmHg at 6 months and 12 months postoperatively, respectively. The success rate of subscleral trabeculectomy with mitomycin C after intravitreal bevacizumab was 77.8%. Visual acuity was improved in 17 cases (85%) from preoperative 0.12 ± 0.11 to 0.26 ± 0.2 postoperative. Intravitreal bevacizumab has a role in regression of iris neovessels and IOP control in neovascular glaucoma cases and also in increasing the success rate of subscleral trabeculectomy with mitomycin C; however this role has a limited time and reinjection is needed to maintain this effect.


Toward a Taxonomy for Multi-Omics Science? Terminology Development for Whole Genome Study Approaches by Omics Technology and Hierarchy.
Omics is a form of high-throughput systems science. However, taxonomies for omics studies are limited, inviting us to rethink new ways in which we classify, prioritize, and rank various omics systems science studies. In this overarching context, the genome-wide study approaches have proliferated in number and popularity over the past decade. However, their hierarchy is not well organized and the development of attendant terminology is not controlled. In the present study, we searched the literature in PubMed and the Web of Science databases published from March 1999 to September 2016 using the keywords, including genome-wide, association, whole genome, transcriptome-wide, metabolome, epigenome, and phenome. We identified the whole genome study approaches and sorted them according to the omics technology types (genomics, proteomics, and so on) and hierarchy. Thirty-four studies from over 90 publications were sorted into 10 omics groups: DNA level, transcriptomics, proteomics, interactomics, metabolomics, epigenomics, miRNomics/ncRNomics, phenomics, environmental omics, and pharmacogenomics. We suggest here modifications of terminology for study approaches, which share the same acronyms such as EWAS for epigenome-wide association and environment-wide association studies, and MWAS for methylome-wide association and metabolome-wide association studies. Taken together, our study presented here provides the first systematic review and analyses of whole genome approaches and presents a baseline for further controlled terminology development, with a view to a new taxonomy for omics and multi-omics studies in the future. Finally, we call for greater dialogue and collaboration across diverse omics knowledge domains and applications, for example, across plants, animals, clinical medicine, and ecology.


FMRI evidence for activation of multiple cortical regions in the primary auditory cortex of deaf subjects users of multichannel cochlear implants.
To investigate the activation of the auditory cortex by fMRI, three deaf subjects users of the Ineraid cochlear implant participated in our study. Possible interference between fMRI acquisition and the implanted electrodes was controlled and safe experimental conditions were obtained. For each subject, electrical stimuli were applied on different intracochlear electrodes, in monopolar mode. Stimulation of each electrode was actually producing auditory sensations of different pitches, as demonstrated by psychophysical pitch-ranking measurements in the same subjects. Because deaf subjects did not hear scanner noise, the data were collected in 'silent background' conditions, i.e. as a result of pure auditory sensations. Functional maps showed activation of the primary auditory cortex, predominantly in the left hemisphere. Stimulation of each different intracochlear electrode revealed different clusters of activation. After cluster grouping, at least three regions have been identified in the auditory cortex of each subject, and comparisons with previous architectonic and functional studies are proposed. However, a tonotopic organization could not be clearly identified within each region. These arguments, obtained without interference with unwanted scanner noise, plead in favor of a functional subdivision of the primary auditory cortex into multiple cortical regions in cochlear implant users.


Epidemiological survey of the "natural" mortality in psychiatry.
The authors reviewed articles published from 1838 dealing with excess of "natural" mortality in psychiatric "in-" and "out" patients. The high natural mortality rate has always existed and is still observed today despite the quality of somatic care. The excess is observed in every country, ethnic group, sex, age or site of treatment but does not seem to be associated with specific organic pathology. The risk of "natural" mortality (suicide and accidents excluded) remains 2 to 5 times greater than in normals. Hypotheses concerning the phenomenon are reviewed or suggested.


