Amino acid availability regulates p70 S6 kinase and multiple translation factors.
Incubation of Chinese hamster ovary cells without amino acids for up to 60 min caused a rapid marked decrease in p70 S6 kinase activity and increased binding of initiation factor eIF4E to its inhibitory regulator protein 4E-BP1. This was associated with dephosphorylation of 4E-BP1 and eIF4E and dissociation of eIF4E from eIF4G. All these effects were rapidly reversed by resupplying a mixture of amino acids and this was blocked by rapamycin and by inhibitors of phosphatidylinositol 3-kinase, implying a role for phosphatidylinositol 3-kinase in the signalling pathway linking amino acids with the control of p70 S6 kinase activity and the phosphorylation of these translation factors. Amino acid withdrawal also led to changes in the phosphorylation of other translation factors; phosphorylation of eIF4E decreased whereas elongation factor eEF2 became more heavily phosphorylated, each of these changes being associated with decreased activity of the factor in question. Earlier studies have suggested that protein kinase B (PKB) may act upstream of p70 S6 kinase. However, amino acids did not affect the activity of PKB, indicating that amino acids activate p70 S6 kinase through a pathway independent of this enzyme. Studies with individual amino acids suggested that the effects on p70 S6 kinase activity and translation-factor phosphorylation were independent of cell swelling. The data show that amino acid supply regulates multiple translation factors in mammalian cells.


Cranioplasty with a low-cost customized polymethylmethacrylate implant using a desktop 3D printer.
OBJECTIVECranioplasty implants should be widely available, low in cost, and customized or easy to mold during surgery. Although autologous bone remains the first choice for repair, it cannot always be used due to infection, fragmentation, bone resorption, or other causes, which led to use of synthetic alternatives. The most frequently used allogenic material for cranial reconstructions with long-term results is polymethylmethacrylate (PMMA). Three-dimensional printing technology has allowed the production of increasingly popular customized, prefabricated implants. The authors describe their method and experience with a customized PMMA prosthesis using a precise and reliable low-cost implant that can be customized at any institution with open-source or low-cost software and desktop 3D printers.METHODSA review of 22 consecutive patients undergoing CT-based, low-cost, customized PMMA cranioplasty over a 1-year period at a university teaching hospital was performed. Preoperative data included patient sex and age; CT modeling parameters, including the surface area of the implant (defect); reason for craniectomy; date(s) of injury and/or resections; the complexity of the defect; and associated comorbidities. Postoperative data included morbiditiy and complications, such as implant exposure, infection, hematoma, seroma, implant failure, and seizures; the cost of the implant; and cosmetic outcome.RESULTSIndications for the primary craniectomy were traumatic brain injury (16, 73%), tumor resection (3, 14%), infection (1, 4%), and vascular (2, 9%). The median interval between previous surgery and PMMA cranioplasty was 12 months. The operation time ranged from 90 to 150 minutes (mean 126 minutes). The average cranial defect measured 65.16 cm2 (range 29.31-131.06 cm2). During the recovery period, there was no sign of infection, implant rejection, or wound dehiscence, and none of the implants had to be removed over a follow-up ranging from 1 to 6 months. The aesthetic appearance of all patients was significantly improved, and the implant fit was excellent.CONCLUSIONSThe use of a customized PMMA was associated with excellent patient, family, and surgeon satisfaction at follow-up at a fraction of the cost associated with commercially available implants. This technique could be an attractive option to all patients undergoing cranioplasty.


