Signal transduction of human interleukin 3 and granulocyte-macrophage colony-stimulating factor through serine and tyrosine phosphorylation.
To elucidate the rapid events in signal transduction of human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL 3), we examined phosphorylation of proteins on both serine and tyrosine residues in a cytokine-stimulated human myeloid cell line. We found increases in tyrosine phosphorylation within 30 s of stimulation with GM-CSF or IL 3, with peak responses occurring within 2 min. IL 3 and GM-CSF also induced serine phosphorylation, though 10 min of stimulation was required for maximum phosphate incorporation. Interestingly, both IL 3 and GM-CSF stimulated phosphate incorporation in identical substrates, a 68 kDa seryl-phosphoprotein (p68) and a 140 kDa tyrosyl-phosphoprotein (p140). Treatment of AML 193 cells with phorbol myristate acetate resulted in serine phosphorylation of p68; however, p140 was not phosphorylated on tyrosine. Depletion of protein kinase C isoenzymes with high concentrations of phorbol myristate acetate resulted in p68 phosphorylation, which was not further increased by IL 3 or GM-CSF. In contrast, cytokine-induced phosphorylation on tyrosine of p140 was observed after protein kinase C depletion. These data demonstrate the co-ordinate yet independent serine and tyrosine phosphorylation in IL 3- and GM-CSF-treated human myeloid cells, and thus suggest a common set of protein kinases stimulated by each separate ligand.


Choosing among antiepileptic drugs.
Selecting an antiepileptic drug (AED) for treatment of seizures is daunting because there are now 20 from which to choose. Following simple principles allows a systematic approach to drug selection. Efficacy studies provide limited information. For initial monotherapy of partial seizures, high-level evidence exists for the efficacy of lamotrigine, carbamazepine, oxcarbazepine, and topiramate. For initial monotherapy of generalized seizures, high-level evidence is available for valproate, lamotrigine, topiramate, and oxcarbazepine. For initial monotherapy of absence seizures, high-level evidence exists for valproate, lamotrigine, and ethosaximide. All second-generation AEDs have efficacy as adjunctive therapy for partial seizures. AEDs are often useful for comorbid conditions or have properties that should be avoided in some groups. Thus, AEDs should usually be selected on the basis of comorbid conditions, including depression, migraine, chronic pain, obesity, and nephrolithiasis, or patient characteristics, especially for women of childbearing potential and older adults.


Withanolide A is inherently de novo biosynthesized in roots of the medicinal plant Ashwagandha (Withania somnifera).
Ashwagandha (Withania somnifera Dunal., Solanaceae) is one of the most reputed medicinal plants of Ayurveda, the traditional medical system. Several of its traditionally proclaimed medicinal properties have been corroborated by recent molecular pharmacological investigations and have been shown to be associated with its specific secondary metabolites known as withanolides, the novel group of ergostane skeletal phytosteroids named after the plant. Withanolides are structurally distinct from tropane/nortropane alkaloids (usually found in Solanaceae plants) and are produced only by a few genera within Solanaceae. W. somnifera contains many structurally diverse withanolides in its leaves as well as roots. To date, there has been little biosynthetic or metabolism-related research on withanolides. It is thought that withanolides are synthesized in leaves and transported to roots like the tropane alkaloids, a group of bioactive secondary metabolites in Solanaceae members known to be synthesized in roots and transported to leaves for storage. To examine this, we have studied incorporation of (14)C from [2-(14)C]-acetate and [U-(14)C]-glucose into withanolide A in the in vitro cultured normal roots as well as native/orphan roots of W. somnifera. Analysis of products by thin layer chromatography revealed that these primary metabolites were incorporated into withanolide A, demonstrating that root-contained withanolide A is de novo synthesized within roots from primary isoprenogenic precursors. Therefore, withanolides are synthesized in different parts of the plant (through operation of the complete metabolic pathway) rather than imported.


Multicenter Evaluation of the New Etest Gradient Diffusion Method for Piperacillin-Tazobactam Susceptibility Testing of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii Complex.
Piperacillin-tazobactam (P/T) is a β-lactam-β-lactamase inhibitor combination frequently used in the hospital setting. Etest is a gradient diffusion method that represents an alternative to broth microdilution (BMD) for performing antimicrobial susceptibility testing. We conducted a multicenter evaluation of the performance of the new P/T Etest compared to that of BMD following U.S. Food and Drug Administration (FDA) and International Standards Organization (ISO) standard ISO 20776-2 criteria using Clinical and Laboratory Standards Institute (CLSI)-FDA and European Committee on Antimicrobial Susceptibility Testing (EUCAST) interpretive breakpoints, respectively. A total of 977 isolates (775 Enterobacterales isolates, 119 Pseudomonas aeruginosa isolates, and 83 Acinetobacter baumannii complex isolates) were tested. Overall essential agreement (EA) was 96.4% and 96.6% for Enterobacterales when FDA and ISO 20776-2 criteria, respectively, were followed. EA was 98.3% for P. aeruginosa and 91.6% for the A. baumannii complex when both the FDA and ISO criteria were followed. Applying CLSI-FDA breakpoints, categorical agreement (CA) reached 93.0%, 93.3%, and 89.2% for the Enterobacterales, P. aeruginosa, and the A. baumannii complex, respectively. Two very major errors (VMEs; 1.1%) were found among the Enterobacterales (for 2 Klebsiella pneumoniae isolates). No additional major errors (MEs) or VMEs were found. Applying EUCAST breakpoints, CA was 94.8% and 95.8% for Enterobacterales and P. aeruginosa, respectively (no breakpoints are currently available for the A. baumannii complex). No VMEs were observed among the Enterobacterales, but 2 (0.4%) MEs were found. Among the P. aeruginosa isolates, 2 (6.9%) VMEs and 3 (3.3%) MEs were observed. These errors resulted when P/T Etest MICs were 1 doubling dilution apart from the BMD MICs. In conclusion, the new P/T Etest represents an accurate tool for performing antimicrobial susceptibility testing of Enterobacterales, P. aeruginosa, and A. baumannii complex isolates with limited category errors.


Dreaming in Adolescents During the COVID-19 Health Crisis: Survey Among a Sample of European School Students.
According to the continuity hypothesis of dreaming and contemporary psychodynamic approaches, dreams reflect waking life. The aim of the present study was to explore the relationship between the COVID-19 pandemic and dreaming in adolescents. A cross-sectional survey was conducted in Italy, Romania and Croatia involving 2,105 secondary school students (69% girls, mean age 15.6 ± 2.1 years; 31% boys, mean age 15.1 ± 2.2 years; mean age of whole sample 15.4 ± 2.1 years). No substantial differences between countries were found. Thirty-one percent of the participants reported heightened dream recall, 18% noticed an increase in nightmares during the lockdown, and 15% of the provided dreams (n = 498) included pandemic-related content. The results indicate that subjective emotional reactions to lockdown had a significantly higher correlation to dreaming than objective distress (i.e., illness or death of a close one because of COVID-19). These findings suggest that attention to dreams should be included in preventive programs for adolescents with pandemic-related stress.


CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.
CYLD has been recognized as a tumor suppressor due to its dominant genetic linkage to multiple types of epidermal tumors and a range of other cancers. The molecular mechanisms governing CYLD control of skin cancer are still unclear. Here, we showed that K14-driven epidermal expression of a patient-relevant and catalytically deficient CYLD truncated mutant (CYLD(m)) sensitized mice to skin tumor development in response to 7,12-dimethylbenz[α]anthracene (DMBA)/(12-O-tetradecanoylphorbol-13-acetate) TPA challenge. Tumors developed on transgenic mice were prone to malignant progression and lymph node metastasis and displayed increased activation of c-Jun-NH2-kinase (JNK) and the downstream c-Jun and c-Fos proteins. Most importantly, topical application of a pharmacologic JNK inhibitor significantly reduced tumor development and abolished metastasis in the transgenic mice. Further in line with these animal data, exogenous expression of CYLD(m) in A431, a human squamous cell carcinoma (SCC) cell line, markedly enhanced cell growth, migration, and subcutaneous tumor growth in an AP1-depdendent manner. In contrast, expression of the wild-type CYLD inhibited SCC tumorigenesis and AP1 function. Most importantly, CYLD(m) not only increased JNK activation but also induced an upregulation of K63 ubiquitination on both c-Jun and c-Fos, leading to sustained AP1 activation. Our findings uncovered c-Jun and c-Fos as novel CYLD targets and underscore that CYLD controls epidermal tumorigenesis through blocking the JNK/AP1 signaling pathway at multiple levels.


Heat induction in two-dimensional graphene-Fe3O4 nanohybrids for magnetic hyperthermia applications with artificial neural network modeling.
We report the synthesis and characterization of graphene functionalized with iron (Fe3+) oxide (G-Fe3O4) nanohybrids for radio-frequency magnetic hyperthermia application. We adopted the wet chemical procedure, using various contents of Fe3O4 (magnetite) from 0-100% for making two-dimensional graphene-Fe3O4 nanohybrids. The homogeneous dispersal of Fe3O4 nanoparticles decorated on the graphene surface combined with their biocompatibility and high thermal conductivity make them an excellent material for magnetic hyperthermia. The morphological and magnetic properties of the nanohybrids were studied using scanning electron microscopy (SEM) and a vibrating sample magnetometer (VSM), respectively. The smart magnetic platforms were exposed to an alternating current (AC) magnetic field of 633 kHz and of strength 9.1 mT for studying their hyperthermic performance. The localized antitumor effects were investigated with artificial neural network modeling. A neural net time-series model was developed for the assessment of the best nanohybrid composition to serve the purpose with an accuracy close to 100%. Six Nonlinear Autoregressive with External Input (NARX) models were obtained, one for each of the components. The assessment of the accuracy of the predicted results has been done on the basis of Mean Squared Error (MSE). The highest Mean Squared Error value was obtained for the nanohybrid containing 45% magnetite and 55% graphene (F45G55) in the training phase i.e., 0.44703, which is where the model achieved optimal results after 71 epochs. The F45G55 nanohybrid was found to be the best for hyperthermia applications in low dosage with the highest specific absorption rate (SAR) and mean squared error values.