Using Mobile Apps to Assess and Treat Depression in Hispanic and Latino Populations: Fully Remote Randomized Clinical Trial.
Most people with mental health disorders fail to receive timely access to adequate care. US Hispanic/Latino individuals are particularly underrepresented in mental health care and are historically a very difficult population to recruit into clinical trials; however, they have increasing access to mobile technology, with over 75% owning a smartphone. This technology has the potential to overcome known barriers to accessing and utilizing traditional assessment and treatment approaches. This study aimed to compare recruitment and engagement in a fully remote trial of individuals with depression who either self-identify as Hispanic/Latino or not. A secondary aim was to assess treatment outcomes in these individuals using three different self-guided mobile apps: iPST (based on evidence-based therapeutic principles from problem-solving therapy, PST), Project Evolution (EVO; a cognitive training app based on cognitive neuroscience principles), and health tips (a health information app that served as an information control). We recruited Spanish and English speaking participants through social media platforms, internet-based advertisements, and traditional fliers in select locations in each state across the United States. Assessment and self-guided treatment was conducted on each participant's smartphone or tablet. We enrolled 389 Hispanic/Latino and 637 non-Hispanic/Latino adults with mild to moderate depression as determined by Patient Health Questionnaire-9 (PHQ-9) score≥5 or related functional impairment. Participants were first asked about their preferences among the three apps and then randomized to their top two choices. Outcomes were depressive symptom severity (measured using PHQ-9) and functional impairment (assessed with Sheehan Disability Scale), collected over 3 months. Engagement in the study was assessed based on the number of times participants completed active surveys. We screened 4502 participants and enrolled 1040 participants from throughout the United States over 6 months, yielding a sample of 348 active users. Long-term engagement surfaced as a key issue among Hispanic/Latino participants, who dropped from the study 2 weeks earlier than their non-Hispanic/Latino counterparts (P<.02). No significant differences were observed for treatment outcomes between those identifying as Hispanic/Latino or not. Although depressive symptoms improved (beta=-2.66, P=.006) over the treatment course, outcomes did not vary by treatment app. Fully remote mobile-based studies can attract a diverse participant pool including people from traditionally underserved communities in mental health care and research (here, Hispanic/Latino individuals). However, keeping participants engaged in this type of "low-touch" research study remains challenging. Hispanic/Latino populations may be less willing to use mobile apps for assessing and managing depression. Future research endeavors should use a user-centered design to determine the role of mobile apps in the assessment and treatment of depression for this population, app features they would be interested in using, and strategies for long-term engagement. Clinicaltrials.gov NCT01808976; https://clinicaltrials.gov/ct2/show/NCT01808976 (Archived by WebCite at http://www.webcitation.org/70xI3ILkz).


Antidepressant fluoxetine suppresses neuronal growth from both vertebrate and invertebrate neurons and perturbs synapse formation between Lymnaea neurons.
Current treatment regimes for a variety of mental disorders involve various selective serotonin reuptake inhibitors such as Fluoxetine (Prozac). Although these drugs may 'manage' the patient better, there has not been a significant change in the treatment paradigm over the years and neither have the outcomes improved. There is also considerable debate as to the effectiveness of various selective serotonin reuptake inhibitors and their potential side-effects on neuronal architecture and function. In this study, using mammalian cortical neurons, a dorsal root ganglia cell line (F11 cells) and identified Lymnaea stagnalis neurons, we provide the first direct and unequivocal evidence that clinically relevant concentrations of Fluoxetine induce growth cone collapse and neurite retraction of both serotonergic and non-serotonergic neurons alike in a dose-dependent manner. Using intracellular recordings and calcium imaging techniques, we further demonstrate that the mechanism underlying Fluoxetine-induced effects on neurite retraction from Lymnaea neurons may involve lowering of intracellular calcium and a subsequent retardation of growth cone cytoskeleton. Using soma-soma synapses between identified presynaptic and postsynaptic Lymnaea neurons, we provide further direct evidence that clinically used concentrations of Fluoxetine also block synaptic transmission and synapse formation between cholinergic neurons. Our study raises alarms over potentially devastating side-effects of this antidepressant drug on neurite outgrowth and synapse formation in a developing/regenerating brain. Our data also demonstrate that drugs such as Fluoxetine may not just affect communication between serotonergic neurons but that the detrimental effects are widespread and involve neurons of various phenotypes from both vertebrate and invertebrate species.


