Evaluation of duct-cell and acinar-cell function and endosonographic abnormalities in patients with suspected chronic pancreatitis.
Endoscopic ultrasound (EUS) detects mild and severe structural abnormalities of the pancreas that correlate with fibrosis. Direct pancreatic function tests (PFTs) detect mild exocrine insufficiency associated with early fibrosis. The primary aim of this study was to compare EUS structural criteria with duct-cell and acinar-cell function. Fifty patients evaluated for chronic pancreatitis underwent combined EUS and secretin endoscopic PFTs (ePFT) on day 1 and CCK ePFT on day 2. EUS images were videotaped and interpreted by consensus of 3 blinded expert reviewers. There were inverse correlations of EUS consensus score with both duct-cell bicarbonate secretion (R = -0.71, P < .001) and acinar-cell lipase secretion (R = -0.52, P < .001). With secretin ePFT as reference standard, EUS (>or=4 criteria) showed a sensitivity of 71% (95% confidence interval [CI], 53%-89%) and specificity of 92% (95% CI, 75%-99%). With CCK ePFT as reference standard, EUS had a sensitivity of 63% (95% CI, 43%-82%) and specificity of 85% (95% CI, 71%-98%). Main duct dilation, irregularity, calcifications, and visible side-branches were most predictive of exocrine insufficiency (positive predictive value >80% for both acinar- and duct-cell insufficiency). Acinar- and duct-cell function decreases as EUS structural abnormalities increase. EUS has fair sensitivity and very good specificity compared with secretin and CCK functional reference standards.


Underimmunization of American Indian and Alaska Native children.
The goal was to determine whether disparities in childhood immunization coverage exist between American Indian/Alaska Native children and non-Hispanic white children. We compared immunization coverage with the 4 diphtheria-tetanus-pertussis, 3 poliovirus, 1 measles-mumps-rubella, 3 Haemophilus influenza type b, and 3 hepatitis B(4:3:1:3:3) series and its individual vaccine components (> or = 4 doses of diphtheria, tetanus, and pertussis vaccine; > or = 3 doses of oral or inactivated polio vaccine; > or = 1 dose of measles, mumps, and rubella vaccine; > or = 3 doses of Haemophilus influenzae type b vaccine; and > or = 3 doses of hepatitis B vaccine) between American Indian/Alaska Native children and non-Hispanic white children from 2000 to 2005, using data from the National Immunization Survey. Although immunization coverage increased for both populations from 2001 to 2004, American Indian/Alaska Native children had significantly lower immunization coverage, compared with non-Hispanic white children, over that time period. In 2005, coverage continued to increase for American Indian/Alaska Native children but decreased for non-Hispanic white children, and no statistically significant disparity in 4:3:1:3:3 coverage was evident in that year. Disparities in immunization coverage for American Indian/Alaska Native children have been present, but unrecognized, since 2001. The absence of a disparity in coverage in 2005 is encouraging but is tempered by the fact that coverage for non-Hispanic white children decreased in that year.


Purification of poly(A)-messenger ribonucleic acid by reversed-phase high-performance liquid chromatography.
Polyadenylated messenger ribonucleic acid [poly(A)-mRNA] was purified by reversed-phase high-performance liquid chromatography (RP-HPLC). Partially purified poly(A)-mRNA was prepared from rat liver polysomes by magnesium precipitation followed by affinity chromatography on an oligo(dT) cellulose column. Translatable poly(A)-mRNA, as assayed by in vitro translation in a rabbit reticulocyte system, was resolved from non-translatable RNA by RP-HPLC. The separation appears to be due to the presence of poly(A) residues on the 3' terminus of the mRNA.


Mast Cells Participate in Corneal Development in Mice.
The development of the cornea, a highly specialized transparent tissue located at the anterior of the eye, is coordinated by a variety of molecules and cells. Here, we report that mast cells (MCs), recently found to be involved in morphogenesis, played a potentially important role in corneal development in mice. We show that two different waves of MC migration occurred during corneal development. In the first wave, MCs migrated to the corneal stroma and became distributed throughout the cornea. This wave occurred by embryonic day 12.5, with MCs disappearing from the cornea at the time of eyelid opening. In the second wave, MCs migrated to the corneal limbus and became distributed around limbal blood vessels. The number of MCs in this region gradually increased after birth and peaked at the time of eyelid opening in mice, remaining stable after postnatal day 21. We also show that integrin α4β7 and CXCR2 were important for the migration of MC precursors to the corneal limbus and that c-Kit-dependent MCs appeared to be involved in the formation of limbal blood vessels and corneal nerve fibers. These data clearly revealed that MCs participate in the development of the murine cornea.


Community teamwork in nutrition education: an example in Canada's north.
The nutrition education program, sponsored by the Hudson's Bay Company, in remote northern communities, both Inuit and Indian, is described. The program identifies nutritious foods in the company's community stores by coding in the colours associated with the food groups of Canada's Food Guide. It involves the cooperation of key individuals from the community and various community agencies and organizations.


Investigation of Macrocyclic mTOR Modulators of Rapamycin Binding Site via Pharmacoinformatics Approaches.
The PI3K/Akt/mTOR is an essential intracellular signaling pathway in which the serine/threonine mTOR kinase portrays a major role in cell growth, proliferation and survival. The mTOR kinase is frequently dysregulated in a broad spectrum of cancers, thus making it a potential target. Rapamycin and its analogs (rapalogs) allosterically inhibit mTOR, thereby dodging the deleterious effects prompted by ATP-competitive mTOR inhibitors. However, the available mTOR allosteric site inhibitors exhibit low oral bioavailability and suboptimal solubility. Bearing in mind this narrow therapeutic window of the current allosteric mTOR inhibitors, an in silico study was designed in search of new macrocyclic inhibitors. The macrocycles from the ChemBridge database (12,677 molecules) were filtered for their drug-likeness properties and the procured compounds were subjected for molecular docking within the binding cleft between FKBP25 and FRB domains of mTOR. The docking analysis resulted with 15 macrocycles displaying higher scores than the selective mTOR allosteric site inhibitor, DL001. The docked complexes were refined by subsequent molecular dynamics simulations for a period of 100 ns. Successive binding free energy computation revealed a total of 7 macrocyclic compounds (HITS) demonstrating better binding affinity than DL001, towards mTOR. The consequent assessment of pharmacokinetic properties resulted in HITS with similar or better properties than the selective inhibitor, DL001. The HITS from this investigation could act as effective mTOR allosteric site inhibitors and serve as macrocyclic scaffolds for developing compounds targeting the dysregulated mTOR.


Poly-γ-glutamic acid suppresses osteoclastogenesis in human osteoclast precursors and prevents joint damage in a collagen-induced murine arthritis model.
Poly-γ-glutamic acid (γ-PGA), a natural polymer derived from Bacillus subtilis, shows anti-inflammatory activity. However, the effects of γ-PGA on osteoclasts, which are important cells for joint destruction in inflammatory diseases such as rheumatoid arthritis (RA), have not yet been reported. In this study, we show that γ-PGA markedly inhibits osteoclast differentiation in normal PBMC-derived osteoclast precursors and in synovial fluid macrophages of patients with RA. γ-PGA also reduces RANK expression by down-regulating M-CSF receptors. Additionally, oral administration of γ-PGA attenuated bone destruction in a collagen-induced arthritis (CIA) model, demonstrating decreases in inflammation, cartilage damage, and osteoclast formation in histological analyses. Taken together, these data suggest that γ-PGA could be a good candidate for therapeutic prevention of joint destruction in RA.


Control of protein adsorption on functionalized electrospun fibers.
Electrospun fibers that are protein resistant and functionalized with bioactive signals were produced by solution electrospinning amphiphilic block copolymers. Poly (ethylene glycol)-block-poly(D,L-lactide) (PEG-b-PDLLA) was synthesized in two steps, with a PEG segment of 10 kDa, while the PDLLA block ranged from 20 to 60 kDa. Depending on the PEG and PDLLA segment ratio, as well as solvent selection, the hydrophilicity and protein adsorption could be altered on the electrospun mesh. Furthermore, an alpha-acetal PEG-b-PDLLA was synthesized that allowed the conjugation of active molecules, resulting in surface functionalization of the electrospun fiber. Electrospun material with varying morphologies and diameter were electrospun from 10, 20, and 30 wt.% solutions. Sessile drop measurements showed a reduction in the contact angle from 120 degrees for pure poly(D,L-lactide) with increasing PEG/PDLLA ratio. All electrospun block PEG-b-PDLLA fibers had hydrophilic properties, with contact angles below 45 degrees . The fibers were collected onto six-arm star-poly(ethylene glycol) (star-PEG) coated silicon wafers and incubated with fluorescently labeled proteins. All PEG-b-PDLLA fibers showed no detectable adsorption of bovine serum albumin (BSA) independent of their composition while a dependence between hydrophobic block length was observed for streptavidin adsorption. Fibers of block copolymers with PDLLA blocks smaller than 39 kDa showed no adsorption of BSA or streptavidin, indicating good non-fouling properties. Fibers were surface functionalized with N(epsilon)-(+)-biotinyl-L-lysine (biocytin) or RGD peptide by attaching the molecule to the PEG block during synthesis. Protein adsorption measurements, and the controlled interaction of biocytin with fluorescently labeled streptavidin, showed that the electrospun fibers were both resistant to protein adsorption and are functionalized. Fibroblast adhesion was contrasting between the unfunctionalized and RGD-coupled electrospun fabrics, confirming that the surface of the fibers was functionalized. The PEG-b-PDLLA surface functionalized electrospun fibers are promising substrates for controlling cell-material interactions, particularly for tissue-engineering applications.


Proton nuclear magnetic resonance studies on water structure in peritumoral edematous brain tissue.
Spin-lattice relaxation times (T1) of water protons and cross-relaxation times (TIS) between irradiated protein and water protons were measured to study the water structure in peritumoral edematous brain tissue of rats. Despite small changes in T1, water, and electrolyte contents, TIS values of water protons were significantly reduced in peritumoral edematous brain tissue when compared to those of the controls. Results indicate that the water structure in brain tissues may become altered at an early stage of edemic formation without causing any significant changes in cellular hydration. TIS might serve as a sensitive parameter for studying the water structure in a variety of tissues, such as in edematous brain tissue.