Preparation of gelatin-chitosan bilayer film loaded citral nanoemulsion as pH and enzyme stimuli-responsive antibacterial material for food packaging.
The responsive release of enzymes, pH, temperature, light and other stimuli is an effective means to reduce the loss of volatile active substances and control the release of active ingredients. The purpose of this study is to design a simple and rapid method to synthesize a multifunctional bilayer membrane, which has good mechanical properties, long-lasting pH and enzyme dual sensitive sustained release properties, and excellent antibacterial activity. The citral nanoemulsion was prepared by ultrasonic method, then the chitosan solution loaded with nanoemulsion was assembled on the gelatin film, and the uniform and smooth gelatin-chitosan bilayer film was successfully prepared. Compared with the control group, the bilayer film loaded with nanoemulsion showed better barrier performance, mechanical properties and antibacterial activity.


Wrong-side thoracentesis: lessons learned from root cause analysis.
Despite the recognized value of the Joint Commission's Universal Protocol and the implementation of time-outs, incorrect surgical procedures are still among the most common types of sentinel events and can have fatal consequences. To examine a root cause analysis database for reported wrong-side thoracenteses and to determine the contributing factors associated with their occurrence. We searched the National Center for Patient Safety database for wrong-side thoracenteses performed in ambulatory clinics and hospital units other than the operating room reported from January 1, 2004, through December 31, 2011. Data extracted included patient factors, clinical features, team structure and function, adherence to bottom-line patient safety measures, complications, and outcomes. Fourteen cases of wrong-side thoracenteses are identified. Contributing factors included failure to perform a time-out (n=12), missing indication of laterality on the patient's consent form (n=10), absence of a site mark on the patient's skin within the sterile field (n=12), and absent verification of medical images (n=7). Complications included pneumothoraces (n=4), hemorrhage (n=3), and death directly attributable to the wrong-side thoracentesis (n=2). Teamwork and communication failure, unawareness of existing policy, and a deficit in training and education were the most common root causes of wrong-side thoracentesis. Prevention of wrong-site procedures and accompanying patient harm outside the operating room requires adherence to the Universal Protocol and time-outs, effective teamwork, training and education, mentoring, and patient assessment for early detection of complications. The time-outs provide protected time and place for error detection and recovery.


Effect of milking interval on milk secretion and mammary tight junction permeability in dairy ewes.
Twenty-four lactating ewes (Manchega, n = 12; Lacaune, n = 12) in mid lactation were used to assess the short-term effects of different machine milking intervals (4, 8, 12, 16, 20, and 24 h) on milk yield, milk composition, and tight junction (TJ) permeability of mammary epithelia. Milk samples were analyzed for chemical composition, somatic cell count (SCC), and plasmin activity. Plasma lactose, and milk Na and K concentrations were used as indicators of TJ permeability. Milk accumulated linearly for up to 24 h, showing a different rate according to the milk yield of the breed (Manchega, 38 mL/h; Lacaune, 87 mL/h). Milking interval affected milk fat content, which decreased markedly from 4 to 24 h in both breeds, but no differences were observed in milk protein content. The milk contents of casein, true protein, lactose, and total solids also varied according to milking interval. Values of SCC did not vary by breed (175 x 10(3) cells/mL, on average), showing the lowest log(10) values for the 4-and 24-h milking intervals in both breeds. Plasmin activity in milk increased with milking interval until 20 h of udder filling in both breeds, and was poorly but positively correlated with SCC content (r = 0.39). Plasma lactose increased dramatically after 20 h of milk accumulation, indicating enhanced permeability of mammary TJ. As a result, an increase in Na concentration and in the Na:K ratio, and a decrease in K concentration, were observed in the milk of Manchega ewes. On the contrary, no differences in Na and K concentrations in milk were detected in Lacaune ewes. In conclusion, our results proved that Manchega and Lacaune dairy sheep could maintain high rates of milk secretion during extended milking intervals in the short term, with no effects on udder health and few negative effects on milk yield. Increased TJ permeability, caused by the effect of udder filling, induced changes in milk composition that were more marked in Manchega than in Lacaune ewes.


Impact of sequence diversity in the Moraxella catarrhalis UspA2/UspA2H head domain on vitronectin binding and antigenic variation.
The nasopharyngeal pathogen Moraxella catarrhalis recruits vitronectin to subvert complement-mediated killing. Ubiquitous surface protein (UspA) 2 and its hybrid form UspA2H bind vitronectin at the highly diverse N-terminal head domain. Here we characterized the sequence diversity of the head domain in multiple M. catarrhalis clinical isolates (n = 51) with focus on binding of vitronectin. The head domain of the uspA2 genes from 40 isolates were clustered according to an N-terminal sequence motif of UspA2 (NTER2), i.e., NTER2A (55% of uspA2 variants), NTER2B (32.5%), NTER2C (5%), and finally a group without an NTER2 (7.5%). Isolates harbouring the uspA2H gene (n = 11) contained N-terminal GGG repeats. Vitronectin binding to isolates having UspA2 did not correlate to variation in the NTER2 motifs but occurred in UspA2H containing 6 or ≥11 of GGG repeats. Analyses of recombinant UspA2/UspA2H head domains of multiple variants showed UspA2-dependent binding to the C-terminal of vitronectin. Furthermore, polyclonal anti-UspA2 antibodies revealed that the head domain of the majority of Moraxella UspA2/2H was antigenically unrelated, whereas the full length molecules were recognized. In conclusion, the head domains of UspA2/2H have extensive sequence polymorphism without losing vitronectin-binding capacity promoting a general evasion of the host immune system.


The impact of steam on the electronic structure of the selective propane oxidation catalyst MoVTeNb oxide (orthorhombic M1 phase).
The selective propane oxidation catalyst MoVTeNb oxide M1 was investigated by microwave conductivity, synchrotron X-ray photoelectron, soft X-ray absorption and resonant photoelectron spectroscopy under reaction conditions to identify the influence of steam on the electronic bulk and surface properties. Steam significantly increases both the conversion of propane and the selectivity to the target product acrylic acid. The increased catalytic performance comes along with a decreased conductivity, a modification of the surface chemical and electronic structure with an enrichment of covalently bonded V(5+) species to the extent of Mo(6+), a decreased work function and hence polarity of the surface and a modified valence band structure. The higher degree of covalency in metal oxide bonds affects the mobility of the free charge carriers, and hence explains the decrease of the conductivity with steam. Furthermore we could prove that a subsurface space charge region depleted in electrons and thus an upward bending of the electronic band structure are induced by the reaction mixture, which is however not dependent on the steam content.


The depot-specific and essential roles of CBP/p300 in regulating adipose plasticity.
Fat remodeling has been extensively explored through protein deacetylation, but not yet acetylation, as a viable therapeutic approach in the management of obesity and related metabolic disorders. Here, we investigated the functions of key acetyltransferases CBP/p300 in adipose remodeling and their physiological effects by generating adipose-specific deletion of CBP (Cbp-AKO), p300 (p300-AKO) and double-knockout (Cbp/p300-AKO) models. We demonstrated that Cbp-AKO exhibited marked brown remodeling of inguinal WAT (iWAT) but not epididymal WAT (eWAT) after cold exposure and that this pattern was exaggerated in diet-induced obesity (DIO). Despite this striking browning phenotype, loss of Cbp was insufficient to impact body weight or glucose tolerance. In contrast, ablation of p300 in adipose tissues had minimal effects on fat remodeling and adiposity. Surprisingly, double-knockout mice (Cbp/p300-AKO) developed severe lipodystrophy along with marked hepatic steatosis, hyperglycemia and hyperlipidemia. Furthermore, we demonstrated that pharmacological inhibition of Cbp and p300 activity suppressed adipogenesis. Collectively, these data suggest that (i) CBP, but not p300, has distinct functions in regulating fat remodeling and that this occurs in a depot-selective manner; (ii) brown remodeling occurs independently of the improvements in glucose metabolism and obesity and (iii) the combined roles of CBP and p300 are indispensable for normal adipose development.


A Multi-Year Analysis of Fatal Farm and Agricultural Injuries in Pennsylvania.
Agriculture, forestry, fishing, and hunting comprise the most hazardous industry in the U.S., and production agriculture accounts for the majority of fatalities in the industry. Using Penn State's farm and agricultural injury database, data were coded according to ASABE's Farm and Agricultural Injury Classification (FAIC) code and the U.S. Bureau of Labor Statistics' Occupational Injury and Illness Classification System (OIICS) for source and event or exposure types. Occupational and non-occupational incidents were compared based on age groups, religious sect, source of injury, and the injury event or exposure. There were 355 farm and agricultural fatalities in Pennsylvania from 2000 through 2012, and 56% of these fatalities were occupational. The fatality rate was 33.4 per 100,000 farm household residents per year. Youth under 15 years old, seniors age 65 and older, Anabaptist youth, and young females were at high risk of fatal farm injury. Vehicles and transportation incidents were the most common injury source and event/exposure type, respectively. This research illustrates how state-level or national-level data can be collected, coded, and analyzed based on the FAIC and OIICS classification systems to better understand fatal injury causes and connections among important variables. This process can also help to target intervention programs and efforts.