Family planning to promote physical activity: a randomized controlled trial protocol.
Physical activity is associated with the reduction of several chronic conditions in adults. Additionally, physical activity is extremely important for children for their development and cognitive functioning and also to create a physically active lifestyle that continues into adulthood. Despite the known benefits of physical activity, only one in five adults are achieving the public health recommendations of 150 minutes of moderate-to-vigorous physical activity per week and only 13 % of boys and 6 % of girls between the ages of 5 and 17 years are meeting the guidelines of 60 minutes per day. This study aims to evaluate whether a planning condition improves adherence to regular physical activity compared to an education-only control condition among families. Families are eligible if there is at least one child between the ages of 6 and 12 years who is not meeting the Canadian Physical Activity Guidelines. A six-month longitudinal randomized controlled trial will be used to compare the two conditions. Materials will be delivered at baseline with 'booster' sessions at six weeks and three months. Participants will be assessed at baseline and at six months with a fitness test, as well as questionnaires and accelerometery at baseline, six weeks, three months and six months. A total of 137 families have been recruited thus far from Greater Victoria. This study is ongoing and recruitment will continue until December 2015 with the target goal of reaching 160 families. This protocol describes the implementation of a randomized controlled trial that utilizes planning strategies to try and increase physical activity among families. Research findings could be useful in public health in providing effective strategies to families to help decrease sedentary lifestyles. Additionally, findings may help to inform future interventions aimed at increasing physical activity among families. This trial was registered on June 5, 2012 with the Clinical Trials Registry maintained by the National Library of Medicine at the National Institutes of Health. The registration ID is NCT01882192.


Autocatalytic dioxygen activation to produce an iron(v)-oxo complex without any reductants.
An iron(v)-oxo complex with a tetraamido macrocyclic ligand, [(TAML)FeV(O)]-, was produced by reacting [(TAML)FeIII]- with dioxygen without any electron source in acetone at 298 K. The autocatalytic mechanism of dioxygen activation for the formation of an iron(v)-oxo complex has been clarified based on the autocatalysis by radical chain initiators.


Ultra-long-range dynamic correlations in a microscopic model for aging gels.
We use large-scale computer simulations to explore the nonequilibrium aging dynamics in a microscopic model for colloidal gels. We find that gelation resulting from a kinetically arrested phase separation is accompanied by "anomalous" particle dynamics revealed by superdiffusive particle motion and compressed exponential relaxation of time correlation functions. Spatiotemporal analysis of the dynamics reveals intermittent heterogeneities producing spatial correlations over extremely large length scales. Our study is a microscopically resolved model reproducing all features of the spontaneous aging dynamics observed experimentally in soft materials.


Autoimmune hemolytic anemia as a complication of primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is characterized by a continuous T-lymphocyte mediated attack on small intralobular bile ducts, with their gradual destruction. Patients with PBC often exhibit concomitant autoimmune conditions, and autoimmune hemolytic anemia (AIHA), that is idiopathic in 50% of cases, has rarely been associated to PBC. Ursodeoxycholic acid (UDCA) has been considered the main treatment to PBC patients through a decrease in the detergent effect of endogenous bile acids, concomitantly reducing the hemolytic process. We report the case of a female patient with AIHA complicating PBC, treated with short course prednisone and UDCA, with good response.


Effects of source of gossypol and supplemental iron on plasma gossypol in Holstein steers.
Four experiments were conducted to evaluate factors influencing concentrations of plasma total gossypol (TG) in 30 Holstein steers fed cottonseed products. At the end of each 28-d experiment, steers were weighed and blood samples were collected and analyzed for plasma TG concentrations. During the entire study, steers did not show any overt signs of gossypol toxicity. In the 28 d before experiment 1, 30 steers with a body weight (BW) of 273 kg were fed a standardization diet with 15.0% Upland whole cottonseed (WCS) that resulted in a mean intake of 9.08 g/d of TG per steer/d and a plasma TG of 1.66 microg/mL. In experiment 1, 30 steers were fed 1 of 5 diets with 15.0% Upland WCS, but different levels of supplemental Fe [0, 150, 300, 450, and 600 mg/kg of diet dry matter (DM)]. Average daily gain was not affected by level of Fe in the diet, but DM intake, plasma TG, and plasma TG response decreased linearly as Fe in diets increased. In experiment 2, steers were fed diets with 15.0% Upland cottonseed as whole, cracked, roasted, cracked-roasted, or extruded. Analysis of the seed revealed that roasting or extrusion markedly reduced free gossypol (FG) content. Minor effects on animal performance were observed, but plasma TG decreased with roasting or extrusion of seeds, with the greatest reduction when the seed was cracked and then roasted. In experiment 3, steers were fed 2 levels of WCS (7.0 or 14.0% of DM) with 3 levels of cottonseed meal (2.8, 5.5, or 8.5% of DM) in the diet. Animal performance was not altered by diet, but plasma gossypol concentrations and responses were greater in steers fed diets with more WCS, because of the greater FG intake. In experiment 4, 24 steers were fed diets with 15.0% cottonseed (Upland or Pima) either as whole or cracked. Pima cottonseed increased TG and FG intakes, which resulted in greater plasma TG concentration and response. Animal response to processing of cottonseed tended to differ according to type of cottonseed. However, feeding Pima and cracking of cottonseed increased gossypol availability and plasma TG concentrations.