Working in partnership with parents: the experience and challenge of practice innovation in child and family health nursing.
This study investigated what Family Partnership Model practice means in the day-to-day practice of child and family health nurses working with parents. The Family Partnership Model has been widely implemented in child and family health services in Australia and New Zealand, with limited understanding of the implications for nursing practice. A qualitative interpretive study design was used. Semi-structured interviews were conducted with 22 nurse participants, who had completed the Family Partnership Model training programme. Subsequent focus groups enabled these participants to validate the themes identified in the initial analysis and to confirm that the nurses concurred with the issues raised. Thematic content analysis produced rich descriptions and explanation of nurses' experiences and perspectives. results: Four themes emerged from the analysis: experience of changing practices, exploring with parents, challenging unhelpful constructions and a commitment to examining practice. Overall, the participants embraced the use of the Family Partnership Model, providing examples of change and increasing confidence in their approach to working with parents. This study demonstrates that the effective utilisation of the Family Partnership Model in nursing practice is a more complex and dynamic process than simply embracing the model. There are significant challenges to be negotiated when implementing new ways of working with parents, particularly questioning existing dominant forms of practice for nurses, managers and wider health organisations, and their clients. This paper also raises issues about sustaining practice innovation, which extends beyond the best intent of individual nurses, requiring receptive organisational conditions and leadership.


Methamphetamine-induced changes in AP-1 binding and dynorphin in the striatum: correlated, not causally related events?
Activation of D1 dopamine (DA) receptors in the striatum increases the expression of the opioid neuropeptide, dynorphin (DYN). While cAMP is generally accepted as a second messenger in this signal transduction pathway, the role of Fos/FRA proteins and AP-1 binding in mediating D1 receptor-induced changes in DYN expression remains uncertain. In this study, DYN peptide and mRNA levels, as well as Fos/FRA proteins and AP-1 DNA binding activity, were measured in individual animals following acute challenge with the psychostimulant drug methamphetamine (METH). METH caused an initial decrease in striatal levels of DYN A, reflecting increased peptide release. Six hours postinjection, DYN mRNA levels were significantly elevated by METH as compared to vehicle-injected controls. At the same time, these drugs increased the expression of Fos/FRA-ir proteins, in particular the 35- and 40-kDa molecular weight species, and increased binding to the AP-1 DNA element. Analyses of the time course of METH's effects revealed that DYN mRNA levels, Fos/FRA proteins and AP-1 binding activity showed variable increases by 3 h but all were significantly elevated above control levels by 6 h posttreatment. The D1-specific antagonist, SCH 23390, completely blocked the METH-induced changes in DYN peptide and mRNA levels while a D2 receptor antagonist (sulpiride) had little or no effect. These data indicate that stimulant drugs such as METH increase the expression of DYN and AP-1 factors in the striatum via a D1 receptor-mediated mechanism. However, the finding that AP-1 binding merely paralleled, but did not precede, the increase in DYN expression, as would be expected if it were mediating increased gene transcription, suggests these may be correlative, not causally related events.


Investigation of cation-binding properties of cardiac troponin C peptides by circular-dichroism spectroscopy.
Bovine cardiac troponin C was cleaved at residues cysteine-35 and cysteine-84. Three peptides, N-terminal (residues 1-34), central (residues 35-83) and C-terminal (residues 84-161), of cardiac troponin C were obtained in a homogeneous state. Saturation of troponin C or its C-terminal peptide with Ca2+ or Mg2+ is accompanied by an increase in the ellipticity at 222 nm in the c.d. spectrum. The half-maximal changes in the ellipticity of troponin C were observed at 32 nM-Ca2+ or 56 microM-Mg2+. The corresponding values for the C-terminal peptide are 7.1 nM for Ca2+ and 4.5 microM for Mg2+. The ellipticity of the central peptide (residues 35-83) containing the second cation-binding site was decreased on saturation with Ca2+. The half-maximal changes in the ellipticity occur at 80 microM-Ca2+. Study of the c.d. spectra suggests that the alpha-helices flanking the second cation-binding site of cardiac troponin C exist independently of Ca2+. Saturation of the third and fourth sites with these cations is associated with a considerable increase in the alpha-helix content, probably due to the formation of an alpha-helix flanking the third site on the N-terminus.