Management of acute and chronic gouty arthritis: present state-of-the-art.
There are three stages in the management of gout: (i) treating the acute attack; (ii) lowering excess stores of uric acid to prevent flares of gouty arthritis and to prevent tissue deposition of urate; and (iii) providing prophylaxis to prevent acute flares. It is important to distinguish between therapy to reduce acute inflammation in acute gout and therapy to manage hyperuricaemia in patients with chronic gouty arthritis. During the acute gouty attack nonpharmacological treatments such as topical ice and rest of the inflamed joint are useful. NSAIDs are the preferred treatment in acute gout. The most important determinant of therapeutic success is not which NSAID is chosen, but rather how soon NSAID therapy is initiated. Other treatments include oral and intravenous colchicine, intra-articular and systemic corticosteroids, and intramuscular corticotropin. Optimal treatment of chronic gout requires long-standing reduction in serum uric acid. The urate-lowering drugs used to treat chronic gout are the uricosuric drugs, the uricostatic drugs, which are xanthine oxidase inhibitors, and the uricolytic drugs. Xanthine oxidase inhibitors such as allopurinol, oxipurinol and febuxastat should be used as first-line treatment in patients with renal calculi, renal insufficiency, concomitant diuretic therapy and ciclosporin (cyclosporine) therapy, and urate overproduction. Uricosuric drugs include probenecid, benzbromarone, micronised fenofibrate and losartan. They are the urate-lowering drugs of choice in allopurinol-allergic patients and underexcretors with normal renal function and no history of urolithiasis. The use of recombinant urate oxidase in patients with chronic gout is limited by the need for parenteral administration, the potential antigenicity and production of anti-urate oxidase antibodies, and declining efficacy. The effectiveness of colchicine prophylaxis as an isolated therapy is still to be confirmed by placebo-controlled trials. Another issue is prophylaxis with NSAIDs. There are no comparative studies with colchicine.


'Candidatus Liberibacter asiaticus' Multimeric LotP Mediates Citrus sinensis Defense Response Activation.
'Candidatus Liberibacter asiaticus' is known as the most pathogenic organism associated with citrus greening disease. Since its publicized emergence in Florida in 2005, 'Ca. L. asiaticus' remains unculturable. Currently, a limited number of potential disease effectors have been identified through in silico analysis. Therefore, these potential effectors remain poorly characterized and do not fully explain the complexity of symptoms observed in citrus trees infected with 'Ca. L. asiaticus.' LotP has been identified as a potential effector and have been partially characterized. This protein retains structural homology to the substrate binding domain of the Lon protease. LotP interacts with chaperones like GroEL, Hsp40, DnaJ, and ClpX and may exercise its biological role through interactions with different proteins involved in proteostasis networks. Here, we evaluate the interactome of LotP-revealing a new protein-protein interaction target (Lon-serine protease) and its effect on citrus plant tissue integrity. We found that via protein-protein interactions, LotP can enhance Lon protease activity, increasing the degradation rate of its specific targets. Infiltration of purified LotP strained citrus plant tissue causing photoinhibition and chlorosis after several days. Proteomics analysis of LotP tissues recovering after the infiltration revealed a large abundance of plant proteins associated with the stabilization and processing of mRNA transcripts, a subset of important transcription factors; and pathways associated with innate plant defense were highly expressed. Furthermore, interactions and substrate binding module of LotP suggest potential interactions with plant proteins, most likely proteases.


L-glutaminase: suppression of lymphocyte blastogenic responses in vitro.
Continuous exposure to 0.1 international unit or more of Escherichia coli L-glutaminase inhibited responses of human lymphocytes to phytohemagglutinin, streptolysin O, and allogeneic leukocytes. Inhibition was completety reversed by removing the enzyme from the culture or adding L-glutamine but not L-asparagine. Cytoxicity did not occur. L-Glutaminase should be immunosuppressive in vivo.


Extracting survival parameters from isothermal, isobaric, and "iso-concentration" inactivation experiments by the "3 end points method".
Theoretically, if an organism's resistance can be characterized by 3 survival parameters, they can be found by solving 3 simultaneous equations that relate the final survival ratio to the lethal agent's intensity. (For 2 resistance parameters, 2 equations will suffice.) In practice, the inevitable experimental scatter would distort the results of such a calculation or render the method unworkable. Averaging the results obtained with more than 3 final survival ratio triplet combinations, determined in four or more treatments, can remove this impediment. This can be confirmed by the ability of a kinetic inactivation model derived from the averaged parameters to predict survival patterns under conditions not employed in their determination, as demonstrated with published isothermal survival data of Clostridium botulinum spores, isobaric data of Escherichia coli under HPP, and Pseudomonas exposed to hydrogen peroxide. Both the method and the underlying assumption that the inactivation followed a Weibull-Log logistic (WeLL) kinetics were confirmed in this way, indicating that when an appropriate survival model is available, it is possible to predict the entire inactivation curves from several experimental final survival ratios alone. Where applicable, the method could simplify the experimental procedure and lower the cost of microbial resistance determinations. In principle, the methodology can be extended to deteriorative chemical reactions if they too can be characterized by 2 or 3 kinetic parameters.


Toward hyperpolarized molecular imaging of HIV: synthesis and longitudinal relaxation properties of (15) N-Azidothymidine.
Previously unreported (15) N labeled Azidothymidine (AZT) was prepared as an equimolar mixture of two isotopomers: 1-(15) N-AZT and 3-(15) N-AZT. Polarization decay of (15) N NMR signal was studied in high (9.4 T) and low (~50 mT) magnetic fields. (15) N T1 values were 45 ± 5 s (1-(15) N-AZT) and 37 ± 2 s (3-(15) N-AZT) at 9.4 T, and 140 ± 16 s (3-(15) N-AZT) at 50 mT. (15) N-AZT can be potentially (15) N hyperpolarized by several methods. These sufficiently long (15) N-AZT T1 values potentially enable hyperpolarized in vivo imaging of (15) N-AZT, because of the known favorable efficient (i.e., of the time scale shorter than the longest reported here (15) N T1 ) kinetics of uptake of injected AZT. Therefore, 3-(15) N-AZT can be potentially used for HIV molecular imaging using hyperpolarized magnetic resonance imaging.


Prevalence of Haplorchis taichui among humans and fish in Luang Prabang Province, Lao PDR.
This study confirmed the prevalence of the intestinal fluke Haplorchis taichui (Trematoda: Heterophyidae) among people and fish in Luang Prabang Province, Lao PDR. Fecal specimens were collected from 559 riparian people (229 males and 330 females), residing in 4 Districts (Luang Prabang, Xieng Ngeun, Pak Ou, and Nam Bak) and were examined by the Kato-Katz fecal smear technique. The overall helminth egg positive rate was 64.9%. The positive rate for small trematode eggs (STE), which may include H. taichui and other heterophyids, Opisthorchis viverrini, and lecithodendriids, was 15.2%. For recovery of adult helminths, 10 STE-positive people were treated with 40mg/kg praziquantel and 15mg/kg pyrantel pamoate, and then purged. Mixed infections with 3 Haplorchis species (H. taichui, H. pumilio, and H. yokogawai), a species of cestode (Taenia saginata), and several species of nematodes including Enterobius vermicularis and hookworms were found. The worm load for trematodes was exclusively high for H. taichui with an average of 7691 specimens per infected person, followed by H. yokogawai (8.3 specimens) and H. pumilio (4.1 specimens). Out of 207 freshwater fish (17 species) purchased in a market in Luang Prabang District, 138 (67%) harboured H. taichui metacercariae (metacercarial burden per fish; 520). Lower prevalence of fish and lower metacercarial density were observed for H. yokogawai (52% and 50 per fish, respectively) and H. pumilio (18% and 3 per fish, respectively). STE found in the surveyed population of Luang Prabang Province were verified to be those of intestinal fukes, particularly H. taichui.


Range measurements by a mobile robot using a navigation line.
A continuous, straight-edged line is used for the visual navigation of an autonomous mobile robot in a factor environment. This line, which resides on the floor and contrasts with background, may also be used to determine range information. Two methods are developed for determining the range of an object in the sensor's field of view. The effects of various error conditions in the system geometry on each ranging method are determined. Equations are derived which yield the percent error in calculating ranges given estimates of these error conditions. Numerical examples using typical sensor parameters are given.


Pediatric functional magnetic resonance neuroimaging: tactics for encouraging task compliance.
Neuroimaging technology has afforded advances in our understanding of normal and pathological brain function and development in children and adolescents. However, noncompliance involving the inability to remain in the magnetic resonance imaging (MRI) scanner to complete tasks is one common and significant problem. Task noncompliance is an especially significant problem in pediatric functional magnetic resonance imaging (fMRI) research because increases in noncompliance produces a greater risk that a study sample will not be representative of the study population. In this preliminary investigation, we describe the development and application of an approach for increasing the number of fMRI tasks children complete during neuroimaging. Twenty-eight healthy children ages 9-13 years participated. Generalization of the approach was examined in additional fMRI and event-related potential investigations with children at risk for depression, children with anxiety and children with depression (N=120). Essential features of the approach include a preference assessment for identifying multiple individualized rewards, increasing reinforcement rates during imaging by pairing tasks with chosen rewards and presenting a visual 'road map' listing tasks, rewards and current progress. Our results showing a higher percentage of fMRI task completion by healthy children provides proof of concept data for the recommended tactics. Additional support was provided by results showing our approach generalized to several additional fMRI and event-related potential investigations and clinical populations. We proposed that some forms of task noncompliance may emerge from less than optimal reward protocols. While our findings may not directly support the effectiveness of the multiple reward compliance protocol, increased attention to how rewards are selected and delivered may aid cooperation with completing fMRI tasks. The proposed approach contributes to the pediatric neuroimaging literature by providing a useful way to conceptualize and measure task noncompliance and by providing simple cost effective tactics for improving the effectiveness of common reward-based protocols.


[Experimental dilatation of the cecum and colon in rats. I. Induction by continuous administration of lactose after weaning].
Female weanling Wistar rats, weighing 30-40 g, were allocated into seven groups (I, II, III, IV, V, VI and VII), and given laboratory rat chow containing ascending concentrations of lactose (subgroup L) and sucrose (subgroup S); each group was administered respectively 0, 5, 10, 20, 25, 30 and 35 g of disaccharide per 100 g final weight of diet. The animals were maintained in these diets for 28 days, when they were weighed and sacrificed. The volume of the large intestine was measured, and the weight of cecum and colon were recorded separately. The values were expressed in cm3/100 g of body weight (volume) and g/100 g of body weight (weight of cecum and colon). The results showed that rats given lactose, except group II (L) showed enlargement of the cecum and colon, as revealed by increased volume and weight, proportionally to the concentration of sugar. This increase was more pronounced in the cecum, while the participation of the colon occurred significantly only with high concentrations of lactose (groups VI (L) and VII (L)). Groups V (L), VI (L) and VII (L) showed very low body weights at the end of the experiment and high mortality rates of respectively 37.5, 50 and 80%. It is postulated that the enlargement of the cecum and colon of rats given lactose is probably related to augmented work due to increased fecal flow through the ileo-cecal valve and/or changes in bacterial flora and fermentation. Besides, the low body weight and the high mortality rate of lactose-fed rats may be dependent on the chronic diarrhea observed in these animals.