A randomized, double-blind, multicenter clinical trial on the efficacy of ivermectin against intestinal nematode infections in China.
To assess the efficacy of ivermectin against intestinal nematode infections, a randomized, double-blind, multicenter clinical trial was carried out in a total of 816 human individuals infected with different nematodes from three counties in China. The subjects were randomly assigned into experimental and control groups and orally given a single dose of 0.1, 0.2, 0.2 and 0.2mg/kg ivermectin against Ascaris lumbricoides, hookworm, Trichuris trichiura and Enterobius vermicularis, respectively. Parallel control groups to each of the ivermectin groups were given a single oral dose of 6.7 mg/kg albendazole. The cure rates with ivermectin and albendazole were 100% (102/102) and 99.0% (101/102) for Ascaris, and 66.7% (68/102) and 67.7% (69/102) for Trichuris, respectively, with no significant difference (P>0.05) between the two treatments. The parasitological cure rates of albendazole were 69.6% (71/102) for hookworm and 94.1% (96/102) for Enterobius, which were significantly higher than ivermectin (33.3% and 52.9%, respectively, P<0.0001). The expulsion of worm in the feces reached its peak 1-2 days after ivermectin treatment. The study showed that ivermectin, with few side effects, could be used as an additional treatment tool for intestinal nematodes, especially for the treatment of Ascaris and Trichuris infections in China.


Adverse transfusion reactions in patients with aplastic anaemia or myelodysplastic syndromes.
Patients with aplastic anaemia or myelodysplastic syndromes frequently receive transfusions in an attempt to correct anaemia and/or thrombocytopenia, putting them at risk of adverse transfusion reactions. The aim of this study is to evaluate the incidence and the types of adverse transfusion reactions in these patients. Adverse transfusion reaction reported in transfused patients with aplastic anaemia or myelodysplastic syndromes from all the hospitals in the Auvergne-Rhône-Alpes region of France were extracted from the national haemovigilance database system and analysed. The types of adverse transfusion reactions, their incidence, their severity, the blood component involved and its imputability were evaluated. From 1 January 2010 to 30 June 2016, 7174 adverse transfusion reactions were reported. Seventy adverse transfusion reactions (0·9%) were reported in patients with aplastic anaemia and 193 (2·7%) in patients with myelodysplastic syndromes. Febrile non-haemolytic transfusion reaction was the most common reaction both aplastic anaemia (23 cases, 33·0%) and myelodysplastic syndrome (56 cases, 29·0%). Post-transfusion red blood cell alloimmunization was also high in both these groups (17·1% in patients with aplastic anaemia and 22·3% in patients with myelodysplastic syndrome) frequently involving anti-JK1 (Jka ) specificity. Febrile non-haemolytic transfusion reaction was the most common adverse transfusion reaction in patients with aplastic anaemia or myelodysplastic syndromes who received transfusions. Post-transfusion red blood cell alloimmunization was also observed frequently, but the use of RH-KEL 1 (Rhesus-Kell)-matched red blood cell concentrates reduces this risk.


Pathogenic Germline DNA Repair Gene and HOXB13 Mutations in Men With Metastatic Prostate Cancer.
Germline mutations in DNA repair (DR) genes and susceptibility genes CDKN2A and HOXB13 have previously been associated with prostate cancer (PC) incidence and/or progression. However, the role and prevalence of this class of mutations in metastatic PC (mPC) are not fully understood. To evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/LPVs) in men with mPC, this study sequenced 38 DR genes, CDKN2A, and HOXB13 in a predominantly white cohort of 317 patients with mPC. A PC registry at the University of Utah was used for patient sample acquisition and retrospective clinical data collection. Deep target sequencing allowed for germline and copy number variant analyses. Validated PVs/LPVs were integrated with clinical and demographic data for statistical correlation analyses. All pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; CDKN2A/HOXB13, 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene BRCA2. It was also found that 50% of identified PVs/LPVs were categorized as founder mutations with European origins. Correlation analyses did not support a trend toward more advanced or earlier-onset disease in comparisons between carriers and noncarriers of deleterious DR or HOXB13 G84E mutations. These findings demonstrate a lower prevalence of germline PVs/LPVs in an unselected, predominantly white mPC cohort than previously reported, which may have implications for the design of clinical trials testing targeted therapies. Larger studies in broad and diverse populations are needed to more accurately define the prevalence of germline mutations in men with mPC.


Long-term support by injured brain extract of a subpopulation of ciliary ganglion neurons purified by differential adhesion.
Ciliary ganglion neurons and nonneurons can be separated from each other, based on the greater adhesivity of the nonneurons to untreated tissue culture plastic in the presence of serum. When the separation was carried out in the presence of Serum Plus (a commercially available supplemented serum), two populations of neurons were distinguished. Neurons in the first class (50-60% of total) adhered to plastic within 15 min, tended to aggregate into clumps, and were not well supported in long term culture by brain extracts. Neuronal adhesion to plastic was inhibited by heparin but not by chondroitin sulfate. Neurons in the second class did not attach to plastic for up to 90 min (and could thus be purified), were not as prone to aggregation, and were quantitatively supported for long periods (greater than 2 weeks) by the neurotrophic factor(s) present in extracts of injured brain. Although no direct evidence is provided, these populations may correspond to the well characterized ciliary and choroid neurons.


Alleviating the suppression of glycogen synthase kinase-3beta by Akt leads to the phosphorylation of cAMP-response element-binding protein and its transactivation in intact cell nuclei.
Glycogen synthase kinase-3beta (GSK-3beta) activity is suppressed when it becomes phosphorylated on serine 9 by protein kinase B (Akt). To determine how GSK-3beta activity opposes Akt function we used various methods to alleviate GSK-3beta suppression in prostate carcinoma cells. In some experiments, LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (a kinase involved in activating Akt) and tumor necrosis factor-alpha (TNF-alpha) were used to activate GSK-3beta. In other experiments mutant forms of GSK-3beta, GSK-3betadelta9 (a constitutively active deletion mutant of GSK-3beta) and GSK-3betaY216F (an inactive point mutant of GSK-3beta) were used to alter GSK-3beta activity. LY294002, TNF-alpha, and overexpression of wild-type GSK-3beta or of GSK-3betadelta9, but not GSK-3betaY216F, alleviated the suppression of GSK-3beta activity in prostate carcinoma cells and enhanced the turnover of beta-catenin. Forced expression of wild-type GSK-3beta or of GSK-3betadelta9, but not GSK-3betaY216F, suppressed cell growth and showed that the phosphorylation status of GSK-3beta can affect its intracellular distribution. When transcription factors activator protein-1 and cyclic AMP-response element (CRE)-binding protein were analyzed as targets of GSK-3beta activity, overexpression of wild-type GSK-3beta suppressed AP1-mediated transcription and activated CRE-mediated transcription. Overexpression of GSK-3betadelta9 caused an (80-fold) increase in CRE-mediated transcription, which was further amplified (up to 130-fold) by combining GSK-3betadelta9 overexpression with the suppression of Jun activity. This study also demonstrated for the first time that expression of constitutively active GSK-3betadelta9 results in the phosphorylation of CRE-binding protein on serine 129 and enhancement of CRE-mediated transcription in intact cell nuclei.


Inhibition of Ctsk modulates periodontitis with arthritis via downregulation of TLR9 and autophagy.
The mechanisms underlying the effects of Toll-like receptor 9 (TLR9) and autophagy on rheumatoid arthritis (RA)-aggravated periodontitis are unclear. We aimed to explore a novel target, cathepsin K (Ctsk)-mediated TLR9-related autophagy, during the progress of periodontitis with RA. DBA/J1 mouse model of periodontitis with RA was created by local colonization of Porphyromonas gingivalis (Pg) and injection of collagen. The expression of Ctsk was inhibited by adeno-associated virus (AAV). Micro-CT, immunohistochemistry (IHC), Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of TLR9-related autophagy in periodontitis with RA. Small interfering RNA (siRNA) and CpG oligodeoxynucleotides (CpG ODN) were applied in macrophages. Western blot, immunofluorescence (IF) and qRT-PCR were used to verify the in vivo results. RA can promote periodontitis bone destruction in the lesion area, while inhibiting Ctsk could effectively alleviate this effect. The infiltration of macrophages, TLR9, autophagy proteins (TFEB and LC3) and inflammatory cytokines increased in the periodontitis-with-RA group and was reduced by the inhibition of Ctsk in the periodontal region. Macrophage stimulation confirmed the in vivo results. With the activation of TLR9 by CpG ODN, inhibition of Ctsk could suppress both TLR9 downstream signalling proteins and autophagy-related proteins. This study advanced a novel role for Ctsk in TLR9 and autophagy to explain the interaction between periodontitis and RA.


The inner ear morphology and hearing abilities of the Paddlefish (Polyodon spathula) and the Lake Sturgeon (Acipenser fulvescens).
Concern regarding the spread of silver carp (Hypopthalmichthys molitrix) and bighead carp (Aristichthysc nobilis) through the Illinois River has prompted the development of an Acoustic Fish Deterrent (AFD) system. The application of this technology has resulted in a need to understand the auditory physiology of fish other than the target species, in order to minimise the effect of the AFD barrier on the ecology of indigenous fish populations. To this end, both the structures involved in sound reception and the hearing abilities of the paddlefish (Polyodon spathula) and the lake sturgeon (Acipenser fulvescens) are studied here using a combination of morphological and physiological approaches, revealing that both fish are responsive to sounds ranging in frequency from 100 to 500 Hz. The lowest hearing thresholds from both species were acquired from frequencies in a bandwidth of between 200 and 300 Hz, with higher thresholds at 100 and 500 Hz. The rationale for studying hearing in P. spathula and A. fulvescens in particular, is the value placed on them by both the commercial caviar producing industry and by the recreational fisheries sector. The hearing abilities of twelve P. spathula and twelve A. fulvescens were tested in sound fields dominated by either sound pressure or particle motion, with the results showing that acipenseriform fish are responsive to the motion of water particles in a sound field, rather than the sound pressure component. In this study, we measure the intensity of the sound field required to evoke threshold responses using a pressure sensitive hydrophone, as pressure dominated sound fields are the most audible acoustic condition for specialists like H. molitrix and A. nobilis (the target species). The results of the auditory examination clearly show that P. spathula and A. fulvescens are not sensitive to sound pressure, and will therefore have a significantly higher deterrent threshold than H. molitrix and A. nobilis in a pressure dominated sound field.


Comparison of benorylate and ibuprofen in the treatment of established rheumatoid arthritis.
Benorylate and ibuprofen appear to be useful drugs for pain relief in rheumatoid arthritis but benorylate would appear to have a slightly better effect on the pain score and it improved the grip strength more than the moderate doses of ibuprofen. It could be a most useful drug when gastric problems limit the dose of aspirin or of other analgesics.


Spatial cognition in the gerbil: computing optimal escape routes from visual threats.
Previous studies in our laboratory have shown that when presented with a sudden stimulus simulating an oncoming predator, Mongolian gerbils can compute the optimal trajectory to a safe refuge, taking into account the position of the threat, the location of a clearly visible refuge, and several other contextual variables as well. In the present studies, the main goal was to explore the abilities of gerbils to use mental representations of spaces that were visually occluded by opaque barriers to compute efficient escape trajectories. In all studies, gerbils were placed into a round open field containing a single refuge. On each trial, an overhead visual stimulus was caused to 'fly' overhead, eliciting robust escape movements from the gerbils. By manipulating the shape and position of a series of opaque barriers that were interposed between the gerbils and the refuge, we were able to show that gerbils can compute the shortest route to an invisible target, even when the available routes to the target are made complex by using elaborate barrier shapes. These findings suggest that gerbils can maintain representations of their locations with respect to salient environmental landmarks and refuges, even when such locations are not continuously visible.