Diversity of lanthanide(III)-2,5-dihydroxy-1,4-benzenedicarboxylate extended frameworks: syntheses, structures, and magnetic properties.
Six lanthanide(III)-2,5-dihydroxy-1,4-benzenedicarboxylate frameworks, namely, [Ln(H(2)-DHBDC)(1.5)(H(2)O)(2)](n) (Ln = La (1) and Pr (2); H(4)-DHBDC = 2,5-dihydroxy-1,4-benzenedicarboxylic acid), {[Nd(H(2)-DHBDC)(1.5)(H(2)O)(3)](H(2)O)}(n) (3), {[Eu(H(2)-DHBDC)(NO(3))(H(2)O)(4)](H(2)O)(2)}(n) (4), and {[Ln(2)(H(2)-DHBDC)(2)(DHBDC)(0.5)(H(2)O)(3)](H(2)O)(4)}(n) (Ln = Gd (5) and Dy (6)), with four different structural types ranging from 1D chain, 2D layer to 3D networks have been synthesized and structurally characterized. Compounds La (1) and Pr (2) are isomorphous and exhibit 3D frameworks with the unique 1D tubular channels. Compounds Nd (3) and Eu (4) are 2D layer and 1D zigzag chain, respectively, which are further extended to 3D supramolecular frameworks through extensive hydrogen bonds. Isomorphous compounds of Gd (5) and Dy (6) are 3D frameworks constructed from secondary infinite rod-shaped metal-carboxylate/hydroxyl building blocks. While the hydroxyl groups as secondary functional groups in the 1D chain of Eu (4) and 2D layer of Nd (3) are not bonded to the lanthanide centers, the hydroxyl groups in the 3D frameworks of La (1), Pr (2), Gd (5), and Dy (6) participate in coordinating to lanthanide centers and thus modify the structural types of theses compounds. The magnetic data of compounds Pr (2), Nd (3), Gd (5), and Dy (6) have been investigated in detail. In addition, elemental analysis, IR spectra, powder X-ray diffraction (PXRD) patterns and thermogravimetric analysis of these compounds are described.


National Institutes of Health State-of-the-Science Conference statement: Diagnosis and Management of Ductal Carcinoma In Situ September 22-24, 2009.
To provide health-care providers, patients, and the general public with a responsible assessment of currently available data on the diagnosis and management of ductal carcinoma in situ (DCIS). A non-Department of Health and Human Services, nonadvocate, 14-member panel representing the fields of oncology, radiology, surgery (general and reconstructive), pathology, radiation oncology, internal medicine, epidemiology, biostatistics, nursing, obstetrics and gynecology, preventative medicine and population health, and social work. In addition, 22 experts from pertinent fields presented data to the panel and conference audience. Presentations by experts and a systematic review of the literature prepared by the Minnesota Evidence-based Practice Center, through the Agency for Healthcare Research and Quality. Scientific evidence was given precedence over anecdotal experience. The panel drafted its statement based on scientific evidence presented in open forum and on published scientific literature. The draft statement was presented on the final day of the conference and circulated to the audience for comment. The panel released a revised statement later that day at http://consensus.nih.gov. This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the Federal Government. Clearly, the diagnosis and management of DCIS is highly complex with many unanswered questions, including the fundamental natural history of untreated disease. Because of the noninvasive nature of DCIS, coupled with its favorable prognosis, strong consideration should be given to elimination of the use of the anxiety-producing term "carcinoma" from the description of DCIS. The outcomes in women treated with available therapies are excellent. Thus, the primary question for future research must focus on the accurate identification of patient subsets diagnosed with DCIS, including those persons who may be managed with less therapeutic intervention without sacrificing the excellent outcomes presently achieved. Essential in this quest will be the development and validation of accurate risk stratification methods based on a comprehensive understanding of the clinical, pathological, and biological factors associated with DCIS.