Physician sets diabetes education as top priority.
Rachmel Cherner, MD, FACP, is an endocrinologist in private practice in Jenkintown, an active member of the Philadelphia County Medical Society, and a delegate to the State Society's House. He writes for Consultant magazine and serves on the staff of North Penn Hospital, and his work as a physician-educator was described in a Medical Economics publication called "Patient Satisfaction." In 1987, he established the Pavilion Diabetes Treatment Center.


Decoding glycomics with a suite of methods for differential expression analysis.
Glycomics, the comprehensive profiling of all glycan structures in samples, is rapidly expanding to enable insights into physiology and disease mechanisms. However, glycan structure complexity and glycomics data interpretation present challenges, especially for differential expression analysis. Here, we present a framework for differential glycomics expression analysis. Our methodology encompasses specialized and domain-informed methods for data normalization and imputation, glycan motif extraction and quantification, differential expression analysis, motif enrichment analysis, time series analysis, and meta-analytic capabilities, synthesizing results across multiple studies. All methods are integrated into our open-source glycowork package, facilitating performant workflows and user-friendly access. We demonstrate these methods using dedicated simulations and glycomics datasets of N-, O-, lipid-linked, and free glycans. Differential expression tests here focus on human datasets and cancer vs. healthy tissue comparisons. Our rigorous approach allows for robust, reliable, and comprehensive differential expression analyses in glycomics, contributing to advancing glycomics research and its translation to clinical and diagnostic applications.


Metastatic Breast Lobular Carcinoma to Unusual Sites: A Report of Three Cases and Review of Literature.
Invasive lobular carcinoma of the breast is the second most common type of invasive breast carcinoma. Invasive lobular carcinoma has an unusual pattern of metastases, which poses a diagnostic challenge for both clinicians and pathologists. We herein present three cases of breast invasive lobular carcinoma presented with metastasis to unusual sites, namely, uterus, colon and stomach. We recommend a higher index of suspicion in any case with breast cancer developing gastrointestinal tract or genital tract symptoms.


Exploring the evidence base for how people with dementia and their informal carers manage their medication in the community: a mixed studies review.
Little is known about the general medicines management issues for people with dementia living in the community. This review has three aims: firstly to explore and evaluate the international literature on how people with dementia manage medication; assess understanding of medicines management from an informal carers perspective; and lastly to understand the role that healthcare professionals play in assisting this population with medicines management. A mixed studies review was conducted. Web of Knowledge, PubMed and Cochrane Library were searched post-1999 for studies that explored medicines management in people with dementia dwelling in the community, and the role healthcare professionals play in supporting medicines management in people with dementia. Following screening, nine articles were included. Data from included studies were synthesised using a convergent synthesis approach and analysed thematically to combine findings from studies using a range of methods (qualitative, quantitative and mixed methods). Four themes were generated from the synthesis: The nature of the disease and the effects this had on medicines management; the additional responsibilities informal carers have; informal caregivers' knowledge of the importance of managing medication and healthcare professionals' understanding of medicines management in people with dementia. Consequently, these were found to affect management of medication, in particular adherence to medication. This review has identified that managing medication for people with dementia dwelling in the community is a complex task with a frequently associated burden on their informal caregivers. Healthcare professionals can be unaware of this burden. The findings warrant the need for healthcare professionals to undergo further training in supporting medicines management for people with dementia in their own homes.


Improving pharmacy staff knowledge and practice on childhood diarrhea management in Vietnam: are educational interventions effective?
In many developing countries, private pharmacies play an important role in providing health information and services to local communities for common health issues. The aim of this study was to ascertain medium-term impact of educational interventions on knowledge and practice of pharmacy staff regarding management of childhood diarrhea in Vietnam. This was a pre- and post-intervention study with 32 and 44 months difference from the time of the baseline survey to the conclusion of trainings and the time of the end-line survey, respectively. Interventions included in-class training for pharmacy staff, printed materials at the pharmacy, and supportive supervision. Knowledge/reported practice and actual practice of pharmacy staff were measured before and after interventions. After interventions, significant improvements (p<0.01) were observed for all indexes related to pharmacy staff's knowledge about childhood diarrhea; for instance, 31% and 60% of surveyed staff asked about weight of the child and accompanying symptoms of childhood diarrhea, respectively, an increase from 11% and 45% at the baseline. Oral rehydration solution (ORS) was the most frequently reported product recommended (97% to 99%), but probiotics and antidiarrheals were the products most frequently prescribed at pharmacies. Public health facilities remained the preferred choice for referrals from pharmacies, but the use of private clinics was increasing. Consultations and advice provided to caregivers also improved, but considerable gaps between knowledge and actual practice of staff in real pharmacy settings remained. Educational interventions were effective in improving pharmacy staff knowledge and practice regarding management of childhood diarrhea. Knowledge and actual practice of staff in real pharmacy settings did not always correlate; there is need for a stronger regulatory and law enforcement system. Interventions to improve pharmacy practice in developing countries should be focused, comprehensive, and evidence-based.


Fluorogenic Photo-Crosslinking of Glycan-Binding Protein Recognition Using a Fluorinated Azido-Coumarin Fucoside.
Glycan recognition by glycan-binding proteins is central to the biology of all living organisms. The efficient capture and characterization of relatively weak non-covalent interactions remains an important challenge in various fields of research. Photoaffinity labeling strategies can create covalent bonds between interacting partners, and photoactive scaffolds such as benzophenone, diazirines and aryl azides have proved widely useful. Since their first introduction, relatively few improvements have been advanced and products of photoaffinity labeling remain difficult to detect. We report a fluorinated azido-coumarin scaffold which enables photolabeling under fast and mild activation, and which can leave a fluorescent tag on crosslinked species. Coupling this scaffold to an α-fucoside, we demonstrate fluorogenic photolabeling of glycan-protein interactions over a wide range of affinities. We expect this strategy to be broadly applicable to other chromophores and we envision that such "fluoro-crosslinkers" could become important tools for the traceable capture of non-covalent binding events.


Elephant-to-human transmission of tuberculosis, 2009.
In 2009, the Tennessee Department of Health received reports of 5 tuberculin skin test (TST) conversions among employees of an elephant refuge and isolation of Mycobacterium tuberculosis from a resident elephant. To determine the extent of the outbreak and identify risk factors for TST conversion, we conducted a cohort study and onsite assessment. Risk for conversion was increased for elephant caregivers and administrative employees working in the barn housing the M. tuberculosis-infected elephant or in offices connected to the barn (risk ratio 20.3, 95% confidence interval 2.8-146.7). Indirect exposure to aerosolized M. tuberculosis and delayed or inadequate infection control practices likely contributed to transmission. The following factors are needed to reduce risk for M. tuberculosis transmission in the captive elephant industry: increased knowledge about M. tuberculosis infection in elephants, improved infection control practices, and specific occupational health programs.


Virus infections as potential targets of preventive treatments for type 1 diabetes.
Environmental factors play an important role in the pathogenesis of type 1 diabetes, and are attractive targets for preventive interventions. Several studies have shown that viruses can cause diabetes in animals, indicating their potential as candidates for environmental triggering agents. However, human studies have been hampered by the complex nature of the disease pathogenesis, leaving the question of viral etiology unanswered. Significant progress has recently been made in this field by searching for viruses within pancreatic tissue samples, and by carrying out prospective studies. Consequently, there is increasing evidence for a group of enteroviruses acting as possible environmental key triggers. In past studies, these viruses have been linked to type 1 diabetes. Recent studies have shown that they exert tropism to pancreatic islets, and that they are associated with the start of the beta-cell damaging process. Also, polymorphisms of the gene coding for the innate immune system sensor for enteroviruses (IFIH1) were found to modulate the risk of diabetes. Based on these findings, interest in the possible development of vaccines against these viruses has increased. However, even if enterovirus vaccines (polio vaccines) are effective and safe, we currently lack necessary information for the development of a vaccine against diabetogenic enteroviruses, e.g. regarding the identification of their specific serotypes and the causal relationship between these viruses and diabetes initiation. Ongoing research projects are currently addressing these questions, and will hopefully increase the consensus in this field. Also, new sequencing technologies will provide additional information about the whole virome, which could enable the discovery of new candidate viruses.


Competence trust among providers as fundamental to a culturally competent primary healthcare system for immigrant families.
To explore how an organization's trust in the cultural competency of other service providers (competence trust) can influence the effectiveness of a services network in meeting the needs of recent immigrant families. Primary health care for recent immigrants arriving in Canada is delivered through a network of community-based services. To ensure the functioning of the network and its ability to facilitate access to needed services for new arrivals, network members need to be able to work together collaboratively. A case study involving services for an urban community in Atlantic Canada was undertaken in 2009 to explore how service organizations worked together to address the needs of recent immigrant families with young children. This paper focuses on provider perceptions of cultural competency among local service organizations and how this influenced trust and desire to work together for the benefit of families. The case study utilized both social network analysis and qualitative inquiry methodology. Twenty-one of 27 selected organizations responded to the online social network survey, and 14 key informant interviews were conducted. Social network measures and network mapping were used to demonstrate trusting relationships and associated interactions, while interview data were used to explain the relationships observed. Perceived cultural competency affected the degree of trust and collaboration within the services network when addressing the needs of recent immigrant families. Competence trust toward other providers increased the desire and commitment to work together, while lack of competence trust created avoidance. Non-government organizations were identified among the most culturally competent. The perceived positive and negative experiences of families with different providers influenced the level of trust among network members. The development of systemic cultural competences within a services network is needed in order to improve collaborations and access to services for immigrant families.