Epigenetic regulation in vascular cells.
This review summarizes recent findings in the epigenetics of vascular cells and discusses the new challenges for therapeutic strategies of cardiovascular diseases. There is emerging optimism that epigenetic mechanisms can provide the missing link to connect (epi)genomes with the cause of complex diseases. Environmental factors like intrauterine conditions during fetal development appear to preprogram humans for complex diseases. The purpose of this review is to summarize the newest results about the inheritable epigenetic features of cardiovascular diseases. Also, the recently discovered role of small RNAs in epigenetic gene regulation is discussed. Epigenetic mechanisms of gene regulation will likely become major determinants in the pathogenesis of complex diseases and may offer new opportunities for the treatment of these diseases.


Disruptive innovation: a new diagnosis for health care's "financial flu".
Financial difficulties are threatening many healthcare organizations. To survive and target new markets of growth, strategic decision makers need to adapt existing business frameworks using the principle of disruptive innovation, which involves framing financial problems in a manner that incorporates changes in the marketplace and redefines solutions. Rather than emphasizing technological advances to capture shrinking, highly competitive markets, healthcare providers should consider the possibility of reaching largely untapped sources of revenue through a service line that is more convenient and less costly to consumers with less intensive needs.


A brief overview and introduction to artificial neural networks.
This article is designed to acquaint professionals working in the field of substance use intervention with a range of artificial intelligence nonlinear, powerful tools, artificial neural networks, concepts, and paradigms. The family of ANNs, when appropriately selected and used, permits the maximization of what can be derived from available data as well as our studying and understanding the many people, processes, and phenomena which comprise substance use and its intervention. The latter represent complex, dynamic, multidimensional phenomena which are unpredictable and uncontrollable in the traditional "cause and effect" sense. As such they are likely to be nonlinear in their very essence. Using linear-based paradigms for planned intervention with nonlinear phenomena brooks the all-too-common possibility of using inappropriate intervention paradigms and/or drawing misleading conclusions about what is and/or has happened.


Presence of an intrapineal circadian oscillator in the teleostean family Poeciliidae.
In most fish, rhythmic melatonin production is controlled by circadian oscillators located within the pineal (=pineal clocks) that are reset daily by the ambient light:dark (LD) cycle. However, one question that has yet to be addressed concerns the phylogenetic distribution of the pineal clock within fish families. We tested whether a pineal clock identified in the sailfin molly (Poecilia velifera) in an earlier study is also present in some other representatives of the teleostean family Poeciliidae. Isolated pineals from adults belonging to the genus Poecilia (P. velifera albino, P. reticulata, and P. sphenops), genus Xiphophorus (X. helleri and X. maculatus), and genus Limia (L. vittata) were obtained and cultured under LD and/or continuous darkness (DD) at constant temperature (27 degrees C). With one exception, free-running rhythms in melatonin release with circadian periodicities ranging from 19.5 to 27.4 h (n = 26) were detected in isolated pineals from all poeciliid representatives tested under DD exposure. In addition, rhythmic melatonin production was also observed in isolated pineals of some representatives tested from all three genera under LD exposure, suggesting the property of direct photosensitivity. Taken together, these data suggest that a circadian oscillator residing in the pineal of the sailfin molly also appears to be present in all of the poeciliid representatives tested in our system, supporting the notion that the presence of a pineal clock occurs at the family level of taxonomic organization.