Below versus above Ground Plant Sources of Abscisic Acid (ABA) at the Heart of Tropical Forest Response to Warming.
Warming surface temperatures and increasing frequency and duration of widespread droughts threaten the health of natural forests and agricultural crops. High temperatures (HT) and intense droughts can lead to the excessive plant water loss and the accumulation of reactive oxygen species (ROS) resulting in extensive physical and oxidative damage to sensitive plant components including photosynthetic membranes. ROS signaling is tightly integrated with signaling mechanisms of the potent phytohormone abscisic acid (ABA), which stimulates stomatal closure leading to a reduction in transpiration and net photosynthesis, alters hydraulic conductivities, and activates defense gene expression including antioxidant systems. While generally assumed to be produced in roots and transported to shoots following drought stress, recent evidence suggests that a large fraction of plant ABA is produced in leaves via the isoprenoid pathway. Thus, through stomatal regulation and stress signaling which alters water and carbon fluxes, we highlight the fact that ABA lies at the heart of the Carbon-Water-ROS Nexus of plant response to HT and drought stress. We discuss the current state of knowledge of ABA biosynthesis, transport, and degradation and the role of ABA and other isoprenoids in the oxidative stress response. We discuss potential variations in ABA production and stomatal sensitivity among different plant functional types including isohydric/anisohydric and pioneer/climax tree species. We describe experiments that would demonstrate the possibility of a direct energetic and carbon link between leaf ABA biosynthesis and photosynthesis, and discuss the potential for a positive feedback between leaf warming and enhanced ABA production together with reduced stomatal conductance and transpiration. Finally, we propose a new modeling framework to capture these interactions. We conclude by discussing the importance of ABA in diverse tropical ecosystems through increases in the thermotolerance of photosynthesis to drought and heat stress, and the global importance of these mechanisms to carbon and water cycling under climate change scenarios.


The Epigenetics of Epilepsy and Its Progression.
Epilepsy is a common and devastating neurological disorder characterized by recurrent and unprovoked spontaneous seizures. One leading hypothesis for the development and progression of epilepsy is that large-scale changes in gene transcription and protein expression contribute to aberrant network restructuring and hyperexcitability, resulting in the genesis of repeated seizures. Current research shows that epigenetic mechanisms, including posttranslational alterations to the proteins around which DNA is coiled, chemical modifications to DNA, and the activity of various noncoding RNA molecules exert important influences on these gene networks in experimental epilepsy. Key findings from animal models have been replicated in humans using brain tissue obtained from living patients at the time of neurosurgical resection for pharmacoresistant epilepsy. These findings have spurred efforts to target epigenetic processes to disrupt or modify epilepsy in experimental models with varying degrees of success. In this review, we will (1) summarize the epigenetic mechanisms implicated in epileptogenesis and epilepsy, (2) explore the influence of metabolic factors on epigenetic mechanisms, and (3) assess the potential of using epigenetic markers to support diagnosis and prognosis. Translation of these findings may guide the development of molecular biomarkers and novel therapeutics for prevention or modification of epileptic disorders.


Prediction of color change after tooth bleaching using fuzzy logic for Vita Classical shades identification.
Tooth bleaching is becoming increasingly popular among patients and dentists since it is a relatively noninvasive approach for whitening and lightening teeth. Instruments and visual assessment with respect to commercial shade guides are currently used to evaluate tooth color. However, the association between these procedures is imprecise and the degree of color change after tooth bleaching is known to vary substantially between studies; there are currently no objective guidelines to predict the effectiveness of a tooth-bleaching treatment. We propose a new methodology based on fuzzy logic as a natural means of representing the imprecision present when modeling the color change produced by a tooth-bleaching treatment on the basis of a tooth's initial chromatic values. This system has the advantage of producing a set of interpretable fuzzy rules that can subsequently be used by scientists and dental practitioners. The fuzzy system obtained has the special characteristic whereby the rule antecedents correspond to prebleaching shades of the well-known Vita commercial shade guide. Additionally, the rule consequents directly correspond with the expected CIELAB postbleaching values for each Vita shade, thanks to a modification of the system's inference structure. Finally, the values of these postbleaching CIELAB coordinates have been associated with Vita shades by evaluating their respective membership functions, thereby approximating which posttreatment Vita shades are to be expected for each prebleaching shade.