Proton-enhanced 13C nuclear magnetic resonance of lipids and biomembranes.
A recently developed nuclear double resonance technique which permits sensitive detection, together with high resolution, of rare spins in solids or other dipolar-coupled nuclear systems [Pines, Gibby, and Waugh (1973) J. Chem. Phys. 59, 569] has been applied to the study of natural abundance (13)C-nuclear magnetic resonance in lipid mesophases and of selectively labeled carbon sites in bacterial membranes.Detailed microscopic information on the molecular organization and phase transitions of the lipid phases and their interaction with ions and other molecules can be obtained from the study of the chemical shift anisotropies and dynamical aspects of the (13)C NMR spectra of unsonicated lipid dispersions (liposomes). Experiments are reported which demonstrated the feasibility of quantitatively observing the (13)C-nuclear magnetic resonance of specifically labeled sites in unperturbed Escherichia coli membrane vesicles for the study of the physical state of the lipids with the aim of relating it to the known lipid-dependent functional properties of the membranes.


Understanding the Context of High- and Low-Testosterone Prescribing Facilities in the Veterans Health Administration (VHA): a Qualitative Study.
Inappropriate testosterone use and variations in testosterone prescribing patterns exist in the Veterans Health Administration (VHA) despite the presence of clinical guidelines. We examined system and clinician factors that contribute to patterns of potentially inappropriate testosterone prescribing in VHA. Qualitative study using a positive deviance approach to understand practice variation in high- and low-testosterone prescribing sites. Twenty-two interview participants included primary care and specialty clinicians, key opinion leaders, and pharmacists at 3 high- and 3 low-testosterone prescribing sites. Semi-structured phone interviews were conducted, transcribed, and coded using a priori theoretical constructs and emergent themes. Case studies were developed for each site and a cross-case matrix was created to evaluate variation across high- and low-prescribing sites. We identified four system-level domains related to variation in testosterone prescribing: organizational structures and processes specific to testosterone prescribing, availability of local guidance on testosterone prescribing, well-defined dissemination process for local testosterone polices, and engagement in best practices related to testosterone prescribing. Two clinician-level domains were also identified, specifically, structured initial testosterone prescribing process and specified follow-up testosterone prescribing process. High- and low-testosterone prescribing sites systematically varied in the four system-level domains, while the clinician-level domains looked similar across all sites. The third high-prescribing site was unusual in that it exhibited the four domains similar to the 3 low-prescribing sites at the time of our visit. This site had greatly reduced its prescribing of testosterone in the interim. Findings suggest that local organizational factors play an important role in influencing prescribing. Sites have the potential to transform their utilization patterns by providing access to specialty care expertise, an electronic health record-based system to facilitate guideline-concordant prescribing, well-defined dissemination processes for information, guidance from multiple sources, and clarity regarding best practices for prescribing.


A review on removing pharmaceutical contaminants from wastewater by constructed wetlands: design, performance and mechanism.
This paper presents a comprehensive review of the current state of research activities on the application of constructed wetlands for removing pharmaceutical contaminants from wastewater. The focus of the review was placed on the application of constructed wetlands as an alternative secondary wastewater treatment system or as a wastewater polishing treatment system. The design parameters of the reported constructed wetlands including the physical configuration, hydraulic mode, vegetation species, and targeting pharmaceuticals were summarized. The removal efficiencies of pharmaceuticals under different conditions in the wetlands were evaluated at the macroscopic level. In addition, the importance of the three main components of constructed wetlands (substrate, plants and microbes) for pharmaceutical removal was analyzed to elucidate the possible removal mechanisms involved. There is a general consensus among many researchers that constructed wetlands hold great potential of being used as an alternative secondary wastewater treatment system or as a wastewater polishing treatment system for the removal of pharmaceuticals, but relevant reported studies are scarce and are not conclusive in their findings. Current knowledge is limited on the removal efficiencies of pharmaceuticals in constructed wetlands, the removal mechanisms involved, the toxicity to constructed wetlands caused by pharmaceuticals, and the influences of certain important parameters (configuration design, hydraulic mode, temperature and seasonality, pH, oxygen and redox potential, etc.). This review promotes further research on these issues to provide more and better convincing evidences for the function and performance of larger laboratory-scale, pilot-scale or full-scale constructed wetlands.


Natural antioxidant polyphenols on inflammation management: Anti-glycation activity vs metalloproteinases inhibition.
The diet polyphenols are a secondary metabolites of plants able to act on inflammation process. Their anti-inflammatory activity is articulated through several mechanisms that are related to their antioxidative and radical scavengers properties. Our work is focused on a novel approach to inflammatory disease management, based on anti-glycative and matrix metalloproteinases (MMPs) inhibition effects, as a connected phenomena. To better understand these correlation, polyphenols Structure-Activity Relationship (SAR) studies were also reported. The antioxidant polyphenols inhibit the AGEs at different levels of the glycation process in the following ways: (1) prevention of Amadori adduct oxidation; (2) trapping reactive dycarbonyl compounds; (3) attenuation of receptor for AGEs (RAGE) expression. Moreover, several flavonoids with radical scavenging property showed also MMPs inhibition interact directly with MMPs or indirectly via radical scavengers and AGEs reduction. The essential polyphenols features involved in these mechanisms are C2-C3 double bond and number and position of hydroxyl, glycosyl and O-methyl groups. These factors induce a change in molecular planarity interfering with the hydrogen bond formation, electron delocalization and metal ion chelation. In particular, C2-C3 double bond improve the antioxidant and MMPs inhibition, while the hydroxylation, glycosylation and methylation induce a positive and negative correlation, respectively.


Twist controls skeletal development and dorsoventral patterning by regulating runx2 in zebrafish.
Twist1a and twist1b are the principal components of twists that negatively regulate a number of cellular signaling events. Expression of runx2 and downstream targets is essential for skeletal development and ventral organizer formation and specification in early vertebrate embryos, but what controls ventral activity of maternal runx2 and how twists function in zebrafish embryogenesis still remain unclear. By studying the loss of twist induced by injection of morpholino-oligonucleotide in zebrafish, we found that twist1a and twist1b, but not twist2 or twist3, were required for proper skeletal development and dorsoventral patterning in early embryos. Overexpression of twist1a or twist1b following mRNA injection resulted in deteriorated skeletal development and formation of typical dorsalized embryos, whereas knockdown of twist1a and twist1b led to the formation of abnormal embryos with enhanced skeletal formation and typical ventralized patterning. Overexpression of twist1a or twist1b decreased the expression of runx2b, whereas twist1a and twist1b knockdown increased runx2b expression. We have further demonstrated that phenotypes induced by twist1a and twist1b knockdown were rescued by runx2b knockdown. Together, these results suggest that twist1a and twist1b control skeletal development and dorsoventral patterning by regulating runx2b in zebrafish and provide potential targets for the treatment of diseases or syndromes associated with decreased skeletal development.


Spin-droplet state of an interacting 2D electron system.
We report thermodynamic magnetization measurements of two-dimensional electrons in several high-mobility Si metal-oxide-semiconductor field-effect transistors. We provide evidence for an easily polarizable electron state in a wide density range from insulating to deep into the metallic phase. The temperature and magnetic field dependence of the magnetization is consistent with the formation of large-spin droplets in the insulating phase. These droplets melt in the metallic phase with increasing density and temperature, though they survive up to large densities.


Private pay clients in adult day services.
Data collected for all 3,992 participants in Maryland's adult day care programs as of December 31, 1993 showed that the majority of clients were supported by publicly supported "welfare" funding sources. The authors examined the differences in characteristics and service needs between the public payer population and private pay patients, including those who were charged on a sliding scale. They found that private pay clients were not dependent on others to "initiate service arrangements when they want and can find them." Private pay clients were twice as likely to be self or family referrals and more likely to be older, white, and living with a spouse or adult child. Private pay patients were also much more likely to have a history of the recent onset of cognitive impairment and associated memory loss but less likely to fall into the more ADL dependent categories. The nuclear families of private pay clients who are primary caregivers are described as the "critical marketing targets" and that services specifically for the cognitively impaired should be developed.


A New Hypothesis on the Frequency Discrimination of the Cochlea.
Medial olivocochlear efferent (MOCE) neurons innervate outer hair cells (OHCs) of the cochlea, which in turn leads to basilar membrane motion. We hypothesized that MOCE-induced alterations in basilar membrane motion, independent of traveling waves, is responsible for the cochlear frequency discrimination of sound. Eleven guinea pigs underwent bilateral otoscopic and audiologic evaluations under general anesthesia. The study comprised two parts. Part I (n=11) included spontaneous otoacoustic emission (SOAE) recordings with or without contralateral pure-tone acoustic stimuli (1 and 8 kHz) at 60 dB sound pressure level (SPL). Part II involved pure-tone (1 or 8 kHz) acoustic trauma in the right ears of two randomly selected subgroups (G1: 1 kHz; n=4 and G8: 8 kHz; n=4). The remaining three animals served as controls. After frequency-specific deafness was confirmed by distortion product otoacoustic emission (DPOAE), SOAEs were recorded in the left ears in the presence of a contralateral pure-tone (1 and 8 kHz) stimulus of 60 dB SPL. Furthermore, the surface of the organ of Corti was examined by scanning electron microscopy (SEM). The contralateral pure tone led to frequency-specific activation in SOAEs in part I (without trauma) and part II (with trauma) measurements. SEM showed heterogeneous OHC damage along the cochlea in traumatized ears with pure tone. We suggest that MOCEs convey acoustic information from traumatized ears to intact ears. Traumatized ears can show frequency-specific activation in the presence of diffuse damage in OHCs that excludes the passive transmission of the pressure wave from the perilymph to the basilar membrane.


Fibrates, glitazones, and peroxisome proliferator-activated receptors.
Several decades ago, fibrates were approved for the treatment of dyslipidemia, whereas thiazolidinediones were screened in animal models to improve glucose homeostasis and were subsequently developed for the treatment of type 2 diabetes mellitus. Relatively recently, these drugs were found to act via peroxisome proliferator-activated receptors, nuclear receptors that control lipid metabolism and glucose homeostasis. In this historical perspective, we discuss the history of discovery of the peroxisome proliferator-activated receptors, from the clinical development of their agonists to the subsequent discovery of these receptors and their mechanisms of action, to finally evoke possibilities of targeted pharmacology for future development of selective peroxisome proliferator-activated receptor modulators.