Reductive transformation of carbamazepine by abiotic and biotic processes.
The antiepileptic drug carbamazepine (CBZ) is ubiquitously present in the anthropogenic water cycle and is therefore of concern regarding the potable water supply. Despite of its persistent behavior in the aquatic environment, a redox dependent removal at bank filtration sites with anaerobic aquifer passage was reported repeatedly but not elucidated in detail yet. The reductive transformation of CBZ was studied, using abiotic systems (catalytic hydrogenation, electrochemistry) as well as biologically active systems (column systems, batch degradation tests). In catalytic hydrogenation CBZ is gradually hydrogenated and nine transformation products (TPs) were detected by liquid chromatography high-resolution mass spectrometry. 10,11-Dihydro-CBZ ((2H)-CBZ) was the major stable product in these abiotic, surface catalyzed reduction processes and turned out to be not a precursor of the more hydrogenated TPs. In the biotic reduction processes the formation of (2H)-CBZ alone could not explain the observed CBZ decline. There, also traces of (6H)-CBZ and (8H)-CBZ were formed by microbes under anaerobic conditions and four phase-II metabolites of reduced CBZ could be detected and tentatively identified. Thus, the spectrum of reduction products of CBZ is more diverse than previously thought. In environmental samples CBZ removal along an anaerobic soil passage was confirmed and (2H)-CBZ was determined at one of the sites.


Osteopontin up-regulates critical epithelial-mesenchymal transition transcription factors to induce an aggressive breast cancer phenotype.
Tumor cells undergoing epithelial-mesenchymal transition (EMT) develop cellular properties leading to stroma invasion and intravasation. We have previously shown in a xenograft breast cancer model that blocking osteopontin (OPN), a secreted phosphoprotein, decreases EMT. This study examines OPN's role in EMT initiation through its regulation of EMT transcription factors (TFs) Snail, Slug, and Twist. OPN's role in Twist activation is examined through immunoprecipitation and Western blot. MDA-MB-231 breast cancer cells secreting high levels of OPN were treated with OPN aptamer (APT) or mutant APT. Osteopontin APT binds to and inhibits extracellular OPN. Low-OPN-secreting breast cancer cells, MCF-7, were treated with OPN, OPN+APT, or OPN+mutant APT. Twist was isolated in MDA-MB-231 with immunoprecipitation. Phospho-serine antibody detected activated Twist in Western blot. Activation of Twist was confirmed by chromatin immunoprecipitation. Analysis through quantitative polymerase chain reaction demonstrated APT inhibition of OPN in MDA-MB-231 cells caused a decrease in EMT-TF expression (MDA-MB-231 vs MDA-MB-231+APT: *Twist ΔΔCT: 1.0 vs 0.07; *Snail ΔΔCT: 1.0 vs 0.11; *Slug ΔΔCT: 1.0 vs 0.11; *p < 0.001). Mutant APT did not change EMT-TF expression (NS). Treatment of MCF-7 cells with OPN caused an increase in EMT-TF expression (MCF-7 vs MCF-7+OPN: Twist ΔΔCT: 1.0 vs 9.1; *Snail ΔΔCT: 1.0 vs 11.2; *Slug ΔΔCT: 1.0 vs 10.9; *p < 0.001). The EMT-TF expression in MCF-7 treated with OPN+APT did not differ significantly from MCF-7 alone. Phosphorylated Twist protein was reduced 2-fold with APT in MDA-MB-231 compared with MDA-MB-231 and MDA-MB-231+mutant APT. Twist phorphorylation induced binding to the promoter regions of Twist-regulated gene, B lymphoma Mo-MLV insertion region 1 homolog, a critical protein for EMT progression. This study shows that OPN is critical in EMT initiation through activation of Twist via serine phosphorylation. These unique observations indicate that OPN APT can serve a clinical role as a novel therapeutic agent by diminishing breast cancer oncogenesis.


Osteoblastic activation in the hematopoietic stem cell niche.
Hematopoietic stem cells (HSC) are rare primitive cells capable of reconstituting all blood cell lineages throughout the life of an individual. The microenvironment in which stem cells reside is essential for their survival, self-renewal, and differentiation. This microenvironment, or HSC niche, has been difficult to define in bone and bone marrow, but recent studies from our laboratory and others have shown that osteoblasts, the bone-forming cells, are an essential regulatory component of this complex cellular network. We established that parathyroid hormone (PTH), through activation of the PTH/PTHrP receptor (PTH1R) in osteoblastic cells, could alter the HSC niche resulting in HSC expansion in vivo and in vitro and improving dramatically the survival of mice receiving bone marrow transplants. These findings are of great clinical appeal, because they suggest that a strategy aimed at modifying supportive cells in a stem cell niche can expand HSC. While a number of molecules have been found to be important for hematopoietic/osteoblastic interactions, we have focused on the Jagged1/Notch signaling pathway, which was necessary for the PTH-dependent HSC expansion. Since the Jagged1/Notch signaling pathway has been implicated in the microenvironmental control of stem cell self-renewal in several organ systems, definition of Jagged1 modulation, which is currently poorly understood, should provide additional molecular targets for stem cell regulation and advance the understanding of stem cell-microenvironmental interactions.


Genetic relationship between bacteria isolated from intraoperative air samples and surgical site infections at a major teaching hospital in Ghana.
In low- and middle-income countries (LMICs) the rate of surgical site infections (SSI) is high, leading to negative patient outcomes and excess healthcare costs. A causal relationship between airborne bacteria in the operating room and SSI has not been established, at a molecular or genetic level. We studied the relationship between intraoperative airborne bacteria and bacteria causing SSI in an LMIC. Active air sampling using a portable impactor was performed during clean or clean-contaminated elective surgical procedures. Active patient follow-up consisting of phone calls and clinical examinations was performed 3, 14 and 30 days after surgery. Bacterial isolates recovered from SSI and air samples were compared by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) identification, ribotyping, whole genome sequencing (WGS), and metagenomic analysis. Of 128 included patients, 116 (91%) completed follow-up and 11 (9%) developed SSI. Known pathogenic bacteria were isolated from intraoperative air samples in all cases with SSI. A match between air and SSI isolates was found by MALDI-TOF in eight cases. Matching ribotypes were found in six cases and in one case both WGS and metagenomic analysis showed identity between air- and SSI-isolates. The study showed high levels of intraoperative airborne bacteria, an SSI-rate of 9% and a genetic link between intraoperative airborne bacteria and bacteria isolated from SSIs. This indicates the need for awareness of intraoperative air quality in LMICs.


pp60c-src is developmentally regulated in the neural retina.
We have localized normal cellular pp60c-src in the developing chick neural retina by immunocytochemical staining using antisera raised against bacterially expressed pp60v-src, the src gene product of Rous sarcoma virus. pp60c-src was expressed in developing retinal neurons at the onset of differentiation. Expression of pp60c-src persisted in mature neuronal cells that were postmitotic, fully differentiated, and functional. pp60c-src immunoreactivity was localized within processes and cell bodies of ganglion neurons, processes of rods and cones, and in some but not all neurons of the inner nuclear layer. Protein kinase assays and Western transfer analyses identified the immunoreactive protein as pp60c-src, and confirmed that its expression occurs at the time the first neuronal cells in the retina differentiate. We conclude from these studies that pp60c-src is the product of a developmentally regulated gene that is more important in neuronal differentiation or function than cell proliferation.


[Positive effects of chenodeoxycholic acid (CDCA) on the biohumoral clinical aspect of cholesterin calculosis of the gallbladder].
The efficacy and possible sideeffects of chenodeoxycholic acid have been studied in 35 patients with biliary calculosis lithiasis. In 53% of the cases treated for six months or more partial or complete gallstone dissolution was observed. The action of this drug on hematic triglyceride level and on severity and frequency of the hypostenic dyspeptic symptoms and biliary colic is interesting from the viewpoint of new therapeutic prospects. Diarrhea has been the only relevant side-effect.


Quantitative multiregional blood flow measurements during cervical sympathetic stimulation.
The ethanol tissue sampling method for rCBF measurement was used to obtain information on the effects of cervical sympathetic stimulation in 8 cerebral structures in the non-anaesthetized rabbit. Sympathetic stimulation induced flow decreases of 12-29% according to structure, confirming the capability of this nerve to significantly reduce rCBF. Furthermore, a regional differentiation of cerebral structures into an 'anterior' group (mean decrease 22%) and a 'posterior' group (mean decrease 12%) with different reactivity to stimulation was established, thus confirming previous work in this laboratory with a local thermoclearance technique, and histochemical studies on sympathetic innervation to cerebral arteries and arterioles. These results provide strong evidence of the functional nature of the sympathetic nervous system in CBF regulation. The complementary nature of the ethanol technique (quantitative, multiregional measurement) and the local thermoclearance technique (continuous, semiquantitative measurements in 2-3 regions), and the absence of anaesthesia and significant trauma, means that combination of these two techniques offers considerable advantages in research on dynamic phenomena of the kind studied here.


Surgical and histological evidence of case reports showing Schwannomas in the nasal area.
Schwannomas are benign neurogenic neoplasms with an uncommon involvement of the nasal cavity and paranasal sinus, which usually appear as a painless formation. We report two cases of nasal schwannoma that was successfully treated by surgical excision with satisfactory functional outcomes. The aim of this study is to discuss the clinical assessment and imaging, (CT, MRI) differential diagnosis, histological examination, surgical approaches of this rarely encountered neoplasm in the sinus-nasal area. Case 1: a 53 years-old Caucasian male, hospitalized in the ENT Department with a 5-month progressive history of right nasal obstruction without epistaxis was diagnosed as a Schwannoma following clinical, histology and ENT endoscopy examination. Case 2: a 45 years-old Caucasian male with asymptomatic swelling arising 4 months before in the nasal tip area with progressive nasal deformity, diagnosed as a schwannoma and analyzed with MRI. Case 1: The patient had an uneventful post-operative course and a follow-up examination at 36 months showed no recurrence of the neoplasm with satisfactory functional result. Case 2: The patient had an uneventful post-operative course and a follow-up examination at 5 years showed no recurrence of the neoplasm and satisfactory aesthetic result. Schwannomas arising from sinonasal area are extremely rare, painless and with slow-growing evolution. The surgical option and histologic analysis are mandatory for a correct diagnosis.