Prophylactic Cerclage Cabling Decreases the Intraoperative Periprosthetic Fracture Rate during Cement-Less Total Hip Arthroplasty in Patients with Severe Developmental Hip Dysplasia.
PURPOSE OF THE STUDY Cementless stems in highly dysplastic hips are considered to increase the risk of femoral fracture and associated morbidity. Several authors speculated to use prophylactic cabling in this patient group to prevent intraoperative fractures. This study aims to reveal objective results regarding the perioperative complications in a large and consecutive patient group with respect to use of prophylactic cabling. MATERIAL AND METHODS A retrospective comparative study was planned. A total of 122 consecutive patients with dysplastic hips of Crowe type 3 or 4, operated on with total hip arthroplasty (THA) and shortening osteotomy using a rectangular femoral stem were included. Patients were stratified according to use of a diaphyseal prophylactic cerclage cable. Perioperative complications were recorded. Clinical outcome was measured in terms of Harris Hip Score and Visual Analog Scale (VAS) for pain. All results were compared between the groups. RESULTS The mean follow-up time was 27 months. Two (2%) versus five (14%) patients had a fracture at the diaphyseal level in cabled versus non-cabled groups. Difference between groups was statistically significant (p=0.01). Relative risk of fracture in case of a non-cabling was 5.8 (p=0.03). Eleven (9%) patients had a non-displaced fracture at the metaphyseal level. No significant differences were detected with respect to preoperative clinical outcome scores or change in these scores between groups. CONCLUSIONS Femoral diaphyseal fracture rates are low when cementless, rectangular stems are used in dysplastic high riding hips. Prophylactic cerclage cabling further decreases the fracture risk and eases treatment in case of a fracture without causing additional complications and therefore is recommended. Key words: intraoperative fracture, periprosthetic fracture, total hip arthroplasty, cerclage cabling, developmental hip dysplasia, transverse shortening osteotomy.


A comparison of single-sample estimators of effective population sizes from genetic marker data.
In molecular ecology and conservation genetics studies, the important parameter of effective population size (Ne ) is increasingly estimated from a single sample of individuals taken at random from a population and genotyped at a number of marker loci. Several estimators are developed, based on the information of linkage disequilibrium (LD), heterozygote excess (HE), molecular coancestry (MC) and sibship frequency (SF) in marker data. The most popular is the LD estimator, because it is more accurate than HE and MC estimators and is simpler to calculate than SF estimator. However, little is known about the accuracy of LD estimator relative to that of SF and about the robustness of all single-sample estimators when some simplifying assumptions (e.g. random mating, no linkage, no genotyping errors) are violated. This study fills the gaps and uses extensive simulations to compare the biases and accuracies of the four estimators for different population properties (e.g. bottlenecks, nonrandom mating, haplodiploid), marker properties (e.g. linkage, polymorphisms) and sample properties (e.g. numbers of individuals and markers) and to compare the robustness of the four estimators when marker data are imperfect (with allelic dropouts). Extensive simulations show that SF estimator is more accurate, has a much wider application scope (e.g. suitable to nonrandom mating such as selfing, haplodiploid species, dominant markers) and is more robust (e.g. to the presence of linkage and genotyping errors of markers) than the other estimators. An empirical data set from a Yellowstone grizzly bear population was analysed to demonstrate the use of the SF estimator in practice.