Amplitude control of protein kinase C by RINCK, a novel E3 ubiquitin ligase.
Protein kinase C (PKC) isozymes play a central role in cellular signaling. Levels of PKC control the amplitude of agonist-induced signaling and alterations in these levels are associated with disease states, most notably cancer, yet mechanisms that control the turnover of the protein are poorly understood. Here we identify an E3 ligase that catalyzes the ubiquitin-mediated degradation of PKC. Specifically, we identified a RING finger domain-containing protein, RINCK (for RING-finger protein that interacts with C kinase) from a yeast two-hybrid screen using the amino terminus of PKCbeta as bait. RINCK encodes a protein of 581 amino acids that contains a RING finger domain, a B-box, and two coiled-coil regions, the three domains that form the signature motif of the large family of diverse TRIM (tripartite motif) proteins. Co-immunoprecipitation studies using tsA201 cells reveal that RINCK and PKC associate with each other in cells. Studies using fragments of PKCbeta reveal that this interaction is mediated by the C1A domain of PKC. RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. This increase was observed for all PKC isozymes examined (including conventional, novel, and atypical). The RINCK-mediated degradation of PKC occurs independently of the classic phorbol ester-mediated down-regulation: genetic depletion of RINCK had no effect on the phorbol ester-mediated down-regulation and, additionally, up-regulated the levels of isozymes that cannot bind phorbol esters. Our data reveal a novel mechanism that provides amplitude control in PKC signaling through ubiquitination catalyzed by RINCK, an E3 ligase that specifically recognizes the C1 domain of PKC isoforms.


Relationships between characteristics of the ward atmosphere and treatment outcome in a psychiatric day-care unit based on occupational therapy.
The relationships between characteristics of the ward atmosphere and treatment outcome in a psychiatric day-care unit were investigated. The treatment programme was based on occupational group therapy and included long-term mentally ill patients, equally distributed with regard to psychosis and non-psychosis diagnoses. The ward atmosphere was rated on the Community-Oriented Programs Environment Scale (COPES), and outcome variables concerned symptoms, global mental health, quality of life, and functioning in daily life. The COPES ratings were re-coded in order to control for the fact that different levels of ward atmosphere factors are recommended for psychotic and non-psychotic patients. The results revealed that an optimal initial level of anger and aggression in treatment was significantly associated with improvement in global mental health and functioning in everyday life. Initial optimal levels of staff control and practical orientation were significantly associated with improvement in psychiatric symptoms. The characteristics of the ward atmosphere at the end of the treatment period were significantly correlated with various aspects of functioning in daily life. The study demonstrated associations with outcome variables not previously linked with ward atmosphere characteristics, e.g. functioning in daily life and quality of life.


Impact of stressors in the aviation environment on xenobiotic dosimetry in humans: physiologically based prediction of the effect of barometric pressure or altitude.
Standard health risks from volatile organic compounds (VOCs) are generally interpreted at ambient environmental conditions. The aim of this study was to develop a strategy for using physiologically based pharmacokinetic (PBPK) modeling to compare known risks in the general population to calculated risks in pilots experiencing pressure-based stressors. PBPK models facilitate these comparisons by prediction of how target-tissue specific doses are altered when a stressor, such as high altitude, produces changes in physiological parameters. Cardiac output, regional blood flow, and alveolar ventilation rate following acute exposure to altitude ranging from moderate to extremely high were estimated from published data from 52 groups of human subjects. Scenarios where pilots might inhale toluene, 1,2,4-trimethylbenzene (1,2,4-TMB), or cyclohexane during routine military flight training were simulated. At the recommended Threshold Limit Values (TLV), arterial blood concentrations were predicted to be higher for exposure at 15000 ft (4572 m) than at sea level. The differences were greater for toluene and TMB, which have higher blood: air and fat: blood partition coefficients than less lipophilic cyclohexane. In summary, quantitative approaches to internal dosimetry prediction that take advantage of existing knowledge of physiological changes induced by occupational stressors possess potential as tools in performing a human health risk assessment.


Elucidating the correlation between treatment with tyrosine kinase inhibitors and mean platelet volume in patients with metastatic renal cell cancer.
Patients with cancer are at increased risk of thrombosis. Additionally, an increased mean platelet volume (MPV) has been demonstrated to be associated with thromboembolism. Tyrosine kinase inhibitors (TKIs) may modulate the activation of systemic coagulation in cancer patients, rendering them more susceptible to thromboembolism. The aim of the current study was to investigate the association between antiangiogenic TKIs and MPV. A total of 45 patients with metastatic renal cell carcinoma (RCC), who were treated with TKIs and were patients at the Akdeniz University Hospital and Afyon Kocatepe University Ahmet Necdet Sezer Research and Practice Hospital, were retrospectively reviewed. The results prior to treatment and after three months for the MPV values and platelet levels were evaluated. The MPV values increased following the treatment with TKIs; however, no statistically significant difference was observed between the baseline and three month values (P=0.286). Conversely, a significant decrease was observed in the platelet levels following treatment (P=0.005). Treatment with TKIs in patients with metastatic RCC caused a modest increase in MPV, which is an indicator of thrombocytic reactivity; however, further studies are required to validate these results.