A Laboratory Bioassay Method to Assess the Use of Toxic Bait on Anastrepha fraterculus (Weidemann 1830).
The lack of standardization of bioassays for the evaluation of toxic bait toxicity on the South American fruit fly, Anastrepha fraterculus (Weidemann 1830), has led to erroneous interpretations of assay results. The objective of this study was to develop a methodology for the standardization and validation of toxicological tests on A. fraterculus toxic bait using the Success™ 0.02CB formulation (80 mg L-1 of spinosad). Anastrepha fraterculus adults, obtained from larvae reared on an artificial diet, showed higher susceptibility (LT50 = 48.96 h) than adults from larvae reared on cattley guava (LT50 = 53.83 h) and mango fruit (LT50 = 53.55 h). Anastrepha fraterculus adults at the age of five (LT50 = 65.30 h), 15 (LT50 = 59.01 h), and 30 (LT50 = 55.53 h) days presented similar toxicity. The consumption of toxic bait (4.74 mg) increased at 15 days, a fact also observed with insects without food deprivation. In addition, the absence of a food source (artificial diet) with the toxic bait significantly reduced adult mortality time by 7 h (LT50 = 57.42 h). In relation to exposure time, adults exposed to toxic bait for 1 h reduced consumption by 25%; however, they showed the same susceptibility as insects exposed to 2 (LT50 = 55.72 h), 4 (LT50 = 57.64 h), and 8 h (LT50 = 57.76 h). However, with 24 h of food deprivation, they had a higher susceptibility (LT50 = 46.48 h). Five-day-old A. fraterculus adults fed an artificial diet before being deprived of food for 12 or 24 h, then exposed to toxic bait for 4 h in the absence of a food source, are considered optimum conditions to evaluate the toxicity of toxic bait.


Development of a deep learning method for improving diagnostic accuracy for uterine sarcoma cases.
Uterine sarcomas have very poor prognoses and are sometimes difficult to distinguish from uterine leiomyomas on preoperative examinations. Herein, we investigated whether deep neural network (DNN) models can improve the accuracy of preoperative MRI-based diagnosis in patients with uterine sarcomas. Fifteen sequences of MRI for patients (uterine sarcoma group: n = 63; uterine leiomyoma: n = 200) were used to train the models. Six radiologists (three specialists, three practitioners) interpreted the same images for validation. The most important individual sequences for diagnosis were axial T2-weighted imaging (T2WI), sagittal T2WI, and diffusion-weighted imaging. These sequences also represented the most accurate combination (accuracy: 91.3%), achieving diagnostic ability comparable to that of specialists (accuracy: 88.3%) and superior to that of practitioners (accuracy: 80.1%). Moreover, radiologists' diagnostic accuracy improved when provided with DNN results (specialists: 89.6%; practitioners: 92.3%). Our DNN models are valuable to improve diagnostic accuracy, especially in filling the gap of clinical skills between interpreters. This method can be a universal model for the use of deep learning in the diagnostic imaging of rare tumors.


From Human Pose Similarity Metric to 3D Human Pose Estimator: Temporal Propagating LSTM Networks.
Predicting a 3D pose directly from a monocular image is a challenging problem. Most pose estimation methods proposed in recent years have shown 'quantitatively' good results (below ∼ 50mm). However, these methods remain 'perceptually' flawed because their performance is only measured via a simple distance metric. Although this fact is well understood, the reliance on 'quantitative' information implies that the development of 3D pose estimation methods has been slowed down. To address this issue, we first propose a perceptual Pose SIMilarity (PSIM) metric, by assuming that human perception (HP) is highly adapted to extracting structural information from a given signal. Second, we present a perceptually robust 3D pose estimation framework: Temporal Propagating Long Short-Term Memory networks (TP-LSTMs). Toward this, we analyze the information-theory-based spatio-temporal posture correlations, including joint interdependency, temporal consistency, and HP. The experimental results clearly show that the proposed PSIM metric achieves a superior correlation with users' subjective opinions than conventional pose metrics. Furthermore, we demonstrate the significant quantitative and perceptual performance improvements of TP-LSTMs compared to existing state-of-the-art methods.


Early dose reduction/delay and the efficacy of liposomal irinotecan with fluorouracil and leucovorin in metastatic pancreatic ductal adenocarcinoma (mPDAC): A post hoc analysis of NAPOLI-1.
Chemotherapy dose modification to manage adverse events is commonplace in clinical practice. This exploratory analysis evaluates the impact of liposomal irinotecan dose modification on overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 clinical trial (NCT01494506). Analysis includes only patients enrolled under protocol version 2 who received at least the first 2 scheduled doses of study drug. Within the liposomal irinotecan +5 fluorouracil/leucovorin (5 FU/LV) arm, patients were grouped according to whether or not they had a dose modification within the first 6 weeks. Dose reduction was defined as any decrease from initial dose; dose delay was any dosing delay >3 days from target date. OS and PFS (Kaplan-Meier estimates) were compared within the liposomal irinotecan+5-FU/LV arm and between treatment arms. Unstratified hazard ratios (HRs) were calculated using Cox regression analysis. Of the 93 patients from the liposomal irinotecan+5 FU/LV arm included in the analysis, 53 experienced a dose modification (both delay and reduction, n = 30; delay only, n = 19; reduction only, n = 4). No apparent difference in median OS or PFS was observed between patients who did versus patients who did not have a dose modification (OS: 8.4 vs 6.7 months; HR, 0.89; PFS: 4.2 vs 3.1 months; HR, 0.74). An early dose reduction or delay of liposomal irinotecan+5-FU/LV in the first 6 weeks does not significantly impact OS or PFS compared to patients without dose modifications. This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes.


Positron emission tomographic studies of the cortical anatomy of single-word processing.
The use of positron emission tomography to measure regional changes in average blood flow during processing of individual auditory and visual words provides support for multiple, parallel routes between localized sensory-specific, phonological, articulatory and semantic-coding areas.


Origins of the cytolytic synapse.
Cytotoxic T lymphocytes (CTLs) kill virus-infected and tumour cells with remarkable specificity. Upon recognition, CTLs form a cytolytic immune synapse with their target cell, and marked reorganization of both the actin and the microtubule cytoskeletons brings the centrosome up to the plasma membrane to the point of T cell receptor signalling. Secretory granules move towards the centrosome and are delivered to this focal point of secretion. Such centrosomal docking at the plasma membrane also occurs during ciliogenesis; indeed, striking similarities exist between the cytolytic synapse and the primary cilium that throw light on the possible origins of immune synapses.


On the vicissitudes of Freud's early mothering. III: Freiberg, screen memories, and loss.
Utilizing clinical examples, I attempt to show that the memories Freud recalled on his return to his childhood home in adolescence screened the traumata he had suffered when he lost his Kinderfrau, then his playmates and the Freiberg countryside during his early childhood.


Clinical significance of changes in serum neuroglobin and HIF-1α concentrations during the early-phase of acute ischemic stroke.
Neuroglobin (NGB) has been described as a neuroprotective agent in cerebral ischemia, hypoxia inducible factor (HIF) has shown an important role in modulating hypoxic and ischemic injury, and therefore they have the potential to impact outcomes after acute ischemic stroke (AIS). Thus, we investigated early changes in the concentrations of serum NGB and HIF-1α after AIS and evaluated the relations of both NGB and HIF-1α to stroke severity and prognosis. We prospectively measured the serum concentrations of NGB and HIF-1α in 40 patients with AIS at 24, 48, 72, and 96h after stroke. Correlation combined with infarct size and National Institutes of Health Stroke Scale (NIHSS) score of the patients was analyzed. Receiver operating characteristic (ROC) curve was used to appraise their value in predicting the 90-day outcome after AIS. Serum NGB concentrations increased and peaked at 72h after AIS, whereas serum concentrations of HIF-1α increased for 48h. Peak serum NGB concentration correlated significantly with both infarct size (R2=0.484, p<0.001) and admission NIHSS score (R2=0.578, p<0.001), while serum HIF-1α concentration was only correlated to a patient's infarct size (R2=0.394, p<0.001). ROC curve analysis suggested that the serum NGB concentration had a significantly better predictive power for poor outcome. NGB level increased in serum after AIS accompanied by increases in serum HIF-1α, and was suggested as a predictor of stroke severity and poor prognosis.


Development of a new PCR assay to identify Brucella abortus biovars 5, 6 and 9 and the new subgroup 3b of biovar 3.
One hundred twenty-nine Brucella field strains isolated from cattle in Cantabria, Spain, from March 1999 to February 2003, were analysed by using the AMOS-ERY PCR assay and by Southern blot hybridisation with a probe from insertion sequence IS711. Most of the field isolates produced only the ery band in the AMOS-ERY assay and showed a hybridisation pattern identical to that exhibited by reference strains of biovars 5, 6 and 9 of Brucella abortus, but different from strain Tulya, belonging to biovar 3 of B. abortus. However, typing of these strains by standard methods demonstrated that they belonged to biovar 3 of B. abortus. These results indicated that B. abortus biovar 3 was not genetically homogeneous and at least could be divided in two. In one class, that we called biovar 3a, would be the Tulya strain, while the local field strains would belong to biovar 3b. Cloning and nucleotide sequencing of a DNA fragment containing an IS711 copy exclusive of the B. abortus field strains from biovar 3b and reference strains from biovars 5, 6 and 9, revealed the existence of a 5.4 kb deletion close to an IS711 copy. Based on these data, we designed a new primer, which together with the IS711 AMOS primer produced a PCR fragment of 1.7 kb only from the isolates of biovars 3b, 5, 6 and 9 of B. abortus. No amplification products were produced with these primers from strains of the rest of species and biovars of Brucella and from bacteria phylogenetically close to Brucella analysed in this work. Addition of this primer to the AMOS-ERY PCR primer cocktail allows the positive distinction of B. abortus biovars 3b, 5, 6 and 9 from the rest of Brucella species and biovars.


Purification of the pyocin S2 complex from Pseudomonas aeruginosa PAO1: analysis of DNase activity.
Pyocin S2 purified from mitomycin C-induced lysates of Pseudomonas aeruginosa strain PAO1 has been shown to consist of a complex of two proteins. Further analysis of the purified S2 complex revealed that the 74 kd S2 pyocin demonstrates DNase activity which can be blocked by S2-specific antisera. Chromosomal DNA from pyocin sensitive cells treated with the pyocin S2 complex in vitro did not show any degradation, suggesting that the 10 kd protein inhibits the DNase activity of the S2 protein. These results suggest an alternative mechanism for the toxicity associated with the S2 pyocin.