Molecular cardiology in translation: gene, cell and chemical-based experimental therapeutics for the failing heart.
Acquired and inherited diseases of the heart represent a major health care issue in this country and throughout the World. Clinical medicine has made important advancements in the past quarter century to enable several effective treatment regimes for cardiac patients. Nevertheless, it is apparent that even with the best care, current treatment strategies and therapeutics are inadequate for treating heart disease, leaving it arguably the most pressing health issue today. In this context it is important to seek new approaches to redress the functional deficits in failing myocardium. This review focuses on several recent gene, cell and chemical-based experimental therapeutics currently being developed in the laboratory for potential translation to patient care. For example, new advances in bio-sensing inducible gene expression systems offer the potential for designer cardio-protective proteins to be expressed only during hypoxia/ischemia in the heart. Stem cells continue to offer the promise of cardiac repair, and some recent advances are discussed here. In addition, discovery and applications of synthetic polymers are presented as a chemical-based strategy for acute and chronic treatment of diseased and failing cardiac tissue. Collectively, these approaches serve as the front lines in basic biomedical research, with an eye toward translation of these findings to clinically meaningful applications in cardiac disease.


The socio-cultural contexts of sexually transmitted diseases in South Africa: implications for health education programmes.
Sexually transmitted diseases (STDs) are widespread in South Africa and contribute to the growing HIV epidemic. As an important step in curtailing the spread of STDs, this study explores STD patients' illness representations within its socio-cultural context, particularly gender relationships. In-depth interviews were conducted with Xhosa- and Zulu-speaking patients in clinics in Cape Town, Western Cape (N = 67) and in rural areas of Kabokweni, Mpumalanga (N = 21) The findings suggest that STD patients' illness representations are reflections of their socio-cultural understanding of disease and of culturally defined gender relations. This, in turn, impacts on their general perceptions of the cause of STDs, their perceptions of the risk of contracting STDs, them entering and using formal and traditional medical treatment and on their ideas of prevention. Thus, healthy behaviours need to be facilitated through multiple educational strategies focusing on an improved understanding of the cause of the STD in its context of gender relations, the development of interpersonal and technical skills, as well as focusing on cues for action.


Mefloquine-resistant falciparum malaria on the Thai-Burmese border.
Mefloquine is the treatment of choice for uncomplicated multiresistant falciparum malaria, and in combination with sulphadoxine and pyrimethamine (MSP) at a single dose of 15/30/1.5 mg/kg, respectively, has been used in Thailand for the past 6 years. In 1985-86, MSP cured over 98% of 5192 patients with falciparum malaria on the Thai-Burmese border. 4 years later we studied the efficacy of MSP in 395 patients at the same location. The cure rate at 28 days was 70.8% (95% Cl 67-77.2%). The proportion of early treatment failures (in whom parasitaemia did not clear) had risen from 0.27 to 3.7% (p less than 0.0001). Failure rates were 50% in children under 6 years old, 29% in the 6-15 age group, and 19% in adults (p less than 0.001). Patients with early treatment failure were retreated with 25 mg/kg mefloquine, but 27% had a further recrudescence of infection within 28 days. The mean (95% Cl) serum mefloquine concentration at the time of first recrudescence was 638 (546-730) ng/ml, a value previously associated with successful treatment. Mefloquine concentrations were no lower in those with recrudescent infections than in age-matched successfully treated patients, suggesting that pharmacokinetic factors were not responsible for the high treatment-failure rate. Plasmodium falciparum has developed resistance to mefloquine rapidly, despite the addition of sulphadoxine and pyrimethamine and strict control of drug administration. The MSP combination should now be abandoned.


Role of focal adhesion kinase Ser-732 phosphorylation in centrosome function during mitosis.
Focal adhesion kinase (FAK) is the major cytoplasmic tyrosine kinase in focal adhesions and a critical mediator of integrin signaling in a variety of cells, including endothelial cells (ECs). Here we describe a new function for FAK in the regulation of centrosome functions in a Ser-732 phosphorylation-dependent manner during mitosis. Deletion of FAK in primary ECs causes increases in centrosome numbers, multipolar and disorganized spindles, and unaligned chromosomes during mitosis. Re-expression of wild-type FAK, but not S732A mutant, rescued these mitotic defects, suggesting a role for Ser-732 phosphorylation in the regulation of centrosomal functions. Consistent with this possibility, Ser-732-phosphorylated FAK was found to co-localize in centrosomes in mitotic cells. FAK also associated with cytoplasmic dynein in a Ser-732 phosphorylation-dependent manner. Further analysis in FAK-null primary ECs showed that S732A mutant could rescue EC migration but not proliferation or tubulogenesis in vitro. Last, we showed that deletion of FAK in ECs reduced tumor angiogenesis in vivo, which could be restored by re-expression of wild-type FAK but not S732A mutant. Together, these studies demonstrated a novel role for Ser-732 phosphorylation of FAK in the regulation of centrosome function during mitosis, which may contribute to EC proliferation and angiogenesis.


The role of collaborative working between the arts and care sectors in successfully delivering participatory arts activities for older people in residential care settings.
In the UK support for older people living in residential care to undertake meaningful activities is provided by Activities Co-ordinators. There is also a growing trend for care home providers to invite arts organisations into care settings to deliver a range of arts and cultural activities. These arts and cultural activities are delivered by Arts Facilitators, who are distinct from Activities Co-ordinators because their practice is specifically in an art form. This paper presents findings from the Creative Journeys research project which focused on exploring the role of participatory arts within residential care home in developing and maintaining social relationships between residents and staff. One of the objectives of the research was to identify factors which facilitated or hindered the delivery and impact of the activities. Data collection methods included observations and semi-structured interviews with residents and staff. Thematic analysis was conducted on the qualitative data. It was found that a key factor in the successful delivery of the groups was the working relationship between the Arts Facilitators and the Activities Co-ordinators. This relationship is explored and presented under three main themes: the collaborative process, practicalities and preparation and the approach of the Arts Facilitator. The Activities Co-ordinators' role is an under-researched area, but they play a central role in supporting visiting arts organisations to deliver the sessions and in enabling residents to attend and engage with meaningful activities.


[Immunology in medical practice. XIV. Central nervous system complications in systemic autoimmune diseases].
Complications of the central nervous system (CNS) are common in systemic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and primary Sjögren's syndrome. Specific diagnostic tests are lacking and early intervention with immunosuppressive therapy is frequently necessary. Therefore knowledge of these CNS complications is essential for early diagnosis and treatment. Residual cognitive effects were observed in some but not in all tests after prolonged heavy cannabis use. The effects were mostly mild. The relationship of cannabis use, psychotic effects and schizophrenia was unclear; the cannabis conceivably gave relief, but it also appeared that cannabis caused schizophrenia in young people and (or) enhanced the symptoms, especially in young people poorly able to cope with stress or in whom the antipsychotic therapy was unsuccessful.


Characterization of domain interfaces in monomeric and dimeric ATP synthase.
We disassembled monomeric and dimeric yeast ATP synthase under mild conditions to identify labile proteins and transiently stable subcomplexes that had not been observed before. Specific removal of subunits alpha, beta, oligomycin sensitivity conferring protein (OSCP), and h disrupted the ATP synthase at the gamma-alpha(3)beta(3) rotor-stator interface. Loss of two F(1)-parts from dimeric ATP synthase led to the isolation of a dimeric subcomplex containing membrane and peripheral stalk proteins thus identifying the membrane/peripheral stalk sectors immediately as the dimerizing parts of ATP synthase. Almost all subunit a was found associated with a ring of 10 c-subunits in two-dimensional blue native/SDS gels. We therefore postulate that c10a1-complex is a stable structure in resting ATP synthase until the entry of protons induces a breaking of interactions and stepwise rotation of the c-ring relative to the a-subunit in the catalytic mechanism. Dimeric subunit a was identified in SDS gels in association with two c10-rings suggesting that a c10a2c10-complex may constitute an important part of the monomer-monomer interface in dimeric ATP synthase that seems to be further tightened by subunits b, i, e, g, and h. In contrast to the monomer-monomer interface, the interface between dimers in higher oligomeric structures remains largely unknown. However, we could show that the natural inhibitor protein Inh1 is not required for oligomerization.


Solid-phase synthesis provides a modular, lysine-based platform for fluorescent discrimination of nitroxyl and biological thiols.
We describe a modular, synthetically facile solid-phase approach aimed at separating the fluorescent reporter and binding unit of small-molecule metal-based sensors. The first representatives contain a lysine backbone functionalized with a tetramethylrhodamine fluorophore, and they operate by modulating the oxidation state of a copper ion ligated to an [N4] (cyclam) or an [N2O] (quinoline-phenolate) moiety. We demonstrate the selectivity of their Cu(ii) complexes for sensing nitroxyl (HNO) and thiols (RSH), respectively, and investigate the mechanism responsible for the observed reactivity in each case. The two lysine conjugates are cell permeable in the active, Cu(ii)-bound forms and retain their analyte selectivity intracellularly, even in the presence of interfering species such as nitric oxide, nitrosothiols, and hydrogen sulfide. Moreover, we apply the new probes to discriminate between distinct levels of intracellular HNO and RSH generated upon stimulation of live HeLa cells with ascorbate and hydrogen sulfide, respectively. The successful implementation of the lysine-based sensors to gain insight into biosynthetic pathways validates the method as a versatile tool for producing libraries of analogues with minimal synthetic effort.