Proteome alterations during clonal isolation of established human pancreatic cancer cell lines.
Clonal isolation is an integral step of numerous workflows in genome editing and cell engineering. It comprises the isolation of a single progenitor cell from a defined cell line population with subsequent expansion to obtain a monoclonal cell population. This process is associated with transient loss of cell-cell contacts and absence of a multicellular microenvironment. Previous studies have revealed transcriptomic changes upon clonal isolation with cell line specific extent. Since transcriptome alterations are only partially reflected on the proteome level, we sought to investigate the impact of clonal isolation on the cellular proteome to a depth of > 6000 proteins in three established pancreatic cancer cell lines. We show that clonal isolation does have an impact on the cellular proteome, however, with cell line specific extent, affecting different biological processes, and also depending on the isolation method. We demonstrate a different impact of clonal isolation on mesenchymal- and epithelial-derived cell lines mainly affecting cell proliferation, metabolism, cell adhesion and cellular stress. The results bear relevance to the field of genomic editing and cell engineering and highlight the need to consider the impact of clonal isolation when interpreting data stemming from experiments that include this step.


Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors.
Reprogramming of somatic cells is a valuable tool to understand the mechanisms of regaining pluripotency and further opens up the possibility of generating patient-specific pluripotent stem cells. Reprogramming of mouse and human somatic cells into pluripotent stem cells, designated as induced pluripotent stem (iPS) cells, has been possible with the expression of the transcription factor quartet Oct4 (also known as Pou5f1), Sox2, c-Myc and Klf4 (refs 1-11). Considering that ectopic expression of c-Myc causes tumorigenicity in offspring and that retroviruses themselves can cause insertional mutagenesis, the generation of iPS cells with a minimal number of factors may hasten the clinical application of this approach. Here we show that adult mouse neural stem cells express higher endogenous levels of Sox2 and c-Myc than embryonic stem cells, and that exogenous Oct4 together with either Klf4 or c-Myc is sufficient to generate iPS cells from neural stem cells. These two-factor iPS cells are similar to embryonic stem cells at the molecular level, contribute to development of the germ line, and form chimaeras. We propose that, in inducing pluripotency, the number of reprogramming factors can be reduced when using somatic cells that endogenously express appropriate levels of complementing factors.


Cost-Effectiveness of Primary HPV Screening Strategies and Triage With Cytology or Dual Stain for Cervical Cancer.
To identify the optimal cost-effective strategy for cervical cancer screening program in Thailand by comparing the different algorithms which based on the use of primary human papilloma virus (HPV) assay. We use a Microsoft Excel-based spreadsheet to calculate the accumulated cases of preinvasive and invasive cervical cancer and the budget impact of each screening program. The model was developed to determine the cost-effectiveness of 3 screening strategies: pooled HPV test with reflex liquid-based cytology triage, HPV genotyping with reflex p16/ki67 dual stain cytology, and pooled HPV test with dual stain. The main outcomes were the total cost, incremental quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). Strategy entailing primary HPV genotyping and reflex dual stain cytology is the least costly strategy (total cost US$37 893 407) and provides the similar QALY gained compared to pooled high-risk HPV testing with reflex dual stain (Average QALY 24.03). Pooled HPV test with reflex dual staining is more costly compared to strategy without reflex dual staining. The ICER was US$353.40 per QALY gained. One-way sensitivity analysis showed that the model is sensitive to the cost of dual stain and the cost of cancer treatment. Decreasing the incidence of cervical cancer case and increasing the QALYs can be successful by using dual stain cytology as the triage test for pooled HPV test or HPV genotyping. The result of our analysis favors the use of HPV genotyping with the reflex dual stain as it offers the most QALY at the lowest cost.


Stereotactic Body Radiotherapy for Localized Ureter Transitional Cell Carcinoma: Three Case Reports.
The gold standard management for ureter transitional cell carcinoma (UTCC) is radical nephroureterectomy with excision of the bladder cuff. However, some patients cannot undergo this procedure for several reasons. In the case reports described herein, we performed stereotactic body radiotherapy (SBRT) on three patients with inoperable or surgery-rejected localized UTCC. Two out of the three patients did not develop local recurrence or distant metastasis during the observation period. However, recurrence was detected in the bladder of one patient 22 months after the treatment. No acute or late adverse events occurred in any of the three patients. SBRT may become one of the treatment options for inoperable or surgery-rejected UTCC patients.