New treatments to reach functional cure: Virological approaches.
Current therapies of chronic hepatitis B (CHB) remain limited to pegylated-interferon-alpha (pegIFN-α) or any of the five approved nucleos(t)ide analogues (NA). If viral suppression can be achieved in the majority of patients with the high-barrier-to-resistance new-generation of NA, i.e. entecavir and tenofovir, HBsAg loss is achieved by PEG-IFN-α and/or NA in only 10% of patients, after a 5-year follow-up. Attempts to improve the response by administering two different NA or a combination of NA and PEG-IFN-α have not provided a dramatic increase in the rate of "functional cure". Because of this and the need of long-term NA administration, there is a renewed interest regarding the understanding of various steps of the HBV replication cycle, as well as specific virus-host cell interactions, in order to define new targets and develop novel drugs. This includes the direct inhibition of several HBV life cycle steps by either entry inhibitors, drugs targeting cccDNA, siRNA targeting viral transcripts, capsid assembly modulators, and approaches targeting the secretion of viral envelope proteins. The addition of one or several new drugs to current therapies should offer the prospect of a markedly improved response to treatments and an increased rate of functional cure. This should lead to a reduced risk of antiviral drug resistance, and to a decreased incidence of cirrhosis and hepatocellular carcinoma (HCC). In this chapter, we review investigational and early clinical efforts regarding the identification and characterization of antiviral targets that are being evaluated for the development of innovative DAA concepts for chronic HBV infections.


A new technique for intra-abdominal arteries revascularization via extra-anatomic bypass from the brachiocephalic artery with a videoscopic retrosternal tunnel.
Extra-anatomic revascularizations of intra-abdominal or lower limbs arteries, or both, are indicated (1) when the aorta is unsuitable for anatomic bypasses, (2) in patients unfit for aortic surgery, (3) for graft infections, and (4) for visceral debranching during hybrid treatment of a thoracoabdominal aneurysm. We describe a new extra-anatomic bypass from the brachiocephalic artery with video-guided retrosternal tunneling. We discuss the advantages and drawbacks of this technique.


Radiation-induced translocations in spermatogonial stem cells of Macaca fascicularis and Macaca mulatta.
3 adult monkeys, one Macaca fascicularis and two Macaca mulatta, were whole-body irradiated with 1 Gy gamma-rays (60 Co). Reciprocal translocations induced in spermatogonial stem cells were scored as translocation multivalents in primary spermatocytes from 7.5 to 27.5 months after exposure. The translocation yields ranged from 4.1% at the earliest to 1.8% at the latest sampling interval. No significant differences were observed in the responses of the individual animals. A decline in the translocation frequencies with time after treatment was found in all 3 animals. The present data are different from those reported for testicular X-irradiation of the rhesus monkey Macaca mulatta (van Buul, 1980; Lyon et al., 1976) in that the translocation yields are higher. They are consistent with the results reported for testicular gamma-irradiation of the crab-eating monkey Macaca fascicularis (Matsuda et al., 1984, 1985). In view of the present results it appears unlikely that a species difference exists within the genus Macaca in the sensitivity of spermatogonial stem cells to the induction of translocations by ionizing radiation.


A new Ca++ antagonist, Ro 11-1781, and its metabolites. Synthesis and physicochemical properties.
The alkylation of 2-(3,4-dimethoxyphenyl)-m-dithiane-1,1,3,3-tetraoxide (4) with N-(3-chloropropyl)-3,4-dimethoxy-N-methylphenethylamine (2) leads to N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine-1,1,3,3-tetraoxide (5) (Ro 11-1781). The corresponding hydrochloride (5a), a new Ca++ antagonist, induces in the anaesthetized dog a substantial increase in myocardial flow. The preparation of two metabolites of 5a are described.


Evidence that the adaptive response of human lymphocytes to ionizing radiation acts on lethal damage in nonaberrant cells.
In a previous study we found that a cytogenetic adaptive response could lead to increases in survival if there was a sufficient increase in nonaberrant cells (Shadley and Dai, 1992). Since the high challenge doses used produced mainly multiply aberrant cells, we suggested using challenge doses that gave mainly singly aberrant cells in order to improve detection of a survival adaptive response. To test this, human lymphocytes from 6 donors were exposed in the first G1 phase to 5 cGy of X-rays, followed by 100 cGy 6 h later. Nearly all of the aberrant cells bore only one chromosome aberration with this challenge dose, and in agreement with our proposal, survival adaptive responses were seen in 4 of 6 donors. A near 1:1 relationship between the % nonaberrant cells and % survival was found with 100 cGy, suggesting that the lymphocyte populations scored in the survival and aberration assays were representative of each other. However, the increase in nonaberrant cells was not sufficient to account for the increase in survival. Thus, a large fraction of the increase in survival was due to a decrease in lethal damage in cytologically nonaberrant cells. Such damage could range from sub-microscopic lesions, to larger alterations not visible in Giemsa-stained cells. In conjunction with adaptive response studies of others, these results intimate that the adaptive response affects damage at different levels of chromosomal hierarchy (i.e. from the chromosome to DNA). The process(es) responsible for the effects observed in this study may act on lethal, rather than mutagenic lesions.


Myoglobin recombination at low temperature. Two phases revealed by Fourier transform infrared spectroscopy.
The low-temperature recombination of CO with myoglobin was studied using Fourier transform infrared spectroscopy. The bound state of carbon monoxide myoglobin has two distinct conformers observed at 1926 and 1945 cm-1 with an intensity ratio of 1 to 8. The recombination of these bands after complete photolysis at 10 K followed by a temperature jump shows distinct kinetics for the two bands. Although both bands apparently follow the nonexponential kinetics originally described by Frauenfelder and co-workers (Austin, R., Beeson, K., Eisenstein, L., Frauenfelder, H., and Gunsalus, I. (1975) Biochemistry 14, 5355-5373), the 1926 cm-1 band does not appear appreciably below 70 K. In fact, after 20 min of recombination at 70 K the 1945 cm-1 band is fully recovered, while no detectable amount of the 1926 cm-1 band is present. This is the first association of a spectroscopic marker of protein substructure with reaction kinetics.


Open exchange as a model for continuing education.
The Global Nursing Exchange is a unique, annual opportunity for a select group of nurses to confer with each other and learn in an unstructured, nonrestrictive forum for free uncensored exchange of ideas. It is an unusual "conference" in that both the structure and process have been designed to encourage spontaneity, creativity, and group sharing. Relaxation and work comingle. Networking, dialog, and inclusiveness are operating themes at all times. Started in 1988 by 9 nurses with a mix of backgrounds and experience, the Global Nursing Exchange has expanded to include international participants. In 2003, over 60 nurses joined in celebrating the 15th year of this group gathering. Examples of outcomes that have resulted from this unique "conferencing" experience are described.


Children of divorce. Counseling guidelines for the primary care physician.
As the divorce rate climbs, more and more children are affected by divorce. For some of these children, the personal losses they suffer are too great to overcome. Young children are particularly vulnerable to feelings of guilt, shame, inferiority, and distrust, which may lead to more serious problems later in life. Dr Price and colleagues offer suggestions to primary care physicians on counseling children of divorce and their parents, with emphasis on a holistic, empathic approach to therapy.


Enhanced production of total flavones and exopolysaccharides viaVitreoscilla hemoglobin biosynthesis in Phellinus igniarius.
The Vitreoscilla hemoglobin gene (vgb) was expressed by chromosomal integration in Phellinus igniarius to alleviate oxygen limitation and improve metabolites yields during submerged fermentation. Firstly, an expression vector containing vgb was constructed, and transformed into protoplast from P. igniarius. Carbon monoxide difference spectrum absorbance assay showed that vgb was successfully expressed and had biological activity. In shake flasks, the vgb expression enhanced dry mycelial weight 1.32-fold and increased total flavones and exopolysaccharides production 1.78- and 1.33-fold, respectively. When P. igniarius (vgb+) and P. igniarius (vgb-) strains were cultured in bioreactor, Vitreoscilla hemoglobin in P. igniarius promoted the mycelia growth from 5.40 to 10.90 g/L and stimulated total flavones and exopolysaccharides synthesis; their maximum productions reached to 11.43 and 1.33 g/L. Furthermore, compared to P. igniarius (vgb-), the acetic acid accumulation in P. igniarius (vgb+) cultures decreased from 1.54 and 1.78 to 1.19 and 1.27 g/L in flask and bioreactor, respectively.


Electron transfer kinetics at a biotin/avidin patterned glassy carbon electrode.
Photolithographic techniques using a laser interference pattern were used to attach photobiotin to micron-sized stripes on the surface of a carbon electrode. Fluorophore-tagged avidin was attached to this spatially-patterned biotin with essentially no loss in spatial resolution. The kinetics of the glassy carbon surface were examined to see if electron transfer sites could indeed be segregated from the attachment sites of photobiotin-immobilized avidin. The ECL of luminol and SECM were used to verify the segregation between underivatized sites (which exhibit normal electron transfer kinetics) and extensively derivatized biotin/avidin surfaces (which presumably exhibit slow electron transfer kinetics). Both techniques were found to be capable of differentiating the protein-covered surface from bare carbon with sufficient resolution to tell whether a significant portion of the carbon surface is still active and available to detect the product of an enzyme generated analyte. These results indicate that extensive biotin/avidin derivatization of the surface does decrease the electron transfer rate of a carbon electrode, and that the photolithographic approach was able to modify specific sections of the electrode surface, while leaving other regions untouched and available for facile electron transfer. This leads to a more general protocol for the construction of enzyme-based biosensors which utilize diffusable mediators.


Lead (Pb)-induced biochemical and ultrastructural changes in wheat (Triticum aestivum) roots.
The focus of the present study was to explore lead (Pb)-induced metabolic alterations vis-à-vis ultrastructural changes in wheat roots to establish Pb toxicity syndrome at a structural level. Pb (50-500 μM) enhanced malondialdehyde (an indicator of lipid peroxidation) and hydrogen peroxide content, and electrolyte leakage, thereby suggesting reactive oxygen species-induced disruption of membrane integrity and oxidative stress in wheat roots. The activities of superoxide dismutases and catalases enhanced upon Pb exposure, whereas those of ascorbate and guaiacol peroxidases declined. Pb-induced metabolic disruption was manifested in significant alterations in wheat root ultrastructure as analyzed by transmission electron microscopy. Pb caused thinning of cell wall (at 50 μM), formation of amoeboid protrusions and folds and intercellular spaces, and appearance of lesions and nicks/breaks (at ≥ 250 μM Pb). Pb was deposited along the cell walls as dark precipitates. At ≤ 250 μM Pb, the number of mitochondria increased significantly, whereas structural damage in terms of change of shape and disintegration was observed at ≥ 250 μM Pb. Pb reduced the size of nucleoli and induced puff formation (at 250 μM), resulting in complete disintegration/disappearance of nucleolus at 500 μM. The study concludes that Pb inhibited wheat root growth involving an ROS-mediated oxidative damage vis-à-vis the ultrastructural alterations in cell membrane and disruption of mitochondrial and nuclear integrity.