International Comparison of the Levels and Potential Correlates of Objectively Measured Sedentary Time and Physical Activity among Three-to-Four-Year-Old Children.
Physical activity (PA) patterns track from childhood through to adulthood. The study aimed to determine the levels and correlates of sedentary time (ST), total PA (TPA), and moderate-to-vigorous PA (MVPA) in preschool-aged children. We conducted cross-sectional analyses of 1052 children aged three-to-four-years-old from six studies included in the International Children's Accelerometry Database. Multilevel linear regression models adjusting for age, gender, season, minutes of wear time, and study clustering effects were used to estimate associations between age, gender, country, season, ethnicity, parental education, day of the week, time of sunrise, time of sunset, and hours of daylight and the daily minutes spent in ST, TPA, and MVPA. Across the UK, Switzerland, Belgium, and the USA, children in our analysis sample spent 490 min in ST per day and 30.0% and 21.2% of children did not engage in recommended daily TPA (≥180 min) and MVPA (≥60 min) guidelines. There was evidence for an association between all 10 potential correlates analyzed and at least one of the outcome variables; average daily minutes spent in ST, TPA and/or MVPA. These correlates can inform the design of public health interventions internationally to decrease ST and increase PA in preschoolers.


How tree species fill geographic and ecological space in eastern North America.
Ecologists broadly accept that the number of species present within a region balances regional processes of immigration and speciation against competitive and other interactions between populations that limit distribution and constrain diversity. Although ecological theory has, for a long time, addressed the premise that ecological space can be filled to 'capacity' with species, only with the availability of time-calibrated phylogenies has it been possible to test the hypothesis that diversification slows as the number of species in a region increases. Focusing on the deciduous trees of eastern North America, this study tested predictions from competition theory concerning the distribution and abundance of species. Local assemblages of trees tabulated in a previous study published in 1950 were analysed. Assemblages were ordinated with respect to species composition by non-metric multidimensional scaling (NMS). Distributions of trees were analysed by taxonomically nested analysis of variance, discriminant analysis based on NMS scores, and canonical correlation analysis of NMS scores and Bioclim climate variables. Most of the variance in species abundance and distribution was concentrated among closely related (i.e. congeneric) species, indicating evolutionary lability. Species distribution and abundance were unrelated to the number of close relatives, suggesting that competitive effects are diffuse. Distances between pairs of congeneric species in NMS space did not differ significantly from distances between more distantly related species, in contrast to the predictions of both competitive habitat partitioning and ecological sorting of species. Eastern deciduous forests of North America do not appear to be saturated with species. The distributions and abundances of individual species provide little evidence of being shaped by competition from related (i.e. ecologically similar) species and, by inference, that diversification is constrained by interspecific competition.


Dietary diversity and adequacy of women caregivers in a peri-urban informal settlement in South Africa.
Simple measures reflecting dietary quality are preferred for assessment of dietary intakes in low-income communities, e.g. dietary diversity that reflects a healthy, varied, nutritious diet, associated with nutrient adequacy. A strong association between household income and food access suggests dietary diversity assessment as one of the indicators of household food security. The aim of this study was to assess the food security situation of black women in an informal settlement by exploring their food access capabilities through dietary diversity measures and the coping strategies they employ to cope with poverty and hunger. A randomly selected sample of black women living in an informal settlement completed a pretested socio-demographic questionnaire (socio-economic circumstances) and validated questionnaires (1-wk quantified food frequency questionnaire: diversity measures; 24-h recall: nutrient intake; Cornell Hunger Scale: coping strategies). Food variety scores and food group diversity scores were calculated from frequency analyses for all foods and food groups. Nutrient adequacy ratios for various nutrients and the mean adequacy ratio for their diet were calculated. Relationships between dietary diversity and nutritional adequacy were investigated with Pearson correlations. Food variety score cut points were tested for sensitivity and specificity against nutritional adequacy. Intakes were deficient for all nutrients except carbohydrates. Individual mean ± SD nutrient adequacy ratios ranging between 0.15 ± 0.18 and 0.95 ± 0.19 confirmed the poor dietary quality. Zero to 40 individual foods were consumed, but the mean ± SD food variety score was only 3.17 ± 1.21, indicating low food diversity, as did the low dietary diversity score (2.82 ± 0.99) using 0 to 6 food groups. Limited food access and food variety in poor households resulted in inadequate nutrient intakes (low nutrient adequacy ratios), confirmed by poor dietary diversity (food variety score and food group diversity score). Dietary diversity assessment can successfully replace traditional dietary assessment tools in poverty-stricken or low-income communities where quick assessments are often required to assess the greatest need.


The interaction between cannabis use and a CB1-related polygenic co-expression index modulates dorsolateral prefrontal activity during working memory processing.
Convergent findings indicate that cannabis use and variation in the cannabinoid CB1 receptor coding gene (CNR1) modulate prefrontal function during working memory (WM). Other results also suggest that cannabis modifies the physiological relationship between genetically induced expression of CNR1 and prefrontal WM processing. However, it is possible that cannabis exerts its modifying effect on prefrontal physiology by interacting with complex molecular ensembles co-regulated with CB1. Since co-regulated genes are likely co-expressed, we investigated how genetically predicted co-expression of a molecular network including CNR1 interacts with cannabis use in modulating WM processing in humans. Using post-mortem human prefrontal data, we first computed a polygenic score (CNR1-PCI), combining the effects of single nucleotide polymorphisms (SNPs) on co-expression of a cohesive gene set including CNR1, and positively correlated with such co-expression. Then, in an in vivo study, we computed CNR1-PCI in 88 cannabis users and 147 non-users and investigated its interaction with cannabis use on brain activity during WM. Results revealed an interaction between cannabis use and CNR1-PCI in the dorsolateral prefrontal cortex (DLPFC), with a positive relationship between CNR1-PCI and DLPFC activity in cannabis users and a negative relationship in non-users. Furthermore, DLPFC activity in cannabis users was positively correlated with the frequency of cannabis use. Taken together, our results suggest that co-expression of a CNR1-related network predicts WM-related prefrontal activation as a function of cannabis use. Furthermore, they offer novel insights into the biological mechanisms associated with the use of cannabis.


[Encounter of cancer cells with bone. Development of bone metastasis-specific targeting therapy].
Bone, as well as liver and lungs, is one of the most preferential metastatic targets for solid cancers including breast, prostate, and lung cancers. Control of the bone metastasis is clinically important ; because they are frequently associated with bone pain and pathological fracture which greatly diminish the quality of life for patients. Interaction between cancer cells and microenvironment of metastatic site play an important role for establishment of cancer metastasis. The understanding of their mechanisms has been improved in recent years, and they will be new therapeutic strategies to cure the bone metastasis. Bisphosphonates has been clinically used for the bone metastasis. In addition, RANKL-RANK targeted drugs and cathepsin K inhibitors are also expected to be fruitful drugs for the bone metastasis. In this review paper, we summarize the molecular mechanism of these drugs, especially with regarding to the breast cancer bone metastasis. Furthermore, we touch upon the ubiquitin ligase CHIP which recently found as a master gene in the progression and metastasis of breast cancer.


[Regional chemoinfusion and radiation therapy to patients with breast cancer metastases to the brain: preliminary results].
Effectiveness and safety of regional chemoinfusion in combination with radiation therapy in patients with breast cancer with metastases to the brain was clinically assessed. Cerebral angiography with chemoinfusion was fulfilled in six patients. The procedure could not be fulfilled completely in one patient because of transient vascular and neurological disorders. In the other five patients the regional superselective chemoinfusion was fulfilled successfully to the arteries feeding the metastatic foci in the brain with Carmustin in dosage 100 mg in combination with radiation therapy that was fulfilled in all six patients before the planned total focal dose. The incomplete response (n=5) to the treatment and stabilization of the process (n=l) were noted in six observations.


Finite temperature grand canonical ensemble study of the minimum electrophilicity principle.
We analyze the minimum electrophilicity principle of conceptual density functional theory using the framework of the finite temperature grand canonical ensemble. We provide support for this principle, both for the cases of systems evolving from a non-equilibrium to an equilibrium state and for the change from one equilibrium state to another. In doing so, we clearly delineate the cases where this principle can, or cannot, be used.


Integrative taxonomy reveals the conspecific status of Xerotricha madritensis (Rambur, 1868) and Helicella candoni Thach, 2018 (Gastropoda, Geomitridae).
The Mediterranean region is a biodiversity hotspot. Mollusks represent the second most diverse phylum, with high species richness, endemism, and significant numbers of threatened species. The non-marine species are an especially vulnerable group. New taxa are frequently described although the descriptions often lack biological support. This is true for Helicella candoni Thach, 2018, originally described from Puerto de Santa María, Cádiz, Spain. Thatch (2018) considered H. candoni to be similar to Xerotricha madritensis (Rambur, 1868) but the comparison was made on the basis of basic conchological characters. The present study analyzed topotypes of X. madritensis and H. candoni using integrative taxonomy to evaluate the relationship of the two taxa and their status within Helicella A. Férussac, 1821 and Xerotricha Monterosato, 1892 respectively. A matrix of the mitochondrial cytochrome c oxidase subunit I (COI) yielded a total of 618 bp. Bayesian and Maximum Likelihood analyses showed that H. candoni and X. madritensis clustered closely together along with Helicella itala. Mean sequence divergence for COI between H. candoni and X. madritensis was 1.42 %. Both taxa are similar in shell shape and colour. Genitalia dimensions of H. condoni were very similar to those of X. madritensis. These data indicate that H. candoni is a junior synonym of X. madritensis. The phylogenetic analyses showed that, despite its morphological similarities, X. madritensis is a species of Helicella instead of Xerotricha.


Cerebral perfusion in chronic stroke: implications for lesion-symptom mapping and functional MRI.
Lesion-symptom mapping studies are based upon the assumption that behavioral impairments are directly related to structural brain damage. Given what is known about the relationship between perfusion deficits and impairment in acute stroke, attributing specific behavioral impairments to localized brain damage leaves much room for speculation, as impairments could also reflect abnormal neurovascular function in brain regions that appear structurally intact on traditional CT and MRI scans. Compared to acute stroke, the understanding of cerebral perfusion in chronic stroke is far less clear. Utilizing arterial spin labeling (ASL) MRI, we examined perfusion in 17 patients with chronic left hemisphere stroke. The results revealed a decrease in left hemisphere perfusion, primarily in peri-infarct tissue. There was also a strong relationship between increased infarct size and decreased perfusion. These findings have implications for lesion-symptom mapping studies as well as research that relies on functional MRI to study chronic stroke.