Remote Cerebellar Haemorrhage: A Potential Iatrogenic Complication of Spinal Surgery.
We report the case of a 51-year-old man with no significant past medical history, who underwent elective revision spinal surgery and subsequently developed intracranial hypotension, remote cerebellar haemorrhage (RCH), and mild hydrocephalus on the fourth postoperative day. Remote cerebellar haemorrhage is a known complication of supratentorial surgery. This iatrogenic phenomenon may also occur following spinal surgery, due to dural tearing and rapid cerebral spinal fluid (CSF) leakage, resulting in intracranial hypotension and cerebellar haemorrhage. This complication may result in severe permanent neurologic sequelae; hence, it is of pertinence to diagnose and manage it rapidly in order to optimise patient outcome.


Transumbilical multiport laparoscopic nephroureterectomy for congenital renal dysplasia in children: midterm follow-up from a single institution.
To assess the clinical utility and efficiency of transumbilical multiport laparoscopic nephroureterectomy (TMLN) for the treatment of congenital renal dysplasia in children by analyzing consecutive cases from a single institution. Sixteen children underwent TMLN procedure due to dysplastic kidney between January 2010 and December 2011. The surgery was transperitoneally performed through three transumbilical incisions for two 5-mm and one 3-mm ports, which duplicated the standard laparoscopic steps with the usual laparoscopic instruments. Demographic, perioperative, and follow-up data were analyzed. TMLN was performed in all patients, without additional ports or conversion to open surgery. The mean operation time was 108.4 min (range 90-125), and the blood loss was minimal. There were no severe intraoperative or post-operative complications. The post-operative recovery was uneventful in all patients. No urinary incontinence or umbilical hernias occurred. The cosmetic result was excellent as the incision scar was hidden inside the belly button. TMLN is a safe and efficient procedure for the management of congenital renal dysplasia in children with good cosmesis. Future randomized studies with a larger number of cases and a longer follow-up are warranted to elucidate the benefits and limitations of TMLN in children.


Audits and critical incident reporting in paediatric anaesthesia: lessons from 75,331 anaesthetics.
This study reports our experience of audit and critical incidents observed by paediatric anaesthetics from 2000 to 2010 at a paediatric teaching hospital in Singapore. Data pertaining to patient demographics, practices and critical incidents during anaesthesia and in the perioperative period were prospectively collected via an audit form and retrospectively analysed thereafter. A total of 2,519 incidents were noted at the 75,331 anaesthetics performed during the study period. There were nine deaths reported. The majority of incidents reported were respiratory critical incidents (n = 1,757, 69.8%), followed by cardiovascular incidents (n = 238, 9.5%). Risk factors for critical incidents included age less than one year, and preterm and former preterm children. Critical incident reporting has value, as it provides insights into the system and helps to identify active and system errors, thus enabling the formulation of effective preventive strategies. By creating and maintaining an environment that encourages reporting, we have maintained a high and consistent reporting rate through the years. The teaching of analysis of critical incidents should be regarded by all clinicians as an important tool for improving patient safety.


Prepartum Psychosis and Neonaticide: Rare Case Study and Forensic-Psychiatric Synthesis of Literature.
Peripartum psychosis is a rare but serious psychiatric disorder characterized by the presence of a mood episode with psychotic features. Although controversy surrounds the nosological status of peripartum mental disorders, these conditions continue to be of exceptional interest to the medical and forensic mental health communities. The aim of this study was to report a rare case of prepartum psychosis which escalated to the endpoint of neonaticide and summarize literature on peripartum mental disorders and infanticide. A 30-year-old mother murdered her newborn with the spike of her serum delivery system and planned to commit suicide while in hospital after hallucinating due to an acute puerperal psychotic disorder with a prepartum onset and postpartum deterioration. Her disorder was not managed until neonaticide. Throughout this paper, the significance of a multidisciplinary approach for the optimal management of these incidents is highlighted and diagnostic as well as therapeutic issues are addressed.