Simvastatin in the Prevention of Recurrent Pancreatitis: Design and Rationale of a Multicenter Triple-Blind Randomized Controlled Trial, the SIMBA Trial.
Background: One in every four patients with a first episode of non-gallstone-related acute pancreatitis (AP) develops recurrent disease. Recurrent episodes of AP or acute flares of chronic pancreatitis (CP) are associated with decreased quality of life and progression of the disease. Besides removing the etiology of pancreatitis (which sometimes is not possible), there are no effective measures to prevent recurrence. Meta-analyses of randomized controlled trials, as well as epidemiological and cohort studies, suggest that statins may be protective against the development of index AP. Methods: The SIMBA study is a triple-blind randomized placebo-controlled, parallel-group multicenter trial. Patients with recurrent AP or with acute flares of CP (at least two episodes in the last 12 months) will be randomized to receive simvastatin 40 mg daily or placebo. During a 3-year study period, 144 patients (72 per arm of treatment) from 26 centers will be enrolled. The patients will receive the study treatment for 1 year. The primary aim is to compare the recurrence of AP or acute flares in CP. Secondary endpoints include the incidence of new-onset diabetes mellitus, new-onset exocrine pancreatic insufficiency (EPI), new-onset imaging signs of CP, frequency of all-cause hospital admissions, severity of AP, adherence to treatment, and frequency of adverse events. Discussion: The SIMBA trial will ascertain whether simvastatin, a safe, widely used and inexpensive drug, can change the natural course of recurrent pancreatitis. Trial Registration: ClinicalTrials.gov Identifier: NCT04021498.


Forensic Y-SNP analysis beyond SNaPshot: High-resolution Y-chromosomal haplogrouping from low quality and quantity DNA using Ion AmpliSeq and targeted massively parallel sequencing.
Y-chromosomal haplogroups assigned from male-specific Y-chromosomal single nucleotide polymorphisms (Y-SNPs) allow paternal lineage identification and paternal bio-geographic ancestry inference, both being relevant in forensic genetics. However, most previously developed forensic Y-SNP tools did not provide Y haplogroup resolution on the high level needed in forensic applications, because the limited multiplex capacity of the DNA technologies used only allowed the inclusion of a relatively small number of Y-SNPs. In a proof-of-principle study, we recently demonstrated that high-resolution Y haplogrouping is feasible via two AmpliSeq PCR analyses and simultaneous massively parallel sequencing (MPS) of 530 Y-SNPs allowing the inference of 432 Y-haplogroups. With the current study, we present a largely improved Y-SNP MPS lab tool that we specifically designed for the analysis of low quality and quantity DNA often confronted with in forensic DNA analysis. Improvements include i) Y-SNP marker selection based on the "minimal reference phylogeny for the human Y chromosome" (PhyloTree Y), ii) strong increase of the number of targeted Y-SNPs allowing many more Y haplogroups to be inferred, iii) focus on short amplicon length enabling successful analysis of degraded DNA, and iv) combination of all amplicons in a single AmpliSeq PCR and simultaneous sequencing allowing single DNA aliquot use. This new MPS tool simultaneously analyses 859 Y-SNPs and allows inferring 640 Y haplogroups. Preliminary forensic developmental validation testing revealed that this tool performs highly accurate, is sensitive and robust. We also provide a revised software tool for analysing the sequencing data produced by the new MPS lab tool including final Y haplogroup assignment. We envision the tools introduced here for high-resolution Y-chromosomal haplogrouping to determine a man's paternal lineage and/or paternal bio-geographic ancestry to become widely used in forensic Y-chromosome DNA analysis and other applications were Y haplogroup information from low quality / quantity DNA samples is required.