Gestational diabetes: A link between OGTT, maternal-fetal outcomes and maternal glucose tolerance after childbirth.
The relationship among distribution of pathological values at the Oral Glucose Tolerance Test (OGTT), metabolic risk factors and pregnancy outcomes in women with Gestational Diabetes (GDM), has not been clearly identified. We retrospectively compared metabolic and therapeutic parameters, maternal-fetal outcomes and post-partum OGTTs, with respect to the number and distribution of altered values of diagnostic OGTT in pregnancy. Secondly, we assessed whether insulin therapy predictive factors were identifiable. This analysis included 602 pregnant women with GDM, followed in Diabetes and Pregnancy Unit of Perugia Hospital from diagnosis to childbirth. All women were diagnosed diabetic upon 75g OGTT, according IADPSG criteria. Women were divided into 3 groups, respect to distribution of diagnostic blood glucose (BG) values at OGTT: Group 1: only fasting BG (OGTT0h); Group 2: 1 and/or 2h (OGTT1-2h); Group 3: both fasting and 1 h and/or 2h (OGTT0+1-2h) BG. Pregnant women with fasting hyperglycemia at OGTT (Groups 1 and 3) had similar metabolic characteristics (weight, prevalence of obesity, gestational weight gain, HbA1c), a greater need for insulin therapy, and a higher risk of impaired glucose tolerance persistence after childbirth, as compared to Group 2. No significant differences were observed in terms of maternal and neonatal outcomes (p > 0.05), except for a greater prevalence of caesarean sections in Group 3. The metabolic characteristics of GDM women are mirrored by OGTT values at diagnosis, but are not associated with adverse pregnancy outcomes. Intensive management and a tailored treatment of GDM improve maternal-neonatal outcomes, regardless of diagnostic values distribution and pre-gestational metabolic characteristics.


Transport of D-glucose across cultured stratified cell layer of human oral mucosal cells.
To evaluate the role of several specialized mechanisms for D-glucose transport in human oral mucosa, a cultured stratified cell layer derived from human oral mucosa was employed. Although this culture system has been used for reconstructive surgery, we, for the first time, tried to apply this system to the evaluation of nutrients and drug transport. Cell number and transepithelial electrical resistance (TEER) reached steady state 7-8 days after inoculation on the Transwell and TEER values at steady state were 130-140 ohm cm2, which was higher or lower than that of small intestine or Caco-2 cells, respectively. The transport studies were carried out using the cultured epithelium on the Transwell. The transport of D-glucose across the cultured stratified layer of oral epithelial cells was much more extensive than L-glucose, and was inhibited by 2-deoxy-D-glucose, a substrate of facilitative glucose transporters, and 2-methyl-D-glucoside, a specific substrate of a Na/glucose cotransporter (SGLT1). The results indicate that the sugar transporters function not only to take up D-glucose by the epithelial cells but also to transport the sugar across the stratified epithelial layer.


Vγ2+ γδ T Cells in the Presence of Anti-CD40L Control Surgical Inflammation and Promote Skin Allograft Survival.
γδ T cells represent a small fraction of total T cells in the body and do not use classical polymorphic major histocompatibility complex‒loaded peptides for mounting an immune response. The importance of the effector and regulatory function of γδ T cells in infections, autoimmunity, and tumor models are well characterized. In this study, we investigated the mechanistic role of γδ T cells in costimulatory blockade‒induced transplantation tolerance. We used donor-specific transfusion and anti-CD40L treatment in C57BL/6 mice to induce tolerance to BALB/c skin allografts. We show that depletion of γδ T cells, specifically Vγ2+ γδ T cells, led to the acute rejection of skin allografts despite tolerogen treatment. Tolerogen treatment promoted CD39+Vγ2+ γδ T cells and suppressed IFN-γ‒producing Vγ2+ γδ T cells in the spleen and allografts. Vγ2+ γδ T cells isolated from tolerized mice suppress T helper type 1 cell differentiation. Adoptive transfer of these regulatory Vγ2+ γδ T cells prolonged the survival of allografts in an untreated recipient and Tcrδ‒/‒ mice. Together, our data show that the Vγ2+ subset promotes costimulatory blockade‒induced survival of skin allografts and that tolerogenic Vγ2+ T cells can be used as an adoptive cellular therapy to promote the survival of allografts.


Transesophageal atrial pacing (TAP) for sinus bradycardia during coronary artery bypass grafting: comparison of TAP to intermittent bolus gallamine.
To assess the relative efficacy of a pacing esophageal stethoscope and intermittent boluses (40 mg) of gallamine in correcting sinus bradycardia (SB) during coronary artery surgery. The study was prospective, randomized, and controlled. A community hospital. Fifty patients scheduled for elective coronary artery surgery. The patients were randomly allocated to receive treatment for an SB (less than 60 BPM) with either transesophageal atrial pacing (TAP) or gallamine. Heart rate, blood pressure, and systemic hemodynamics were measured. The electrocardiogram was monitored for rate, rhythm, and conduction abnormalities. Twenty-four of the 25 TAP patients could be paced at a rate of 70 BPM after SB. Cardiac index increased from 1.90 to 2.56 L/min/m2. In the gallamine group, heart rate was increased from 50 to 66 BPM, but cardiac index only increased to 2.2 L/min/m2, and 2 patients developed nodal rhythms. Eight of these patients had peak heart rates over 80 BPM, and two were over 90 BPM. The ability to reliably and precisely control heart rate was superior with TAP compared with intermittent bolus dosing with gallamine.


Circulating dengue virus serotypes and vertical transmission in Aedes larvae during outbreak and inter-outbreak seasons in a high dengue risk area of Sri Lanka.
Spatial and temporal changes in the dengue incidence are associated with multiple factors, such as climate, immunity among a population against dengue viruses (DENV), circulating DENV serotypes and vertical transmission (VT) of DENV in an area at a given time. The level of VT in a specific location has epidemiological implications in terms of viral maintenance in vectors. Identification of the circulating DENV serotypes in both patients and Aedes mosquito larvae in an area may be useful for the early detection of outbreaks. We report here the results of a prospective descriptive study that was conducted to detect the levels of VT in Aedes mosquito larvae and circulating DENV serotypes in patients and Aedes mosquito larvae from December 2015 to March 2017 in an area of Sri Lanka at high risk for dengue. A total of 200 patients with clinically suspected dengue who had been admitted to a tertiary care hospital during a dengue outbreak (3 study periods: December 2015-January 2016, June-August 2016, December 2016-January 2017) and in the inter-outbreak periods (February-May 2016 and September-November 2016) were investigated. Blood samples were drawn from the study participants to test for DENV. The houses of the study participants were visited within 7 days of admission to the hospital, and Aedes larvae were also collected within a radius of 400 m from the houses. The larvae were separately identified to species and then pooled according to each patient's identification number. Patients' sera and the Aedes larvae were tested to identify the infecting DENV serotypes using a reverse transcription PCR (RT-PCR) method. Levels of VT in Aedes mosquito larvae were also identified. All four DENV serotypes (DENV-1 to -4) were identified in the study area. In the early part of the study (December 2015-February 2016), DENV-3 was predominant and from April 2016 to March 2017, DENV-2 became the most predominant type. Four cases of DENV co-infections were noted during the study period in patients. Interestingly, all four DENV serotypes were detected in Aedes albopictus larvae, which was the prominent immature vectorial form identified throughout the study period in the area, showing 9.8% VT of DENV. With the exception of DENV-4, the other three DENV serotypes were identified in Aedes aegypti larvae with a VT of 8.1%. Comparatively high rates of VT of DENV was detected in Ae. albopictus and Ae. aegypti larvae. A shift in the predominant DENV serotype with simultaneous circulation of all four DENV serotypes was identified in the study area from December 2015 to March 2017.


ZnHCF@PB nanoparticles with reduced bandgap as a promising photocatalyst for the degradation of conventional and emerging water contaminants.
The photocatalytic degradation of conventional and emerging pollutants (i.e., methyl, ethyl, and butyl parabens) was investigated under light irradiation with 315-1050 nm wavelength using core-shell zinc doped hexacyanoferrate@Prussian blue nanoparticles. Different synthesis parameters including precursors loading, drying temperature and different metal ions precursors were studied. The ten different composite systems obtained, were investigated for the photodegradation of methylene blue in deionized water. The optimal performance photocatalyst (20 mg/L) photodegrade 94% of 10 ppm methylene blue within 24 min. The optimized sample was further used for the photodegradation of methylene blue in municipal wastewater matrix; it completely degraded the methylene blue after 51 min. Finally, the developed nanoparticles were investigated for the photodegradation of parabens. The chemical oxygen demand showed 30% of parabens was degraded in the municipal wastewater matrix. The results of this research show that ZnHCF@PB nanoparticles could be used for the effective photocatalytic remediation of conventional and emerging pollutants, i.e., parabens. STATEMENT OF ENVIRONMENTAL IMPLICATION: Through this study, it is anticipated that ZnO-derived ZnHCF@PB NPs can achieve a bandgap of 1.11 eV, which is much lower than that of ZnO NPs (3.15 eV). Interestingly, ZnHCF@PB NPs were efficiently used for the degradation of conventional (i.e., dyes) and emerging contaminants (i.e., parabens) in deionized water and municipal wastewater matrices to mimic industrial wastewater.


Progressive conus medullaris lesions are suggestive of intravascular large B-cell lymphoma.
Spinal cord lesions are observed in 40% of all central nervous system lesions in intravascular large B-cell lymphoma (IVLBCL). However, because IVLBCL is a very rare disease, its clinical features are not well defined, which may delay appropriate diagnosis and treatment, whilst the acute to subacute course of brain lesions in patients with IVLBCL is well established. Therefore, this study aimed to clarify the clinical features of spinal cord lesions in patients with IVLBCL. The medical records of patients with IVLBCL admitted to our hospital between 2010 and 2020 were searched. The inclusion criteria were preceding neurological symptoms without non-neurological symptoms and pathologically confirmed IVLBCL in various organs. Clinical features of spinal cord involvement in patients with IVLBCL were assessed and distinguished from those of brain involvement. Sixteen consecutive patients with IVLBCL were divided into two groups: six patients with spinal involvement (spinal cord type) and 10 patients with brain involvement (brain type). In the spinal cord type, four patients had chronic progression and two had subacute progression. Acute progression (0% vs. 80.0%) and sudden onset (0% vs. 50.0%) occurred significantly less frequently in the spinal cord than in the brain. All spinal cord lesions involved the conus medullaris. Spinal cord involvement in IVLBCL has a predominantly chronic progressive course that is exclusive to brain involvement. Conus medullaris lesions are suggestive of IVLBCL and are useful for early and accurate diagnosis and treatment.