Is processing speed predictive of functional outcome in psychosis?
To investigate the contribution of processing speed in the prediction of various domains of outcome in psychosis. Data were drawn from the UK700 Case Management Trial of 708 patients with chronic psychotic illness. Regression analyses were applied to investigate cross-sectional and longitudinal associations between processing speed at baseline and measures of service use, social outcome and subjective outcome, taking into account current psychopathology and adjusting for baseline values of the outcome measure. Cross-sectionally, processing speed was associated with all three domains of outcome, although only associations in the social and subjective outcome domain remained significant after controlling for psychopathology and the effects differed between and within domains of outcome. Prospectively, only the subjective outcome measure of number of met and unmet needs (CAN) was weakly associated with baseline neurocognitive performance after adjustment for baseline needs. Other associations disappeared after adjustment for the baseline measure of outcome and/or baseline psychopathology. The finding of weak cross-sectional associations in the absence of specific and unconfounded longitudinal associations suggests that processing speed is an independent dimension of disease severity rather than a causal factor impacting on social outcome. Nevertheless, longitudinal change in patient reported needs may be weakly sensitive to baseline cognitive impairment.


On the role of material properties in ascending thoracic aortic aneurysms.
One of the obstacles standing before the biomechanical analysis of an ascending thoracic aortic aneurysm (ATAA) is the difficulty in obtaining patient-specific material properties. This study aimed to evaluate differences on ATAA-related stress predictions resulting from the elastostatic analysis based on the optimization of arbitrary material properties versus the application of patient-specific material properties determined from ex-vivo biaxial testing. Specifically, the elastostatic analysis relies the on the fact that, if the aortic wall stress does not depend on material properties, the aorta has to be statistically determinate. Finite element analysis (FEA) was applied to a group of nine patients who underwent both angio-CT imaging to reconstruct ATAA anatomies and surgical repair of diseased aorta to collect tissue samples for experimental material testing. Tissue samples cut from excised ATAA rings were tested under equibiaxial loading conditions to obtain experimentally-derived material parameters by fitting stress-strain profiles. FEAs were carried out using both optimized and experimentally-derived material parameters to predict and compare the stress distribution using the mean absolute percentage error (MAPE). Although physiological strains were below yield point (range of 0.08-0.25), elastostatic analysis led to errors on the stress predictions that depended on the type of constitutive model (highest MAPE of 0.7545 for Yeoh model and 0.7683 for Fung model) and ATAA geometry (lowest MAPE of 0.0349 for patient P.7). Elastostatic analysis needs better understanding of its application for determining aneurysm mechanics, and patient-specific material parameters are essential for reliable accurate stress predictions in ATAAs.


Predictors affecting quality of life in patients with upper aerodigestive tract cancers: a case-control study from India.
The aim of this study was to measure quality of life (QOL) in patients with upper aerodigestive tract (UADT) cancer in comparison with hospital-based controls. We also assessed the impact of various clinical predictors at time of diagnosis of disease/cancer on QOL in these patients. A case-control study was conducted (N = 480) with 240 UADT cancer cases and 240 controls matched by gender and age (≥5 years) from 2 different hospitals in Pune, India. The University of Washington Quality of Life Questionnaire was used to measure QOL and was administered through face-to-face interviews. Various QOL domains were analyzed by using one-way analysis of variance and Bonferroni adjustments for post hoc comparisons. Cases had significantly lower scores across all domains of QOL compared with controls. Overall, the most affected domains were anxiety and mood. Cancer site significantly influenced QOL, with patients with cancers of the oropharynx and hypopharynx having the worst mean scores across all domains. Patients with stage IV cancer had the worst mean scores across the majority of the QOL domains. Our findings highlight the complex interactions between individual and clinical predictors that have an impact on QOL. QOL needs to be incorporated as an important outcome measure in an individualized approach to therapeutic and palliative care planning to enable a better quality of survival of patients with UADT cancers.


Histological changes and histamine release induced by dactimicin in isolated perfused rat kidney.
The nephrotoxicity of aminoglycosides has been the object of numerous works of research showing that different molecules belonging to the same family of antibiotics can exert their toxic action in different ways. The aim of the present research was to evaluate the nephrotoxicity of dactimicin (DTC), a recently synthesized aminoglycoside antibiotic, as compared to gentamicin (GTM), amikacin (AMK) and fortimicin (FTM). The experimental model used was the isolated perfused rat kidney, and the parameters evaluated were histamine release and histological findings. The results showed that GTM was able to induce a significantly higher release of histamine than AMK, FTM, or DTC. AMK provoked a higher level of histamine release than FTM or DTC, although the differences between the three were not significant. Histological preparations obtained with GTM revealed large-scale lesions, which however were less detectable with AMK, and much less with DTC.


Peak insertion torque correlated to histologically and clinically evaluated bone density.
: Establish a correlation between dental implant insertion torque (IT) and bone density. : In 18 patients, implant site preparation was initiated using a trephine drill to retrieve a bone biopsy and completed with standard drills. Bone type was assessed during drilling according to surgeon's tactile sense. Forty implants were placed and peak IT values were recorded. Osseointegration was evaluated clinically at abutment connection. Data were analyzed using Pearson product-moment correlation coefficient. : All implants but one achieved osseointegration. D1 and D4 bone types were significantly assessed using tactile sense. IT values ranged from 15 to 150 Ncm with a mean value of 78.30 Ncm. Mean IT was significantly higher in D1 bone (126.67 Ncm) and lower in D4 bone (40.22 Ncm) (P value <0.0001), whereas intermediate values were noted in D2 and D3 bone with no significant difference between these bone types (P value = 0.462). Statistically significant correlation was found between bone volume and IT values (r = +0.771, P < 0.0001). No statistically significant correlation was found between implant length and/or diameter and IT in all bone densities. : Clinical assessment of bone density during drilling may be achieved in hard and soft bone but not in intermediate densities. Increasing peak IT values correlated with increasing bone volume. High IT does not seem to alter osseointegration process.


Protein expression profiling of plasma and lungs at different stages of metastatic development in a human triple negative breast cancer xenograft model.
The main objective of this study was to identify single proteins or protein networks that might be used as diagnostic biomarkers or for therapeutic purposes by evaluating the protein expression profiling of plasma and lungs at different stages of metastatic development in a human triple negative MDA-MB-231 breast cancer xenograft model. MDA-MB-231 tumour cells were injected into the mammary fat pads on one side of the groin area. The mice were sacrificed day 19 (pre-metastases) and day 54 (metastases). Non-injected mice served as controls. Plasma was collected and lungs harvested for both immunohistochemistry and protein analysis. The most striking observation in plasma was the initial reduction in haptoglobin level at the pre-metastatic stage, to a following significant increase in haptoglobin level at the metastatic stage, with a more than 4000-fold increase from the pre-metastatic to the metastatic phase. A corresponding increase in haptoglobin level was also found in lung tissue after metastasis. Fibrinogen beta chain also had a similar change in expression level in plasma as haptoglobin, however not as prominent. There were also changes in plasma thrombospondin-4 and transferrin receptor protein 1 levels, from an increase at the pre-metastatic stage, to a significant fall when metastases were established. This suggests that especially changes in haptoglobin, but also fibrinogen beta chain, thrombospondin-4 and transferrin receptor protein 1 is indicative of metastasis, at least in this breast cancer model, and should be further evaluated as general breast cancer biomarkers.


Multi-experiment nonlinear mixed effect modeling of single-cell translation kinetics after transfection.
Single-cell time-lapse studies have advanced the quantitative understanding of cellular pathways and their inherent cell-to-cell variability. However, parameters retrieved from individual experiments are model dependent and their estimation is limited, if based on solely one kind of experiment. Hence, methods to integrate data collected under different conditions are expected to improve model validation and information content. Here we present a multi-experiment nonlinear mixed effect modeling approach for mechanistic pathway models, which allows the integration of multiple single-cell perturbation experiments. We apply this approach to the translation of green fluorescent protein after transfection using a massively parallel read-out of micropatterned single-cell arrays. We demonstrate that the integration of data from perturbation experiments allows the robust reconstruction of cell-to-cell variability, i.e., parameter densities, while each individual experiment provides insufficient information. Indeed, we show that the integration of the datasets on the population level also improves the estimates for individual cells by breaking symmetries, although each of them is only measured in one experiment. Moreover, we confirmed that the suggested approach is robust with respect to batch effects across experimental replicates and can provide mechanistic insights into the nature of batch effects. We anticipate that the proposed multi-experiment nonlinear mixed effect modeling approach will serve as a basis for the analysis of cellular heterogeneity in single-cell dynamics.


KBG syndrome: Common and uncommon clinical features based on 31 new patients.
KBG syndrome (MIM #148050) is an autosomal dominant disorder characterized by developmental delay, intellectual disability, distinct craniofacial anomalies, macrodontia of permanent upper central incisors, skeletal abnormalities, and short stature. This study describes clinical features of 28 patients, confirmed by molecular testing of ANKRD11 gene, and three patients with 16q24 deletion encompassing ANKRD11 gene, diagnosed in a single center. Common clinical features are reported, together with uncommon findings, clinical expression in the first years of age, distinctive associations, and familial recurrences. Unusual manifestations emerging from present series include juvenile idiopathic arthritis, dysfunctional dysphonia, multiple dental agenesis, idiopathic precocious telarche, oral frenula, motor tics, and lipoma of corpus callosum, pilomatrixoma, and endothelial corneal polymorphic dystrophy. Facial clinical markers suggesting KBG syndrome before 6 years of age include ocular and mouth conformation, wide eyebrows, synophrys, long black eyelashes, long philtrum, thin upper lip. General clinical symptoms leading to early genetic evaluation include developmental delay, congenital malformations, hearing anomalies, and feeding difficulties. It is likely that atypical clinical presentation and overlapping features in patients with multiple variants are responsible for underdiagnosis in KBG syndrome. Improved knowledge of common and atypical features of this disorder improves clinical management.