Tyrosine phosphorylation of measles virus nucleocapsid protein in persistently infected neuroblastoma cells.
Subacute sclerosing panencephalitis is a slowly progressing fatal human disease of the central nervous system which is a delayed sequel of measles virus (MV) infection. A typical pathological feature of this disease is the presence of viral ribonucleocapsid structures in the form of inclusion bodies and the absence of infectious virus or budding viral particles. The mechanisms governing the establishment and maintenance of a persistent MV infection in brain cells are still largely unknown. To understand the mechanisms underlying MV persistence in neuronal cells, a tissue culture model was studied. Clone NS20Y/MS of the murine neuroblastoma C1300 persistently infected with the wild-type Edmonston strain of MV secretes relatively high levels of alpha/beta interferon (IFN). As shown previously, treatment of the persistently infected cultures with anti-IFN serum converted the persistent state into a productive infection indicated by the appearance of multinucleated giant cells. In this study, we have investigated whether alpha/beta IFN produced by NS20Y/MS cells activates cellular protein tyrosine kinases which will induce tyrosine phosphorylating activity specific to virus-infected cells. We present data to show augmented protein tyrosine kinase activity in the persistently infected cells. We demonstrate that the MV N protein is phosphorylated on tyrosine in addition to serine and threonine in the persistent state but not in NS20Y cells acutely infected with MV.


[Robot-assisted transaxillary thyroid surgery; 5 years later].
Five years ago, robot-assisted transaxillary thyroidectomy (RATT) was introduced in the Netherlands. The major advantage of this technique, when compared to the conventional approach, is the prevention of a potentially disfiguring scar in the neck. In recent years, multiple large cohort studies have demonstrated that the quality of the resection, postoperative complications and functional and oncological outcomes are similar in patients treated with RATT when compared to the open procedure. However, no randomised controlled trials have been performed to confirm these findings. The Utrecht UMC is currently the only centre in the Netherlands that performs RATT. The most important reason for this is that this surgical technique can only be used in high-turnover thyroid centres that also have experience with robot-assisted surgery.


Selection Bias in Colorectal Surgery in a Non-Tertiary Hospital: Laparoscopic Versus Open Surgery.
Laparoscopy is used increasingly to treat malignant and benign colorectal surgical diseases. However, this practice is still not offered to all patients. Many barriers halt the widespread use of laparoscopic colorectal surgery. Both surgeon's and patient's factors contribute to limit a wider use of laparoscopy in colorectal surgery. We retrospectively analyzed 408 consecutive colorectal resections in a 4-year period, to find out if a selection bias exists in using laparotomy or laparoscopy for colorectal surgical diseases, and which factors are associated with a poor use of laparoscopy or to a preferred laparotomy. In our practice, advanced disease, American Society of Anesthesiologist class III and IV, and emergency status are all patient-related factors associated with laparotomy. Surgeon's age more than 52 years and lack of laparoscopic training are surgeon-related factors that negatively affect the chance of being operated on with the laparoscopic technique. An extensive laparoscopic colorectal training and a supporting environment, especially during the night shift, are needed to facilitate the use of laparoscopy in colorectal surgery avoiding a bias in selecting surgical candidates to one technique or another.


Neural stem cell-based treatment for neurodegenerative diseases.
Human neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are caused by a loss of neurons and glia in the brain or spinal cord. Neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and neural stem cells (NSCs), and stem cell-based cell therapies for neurodegenerative diseases have been developed. A recent advance in generation of a new class of pluripotent stem cells, induced pluripotent stem cells (iPSCs), derived from patients' own skin fibroblasts, opens doors for a totally new field of personalized medicine. Transplantation of NSCs, neurons or glia generated from stem cells in animal models of neurodegenerative diseases, including PD, HD, ALS and AD, demonstrates clinical improvement and also life extension of these animals. Additional therapeutic benefits in these animals can be provided by stem cell-mediated gene transfer of therapeutic genes such as neurotrophic factors and enzymes. Although further research is still needed, cell and gene therapy based on stem cells, particularly using neurons and glia derived from iPSCs, ESCs or NSCs, will become a routine treatment for patients suffering from neurodegenerative diseases and also stroke and spinal cord injury.