Extracellular vesicles derived from mesenchymal stem cells alleviate neuroinflammation and mechanical allodynia in interstitial cystitis rats by inhibiting NLRP3 inflammasome activation.
Neuroinflammation in spinal dorsal horn (SDH) plays an important role in the pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) exert potent anti-inflammatory activities in the treatment of various diseases. This study aimed to determine the therapeutic effects of MSC-EVs on IC and furtherly investigate the potential mechanism to attenuate neuroinflammation. Female IC rat model was established by intraperitoneal injection of cyclophosphamide (50 mg/kg, every 3 days for 3 doses). Inhibition of NLRP3 inflammasome was performed by intraperitoneal injection of MCC950 (10 mg/kg). MSC-EVs were isolated from the culture supernatants of human umbilical cord derived MSCs using ultracentrifugation, and then injected intrathecally into IC rats (20 μg in 10 μl PBS, every other day for 3 doses). Suprapubic mechanical allodynia was assessed using up-down method with von Frey filaments, and micturition frequency was examined by urodynamics. The expression of NLRP3 inflammasome components (NLRP3 and Caspase-1), glial cell markers (IBA-1 and GFAP), proinflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-18) and TLR4/NF-κB signal pathway (TLR4, p65 NK-κB and phospho-p65 NK-κB) in L6-S1 SDH was measured by Western blot analysis. The cellular localization of NLRP3 in SDH was detected using immunofluorescence co-staining. NLRP3 inflammasome was activated in neurons in SDH of IC rats. NLRP3 inflammasome activation contributed to activation of glial cells and process of spinal neuroinflammation in IC rats, and was related to suprapubic mechanical allodynia and frequent micturition. Intrathecal injection of MSC-EVs alleviated suprapubic mechanical allodynia and frequent micturition in IC rats, restrained activation of glial cells and attenuated neuroinflammation in SDH. In addition, MSC-EV treatment significantly inhibited activation of both NLRP3 inflammasomes and TLR4/NF-κB signal pathway. NLRP3 inflammasome activation is involved in the neuroinflammation of IC. Intrathecal injection of MSC-EVs alleviates neuroinflammation and mechanical allodynia in IC by inhibiting the activation of NLRP3 inflammasome, and TLR4/NF-κB signal pathway may be the potential regulatory target.


Strongly sexually dimorphic forelegs are not more condition-dependent than less dimorphic traits in Drosophila prolongata.
Directional sexual selection drives the evolution of traits that are most closely linked to reproductive success, giving rise to trait exaggeration and sexual dimorphism. Exaggerated structures are often costly and, therefore, thought to be expressed in a condition-dependent manner. Sexual selection theory thus predicts a direct link between directional sexual selection, sexual dimorphism, and sex-specific condition dependence. However, only a handful of studies investigate the relationship between sexual dimorphism and condition dependence. Using 21 genetic lines of Drosophila prolongata, we here compared the degree of sexual dimorphism and sex-specific condition dependence, measured as allometric slopes, in sexually selected and non-sexual traits. Our data revealed male-biased sexual dimorphism in all traits examined, most prominently in the sexually selected forelegs. However, there was no relationship between the degree of sex-specific condition dependence and sexual dimorphism across traits and genetic lines. Our results contradict theoretical predictions and highlight the importance of understanding the role of exaggerated traits in the context of both sexual and natural selection. The online version contains supplementary material available at 10.1007/s10682-022-10226-0.


Detailed analysis of an amplified region at chromosome 11q13 in malignant tumors.
We have examined the amplification unit at chromosome band 11q13 in 12 primary tumors and one cancer cell line (A431) with 15 DNA markers. The amplified region and size varied from one tumor to another; the smallest amplicon was estimated to be 700 kb long and the largest was 4.5 Mb long at maximum, on the basis of a physical map. Furthermore, the DNA amplified in tumors was not always continuous, because in three cases one locus within the amplicon was not amplified. The amplified region common to all 13 cancers consisted of 500 kb of DNA which incorporated eight defined loci (BCL-1, cCI11-524, cCI11-283, cCI11-234, HBI-1, cCI11-454, HSTF1, and INT2). As two of them, cCI11-524 and cCI11-454, were found to contain DNA sequences conserved in other species, one or both of these loci might encode the gene(s) that may be associated with progression of these tumors.


Aortic valve regurgitation following transaortic septal myectomy for obstructive hypertrophic cardiomyopathy: Incidence and influence on late outcomes.
In this study, we describe the incidence, sites of valve injury, and the influence of aortic valve regurgitation (AR) on outcomes of septal myectomy for obstructive hypertrophic cardiomyopathy. We analyzed patients who underwent transaortic septal myectomy for obstructive hypertrophic cardiomyopathy from 2001 to 2022. The primary study end point was incidence of procedure-related AR, defined as the need for an unplanned aortic valve (AV) procedure or new-onset moderate AR on early postoperative echocardiography. There were 2807 patients who underwent transaortic septal myectomy for hypertrophic cardiomyopathy and had pre- and postoperative transthoracic echocardiograms. Procedure-related AR was observed in 55 (2%) patients; 27 (1%) required unplanned AV procedures at the time of myectomy, and 29 (1%) additional patients developed moderate AR postoperatively. During follow-up, 9 total patients underwent late AV reoperation, 1 patient who developed new moderate AR postoperatively required late AVR due to severe calcific AS, and none of the patients who had unplanned AV procedures required late reoperation. The overall cumulative incidence of AV reoperation at 10 and 15 years was 1% and 5%. The predicted probability of moderate or severe AR at 5 and 10 years was 1.4% and 1.8%, respectively. There was no difference in survival comparing patients with or without early postoperative mild or worse AR (P = .69). Procedure-related AR was observed in 2% of patients undergoing transaortic septal myectomy, and unplanned AV procedures were necessary for half of these patients. Intraoperative identification and valve repair mitigate the impact of cusp injury on late reintervention and survival.


Nitrogen dynamics in Posidonia oceanica cuttings: implications for transplantation experiments.
A (15)N tracer study was performed during an experimental transplantation trial of natural Posidonia oceanica cuttings. The experiment was done in situ at 17 m depth in the Revellata Bay (Calvi, NW Corsica, France). Despite high survival rates of transplants (>90%) after one year, the weight and the N content of transplants are significantly lower than those of reference plants. In absence of roots, the transplants are not able to meet their N requirement, because leaf uptake is insufficient to replenish the N lost during the natural leaf decay. This could constitute a major cause of long-term failure for transplantation experiments or natural re-colonisation processes. The increase of the (15)N content in the roots shows that the plant re-allocates the nitrogen of one organ (i.e. leaves, rhizomes) to ensure the growth of another (i.e. roots).


[Clinical course, electrophysiologic monitoring and neuroradiologic findings in acute basilar artery thrombosis and local fibrinolytic therapy].
The development of new catheter materials and techniques has made it possible to perform local intraarterial fibrinolysis in the region of the basilar artery in case of thrombotic arterial occlusions. We present the case of a 27-year old patient suffering from thrombosis of the basilar artery in whom local fibrinolysis was performed. The clinical course is demonstrated in respect to imaging methods (angiography, CT and MRT) and electrophysiological monitoring.


Maintained activity, excitation and inhibition of lateral geniculate neurons after monocular deafferentation in the adult cat.
Monocular deafferentation of the lateral geniculate nucleus (LGN) was accomplished by photocoagulation of the retinal vessels and the optic disc of one eye. Single cells with normal excitatory innervation from the intact eye (N-cells) and deafferented (D-) cells were recorded extracellularly with glass micropipettes from layers A and A1 of the LGN 10 days and 10 weeks after visual deafferentation. The maintained activity of D-cells was severely reduced after 10 days but had recovered significantly after 10 weeks. Different interspike interval distributions indicated a change in the main input source for the reactivated cells after 10 weeks. Stimulation of the intact retina with diffuse, high-intensity light flashes revealed missing or very small responses in the acutely deafferented cells. A still weak influence of the non-dominant eye on the deafferented cells after 10 days developed after 10 weeks into a biphasic response with an initial inhibitory period followed by a post-inhibitory exciation. Electrical stimulation of the optic chiasm revealed an increased inhibition during chronic deafferentation. Excitation following this inhibitory period was rare after 10 days but occurred frequently after 10 weeks. An enhanced excitability following stimulation of the visual cortex and the mesencephalic reticular formation was also observed after 10 weeks of deafferentation. An increased efficiency of all remaining inputs to the visually deafferented cells is concluded from the augmented inhibition and non-retinal excitation.


Itch in recessive dystrophic epidermolysis bullosa: findings of PEBLES, a prospective register study.
Itch is common and distressing in epidermolysis bullosa (EB) but has not previously been studied in depth in different recessive dystrophic EB (RDEB) subtypes. As part of a prospective register study of the natural history of RDEB we explored features of itch, medications used, and correlation with disease severity and quality of life. Fifty individuals with RDEB aged 8 years and above completed the Leuven Itch Scale (LIS) (total 243 reviews over a 7-year period). Data included itch frequency, severity, duration, distress, circumstances, consequences, itch surface area and medications for itch. The iscorEB disease severity score and the validated EB quality of life tool, QOLEB, were compared to LIS domains and analysed by RDEB subtype. Itch was frequent, present in the preceding month in 93% of reviews. Itch severity and distress were significantly greater in severe (RDEB-S) and pruriginosa (RDEB-Pru) subtypes compared to intermediate RDEB (RDEB-I). Itch medications were reported in just over half of reviews including emollients, topical corticosteroids and antihistamines; the proportion of participants not using medication despite frequent pruritus suggests limited efficacy. In inversa RDEB (RDEB-Inv) and RDEB-I, LIS domains correlated with iscorEB and QOLEB. In contrast to previous studies, correlations were lacking in RDEB-S suggesting that global disease burden relatively reduces the contribution of itch. This comprehensive study of RDEB-associated itch highlights differences between RDEB subtypes, suggests an unmet need for effective treatments and could serve as control data for future clinical trials incorporating itch as an endpoint.


Minor physical anomalies may be related to treatment resistance in patients with schizophrenia.
This study investigates the relationship between minor physical anomalies (MPA) and treatment resistance in schizophrenia (TRS). We evaluated 137 patients and 100 healthy controls by using a modified Waldrup MPA scale. Thirteen MPA items were found more frequently in the schizophrenia group than in the controls. The total MPA score was higher in TRS, and MPAs in the eye and mouth regions were more frequent in TRS (n = 57) than in non-TRS. Total MPA score was correlated to Brief Psychiatric Rating Scale-Expanded (BPRS-E) total and BPRS-positive scores in TRS. Our findings suggest that MPA might contribute to treatment resistance in schizophrenia.


Orthopedic correction of musculoskeletal deformity in muscular dystrophy.
Correction of deformity and maintenance of the upright posture have increased self-reliant skills, thus significantly enhancing the quality of life for the child with muscular dystrophy. In addition, such techniques offer a method of prolonging independent ambulation and, in so doing, forestall confinement to a wheelchair or bed with its inevitable downhill course. Surgery and bracing, accurately indicated and properly timed, play an important role in the total rehabilitation of the patient with muscular dystrophy.