Discoloration of permanent front teeth in 3,157 Norwegian children due to tetracyclines and other factors.
During routine orthodontic screening in Oslo, Norway, of 3,157 children, aged 1--11 years and born in 1963/64, 36 cases (1.14%) with cosmetically marring discoloration of permanent front teeth were registered. Thirty-four of them arrived for a more exhaustive examination, which in 24 of the children revealed positive tetracycline fluorescence on exposure to ultraviolet light. In 13 (0.4%) of the children, the discolorations were diagnosed to be tetracycline-induced. Enamel hypoplasia was frequently found in teeth with positive fluorescence. Multiple exposures to various tetracyclines were reported in all children who exhibited positive fluorescence.


Reproducibility of the Banff schema in reporting protocol biopsies of stable renal allografts.
There is evidence that biopsy of stable renal allografts may be of value in predicting chronic allograft nephropathy, the main cause of graft loss. However, the reproducibility of such histological evaluation has not been tested in this setting. We tested the reproducibility of the Banff schema for this purpose. We rated acute and chronic changes in 184 protocol biopsies. Individual pathologists at two different Canadian transplant centres reported independently. There was agreement in 73.53, 42.86, and 77.08% of cases in assigning a diagnosis of acute rejection, borderline changes (as defined in the schema), and no acute rejection, respectively. Applying kappa statistics, there was very good agreement in making the diagnosis of acute rejection vs no acute rejection (kappa 0.77). There was good inter-observer agreement in scoring glomerulitis, intimal arteritis, interstitial infiltrates, tubulitis, and arteriolar hyalinosis. Rating chronic changes also gave good inter-observer agreement (kappa=0.53, 0.65, and 0.62, respectively, for mild, moderate, and severe chronic allograft nephropathy). Agreement on transplant glomerulopathy was, however, poor. We conclude that the Banff classification provides a reproducible method for the histological assessment of protocol renal allograft biopsies in stable grafts. Such biopsies may be valuable in detecting subclinical rejection and early chronic allograft nephropathy and may also be used as surrogate end-points in the evaluation of therapy to prevent the latter.


Cardiorespiratory fitness, adiposity, and all-cause mortality in women.
To determine the prospective associations among cardiorespiratory fitness (CRF), different measures of adiposity, and all-cause mortality in women. A total of 11,335 women completed a comprehensive baseline examination between 1970 and 2005. Clinical measures included body mass index (BMI), waist circumference (WC), waist-to-height ratio (W/HT), waist-to-hip ratio (W/Hip), percent body fat (%BF), and CRF quantified as duration of a maximal exercise test. Participants were classified by CRF as low (lowest 20%), moderate (middle 40%), and high (highest 40%) as well as by standard clinical cut points for adiposity measures. Hazard ratios (HR) were computed using Cox regression analysis. During a mean follow-up of 12.3 ± 8.2 yr, 292 deaths occurred. HR for all-cause mortality were 1.0, 0.60, and 0.54 for low, moderate, and high fit groups, respectively (P for trend G0.01). Adjusted death rates of overweight/obese women within each adiposity exposure were somewhat higher compared with normal-weight women and approached statistical significance for BMI, %BF, and W/HT (P = 0.08, P = 0.08, and P = 0.07, respectively). When grouped for joint analyses into categories of fit and unfit (upper 80% and lower 20% of CRF distribution, respectively), HR were significantly higher in unfit women within each stratum of BMI compared with fit–normal BMI women. Fit women with high %BF (HR = 1.0), high WC (HR = 0.9), and high W/HT (HR = 1.2) had no greater risk of death compared with fit–normal-weight women (referent). Low CRF in women was a significant independent predictor of all-cause mortality. Higher CRF was associated with lower mortality within each category of each adiposity exposure. Using adiposity measures as predictors of all-cause mortality in women may be misleading unless CRF is also considered.


Subcellular, time-resolved studies of singlet oxygen in single cells.
In time-resolved and spatially resolved experiments, singlet molecular oxygen, O2(a1Deltag), was created in a single nerve cell upon irradiation of a sensitizer incorporated in the cell using a focused laser beam. The singlet oxygen thus produced was detected by its infrared phosphorescence. Data obtained indicate that in both the cytoplasm and the nucleus of the cell, this reactive species is approximately 1-2 orders of magnitude longer-lived than previously believed. The data demonstrate that deactivation of singlet oxygen in the cell is dominated by interactions with the solvent not cellular constituents such as proteins. These results provide a new perspective for mechanistic studies of the role of O2(a1Deltag) in photoinduced cell death and intracellular signaling.