Anticoagulation in pregnancy and neuraxial blocks.
The peripartum management of the anticoagulated parturient represents a significant clinical challenge to both the obstetrician and the anesthesiologist. This review discusses the causes of thrombosis in the pregnant population, the anticoagulants used for prophylaxis, and treatment of these disorders, along with recommendations for neuraxial blockade in parturients who receive peripartum anticoagulation.


Anaesthetic implications of long term diabetic complications.
A case history in which a patient suffering from long-term diabetes mellitus underwent vascular surgery of a lower extremity is presented. Anaesthesia was commenced with an epidural anaesthesia, but due to insufficient analgesia combined with a high thoracal block general anaesthesia was added. The course was complicated because of cardiomyopathy, autonomic neuropathy, difficult laryngoscopy, aspiration of gastric content, and acute renal failure. Anaesthetic implications of long-term diabetes mellitus are discussed.


Analysis of tamoxifen and 4-hydroxytamoxifen levels in immature rat uterine cytoplasm and KCl-nuclear extracts by gas chromatography-mass spectrometry (GC-MS) using selected ion monitoring (SIM).
A GC-MS (SIM) method has been developed which allows the measurement of tamoxifen and its metabolites in uterine cytosol and 0.5 M KCl-extracts of uterine nuclei from groups of immature rats. The method was shown to be specific, precise and accurate. Using this procedure tamoxifen and 4-hydroxytamoxifen were tentatively identified and measured in uterine extracts after tamoxifen administration. When tamoxifen and 4-hydroxytamoxifen levels in uterine cytosol and 0.5 M KCl nuclear extracts were compared a relative enrichment in the nuclear fraction of 4-hydroxytamoxifen (relative to tamoxifen) was consistently seen. These observations are supportive of a role for 4-hydroxytamoxifen in mediating the antiestrogenic actions of tamoxifen in the immature rat uterus. In some of the uterine cytosolic fractions desmethyltamoxifen and metabolite Y could also be detected.


Ciliated muconodular papillary tumor of the lung: a case report and literature review.
Ciliated muconodular papillary tumor (CMPT) of the lung is characterized as a peripheral low-grade malignant tumor with ciliated columnar cells and goblet cells with basaloid cell proliferation. Herein, we report on a case of CMPT with a radiologically abnormal shadow which was reminiscent of adenocarcinoma. The patient underwent right S6 + S8a segmentectomy because an intraoperative biopsy suggested CMPT, the malignancy of which was difficult to distinguish; however, the tumor was small and located in the peripheral lung. Many details of this tumor remain unclear, as CMPT is a rare tumor with few reports. CMPT has therefore not yet been classified by the WHO. In this report, we will consider the characteristics of CMPT and treatment based on our case and previous case reports.


Whole tumour perfusion of peripheral lung carcinoma: evaluation with first-pass CT perfusion imaging at 64-detector row CT.
To prospectively assess the feasibility of a whole-tumour perfusion technique using 64-detector row computed tomography (CT) and to analyse the variation of CT perfusion parameters in different histological types, sizes, and metastases in patients with peripheral lung carcinoma. Ninety-seven pathologically proved peripheral lung carcinomas (less than 5 cm in largest diameter) underwent dynamic contrast-enhanced CT using a 64-detector row CT machine. Small amounts of iodinated contrast medium with a sharp bolus profile (50 ml, 6-7 ml/s), and 12 repeated fast acquisitions encompassing the entire tumour lesion were adopted to quantify perfusion of the whole-tumour during first-pass of contrast medium. Four kinetic parameters, including perfusion, peak enhancement intensity (PEI), time to peak (TTP), and blood volume (BV), were measured and statistically compared among different histological types, sizes, and metastases. Mean values for perfusion, PEI, TTP, and BV of the 97 lung carcinomas were 57.5+/-45.4 ml/min/ml (range 5.9-243 ml/min/ml), 53.4+/-40.6 HU (range 10.3-234.4 HU), 34+/-11s (range 11-60s), and 30.1+/-21.7 ml/100g (range 3.9-113.4 ml/100g), respectively. No statistical differences were found between the histological types regarding the perfusion parameters (p>0.05). Perfusion, PEI, and BV of stage T2 tumours were significantly lower than those of stage T1 tumours (all p < 0.05), whereas no statistically significant differences was found between other stages of tumours (all p>0.05). Perfusion of the tumours with distant metastasis was significantly higher than that of the tumours without distant metastasis (p<0.05), but there was no statistically significant difference between nodal metastasis positive and negative groups (p>0.05). The present study of first-pass perfusion imaging using 64-detector row CT could provide a feasible method for assessment of whole-tumour perfusion. CT perfusion parameters of peripheral lung carcinoma may be associated with tumour size and distant metastasis.


Reproductive variation and the egg size-clutch size trade-off within and among populations of painted turtles (Chrysemys picta bellii).
Interpopulation variation in egg size, clutch size and clutch mass was studied 3 years in four populations of painted turtles (Chrysemys picta bellii) from western Nebraska. Body size varied among all populations and was larger in two large (56-110 ha), sandhills lake populations than in two populations in smaller habitats (1.5-3.6 ha) of the Platte River floodplain. Reproductive parameters (egg mass, clutch mass, and clutch size) generally increased with maternal body size within populations. Clutch wet and dry mass varied among populations but largely as a function of maternal body size. Clutch size was largest in the sandhills lake populations, both absolutely and relative to maternal body size. Egg mass was smallest in the sandhills lakes and varied annually in one population. Over all populations, an egg sizeclutch size trade-off was detected (a negative correlation between egg mass and clutch size) after statistically removing maternal body size effects. Egg wet mass and clutch size were negatively correlated over all years within the sandhills populations and in some years in three populations. Although egg size varied within populations, egg size and clutch size covaried as expected by optimal offspring size models. Thus, patterns of egg size variation should be interpreted in the context of proximate or adaptive maternal body size and temporal effects. Comparisons among populations suggest that large egg size relative to maternal body size may occur when juvenile growth potential is poor and mean maternal body size is small.


Enantioselective Cytotoxicity of Chiral Diphosphine Ruthenium(II) Complexes Against Cancer Cells.
The chiral cationic complex [Ru(η1 -OAc)(CO)((R,R)-Skewphos)(phen)]OAc (2R ), isolated from reaction of [Ru(η1 -OAc)(η2 -OAc)(R,R)-Skewphos)(CO)] (1R ) with phen, reacts with NaOPiv and KSAc affording [RuX(CO)((R,R)-Skewphos)(phen)]Y (X=Y=OPiv 3R ; X=SAc, Y=OAc 4R ). The corresponding enantiomers 2S -4S have been obtained from 1S containing (S,S)-Skewphos. Reaction of 2R and 2S with (S)-cysteine and NaPF6 at pH=9 gives the diastereoisomers [Ru((S)-Cys)(CO)(PP)(phen)]PF6 (PP=(R,R)-Skewphos 2R -Cys; (S,S)-Skewphos 2S -Cys). The DFT energetic profile for 2R with (S)-cysteine in H2 O indicates that aquo and hydroxo species are involved in formation of 2R -Cys. The stability of the ruthenium complexes in 0.9 % w/v NaCl solution, PBS and complete DMEM medium, as well as their n-octanol/water partition coefficient (logP), have been evaluated. The chiral complexes show high cytotoxic activity against SW1736, 8505 C, HCT-116 and A549 cell lines with EC50 values of 2.8-0.04 μM. The (R,R)-Skewphos derivatives show higher cytotoxicity compared to their enantiomers, 4R (EC50 =0.04 μM) being 14 times more cytotoxic than 4S against the anaplastic thyroid cancer 8505 C cell line.


Tip60/Kat5 may be a novel candidate histone acetyltransferase for the regulation of liver iron localization via acetylation.
Hepcidin (HAMP), an iron regulatory hormone synthesized by liver hepatocytes, works together with ferritin (FTH) and ferroportin (FPN) in regulating the storage, transport, and utilization of iron in the cell. Epigenetic mechanisms, especially acetylation, also play an important role in the regulation of iron metabolism. However, a target protein has not been mentioned yet. With this preliminary study, we investigated the effect of histone acetyltransferase TIP60 on the expression of HAMP, FTH, and FPN. In addition, how the depletion of Tip60, which regulates the circadian system, affects the daily expression of Hamp was examined at six Zeitgeber time (ZT) points. For this purpose, liver-specific Tip60 knockout mice (mutant) were produced with tamoxifen-inducible Cre/lox recombination and an iron overload model in mice was generated. While HAMP and FTH expressions decreased, FPN expression increased in the mutant group. Interestingly, there was no change in the iron content. A significant increase was observed in the expressions of HAMP, FTH, and FPN and total liver iron content in the liver tissue of the iron overload group. Since intracellular iron concentration is involved in regulating the circadian clock, temporal expression of Hamp was investigated in control and mutant groups at six ZT points. In the control group, Hamp accumulated in a circadian manner with maximal and minimal levels reaching around ZT16 and ZT8, respectively. In the mutant group, there was a significant reduction in Hamp expression in the light phase ZT0 and ZT4 and in the dark phase ZT16. These data are the first findings demonstrating a possible relationship between Tip60 and iron metabolism.


Combined effect of angiotensin II receptor blocker and either a calcium channel blocker or diuretic on day-by-day variability of home blood pressure: the Japan Combined Treatment With Olmesartan and a Calcium-Channel Blocker Versus Olmesartan and Diuretics Randomized Efficacy Study.
Day-by-day home blood pressure (BP) variability (BPV) was reported to be associated with increased cardiovascular risk. We aimed to test the hypothesis that the angiotensin II receptor blocker/calcium-channel blocker combination decreases day-by-day BPV more than the angiotensin II receptor blocker/diuretic combination does and investigated the mechanism underlying the former reduction. We enrolled 207 hypertensive subjects treated with olmesartan monotherapy for 12 weeks. The subjects were randomly assigned to treatment with hydrochlorothiazide (n = 104) or azelnidipine (n = 103) for 24 weeks. Home BP was taken in triplicate with a memory-equipped device in the morning and evening, respectively, for 5 consecutive days before each visit. Visits occurred at 4-week intervals. Home BPV was defined as within-individual SD of the 5-day home BP. Arterial stiffness was assessed by aortic pulse wave velocity at baseline and 24 weeks later. The reductions in home systolic BP were similar between the 2 groups, whereas the SD of home systolic BP decreased more in the azelnidipine group than in the hydrochlorothiazide group during the follow-up period (follow-up mean: 6.3 versus 7.1 mm Hg; P = 0.007). In the azelnidipine group, the change in aortic pulse wave velocity was independently associated with the change in SD of home systolic BP (regression coefficient ± SE = 0.79 ± 0.37; P = 0.036). This study demonstrated that the angiotensin II receptor blocker/calcium-channel blocker combination improved home BPV in addition to home BP reduction and that the reduction in home BPV was partly attributable to the arterial stiffness reduction by this combination.