Isolation and characterization of a gene coding for a novel aspartate aminotransferase from Rhizobium meliloti.
Aspartate aminotransferase (AAT) is an important enzyme in aspartate catabolism and biosynthesis and, by converting tricarboxylic acid cycle intermediates to amino acids, AAT is also significant in linking carbon metabolism with nitrogen metabolism. To examine the role of AAT in symbiotic nitrogen fixation further, plasmids encoding three different aminotransferases from Rhizobium meliloti 104A14 were isolated by complementation of an Escherichia coli auxotroph that lacks three aminotransferases. pJA10 contained a gene, aatB, that coded for a previously undescribed AAT, AatB. pJA30 encoded an aromatic aminotransferase, TatA, that had significant AAT activity, and pJA20 encoded a branched-chain aminotransferase designated BatA. Genes for the latter two enzymes, tatA and batA, were previously isolated from R. meliloti. aatB is distinct from but hybridizes to aatA, which codes for AatA, a protein required for symbiotic nitrogen fixation. The DNA sequence of aatB contained an open reading frame that could encode a protein 410 amino acids long and with a monomer molecular mass of 45,100 Da. The amino acid sequence of aatB is unusual, and AatB appears to be a member of a newly described class of AATs. AatB expressed in E. coli has a Km for aspartate of 5.3 mM and a Km for 2-oxoglutarate of 0.87 mM. Its pH optimum is between 8.0 and 8.5. Mutations were constructed in aatB and tatA and transferred to the genome of R. meliloti 104A14. Both mutants were prototrophs and were able to carry out symbiotic nitrogen fixation.


The Acute Effects of Supramaximal High-Intensity Intermittent Exercise on Vascular Function in Lean vs. Obese Prepubescent Boys.
To determine the acute effects of high-intensity intermittent exercise (HIIE) on vascular function. Lean (n = 18, BMI = 17.1 ± 0.7) and obese (n = 17, BMI = 25.4 ± 0.8) prepubescent boys aged 10.2 ± 0.2 years were studied. HIIE consisted of 8 sets of 20 s of cycle ergometry at 100, 130, and 170% of VO2peak alternating with 10 s of rests. The obese group had higher (p < .05) body mass, BMI, body fat percentage, waist-hip ratio than the lean group. Carotid artery wall thickness and arterial stiffness as assessed by brachial-ankle pulse wave velocity (baPWV) were greater in the obese than in the lean group (p < .05). Brachial artery flow-mediated dilation (FMD) was not different between the groups. Total energy expenditure increased gradually as the exercise intensity increased in both groups (p < .05). The obese group had significantly greater total energy expenditure in all three HIIE intensities than the lean group. FMD tended to be higher and baPWV lower as the exercise intensity increased in both groups. Only the HIIE at 170% demonstrated greater FMD compared with the baseline in both groups. baPWV decreased significantly after HIIE at 130 and 170% VO2peak in both groups. Supramaximal HIIE can be a feasible exercise modality for improving vascular function in obese prepubescent boys. Future exercise intervention studies are warranted.


Antipsychotic drug use in the United States, 1976-1985.
Data from the National Prescription Audit and the National Disease and Therapeutic Index were used to assess trends in outpatient prescriptions for antipsychotic drugs in the United States from 1976 to 1985. Retail pharmacies dispensed 21 million prescriptions for antipsychotic drugs in 1976 and 19 million in 1985. The three leading antipsychotic drugs-thioridazine, haloperidol, and chlorpromazine-constituted 66% to 69% of antipsychotic prescriptions and, along with trifluoperazine, thiothixene, and fluphenazine, accounted for 90% to 91% of all antipsychotic prescriptions throughout the period studied. Thioridazine was the leading medication, with a consistent third of the market share, while the market share for chlorpromazine decreased from 1976 to 1985 and that for haloperidol increased for the same years. Data also indicate that haloperidol is the antipsychotic drug used most frequently in office-based, private medical practice for patients 60 years of age and older, a declining proportion of women are treated with antipsychotic medications, and use of antipsychotic drugs as monotherapy for the primary diagnosis is increasing. We also obtained data on diagnoses associated with antipsychotic drug use.


Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect.
Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors gamma-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA-binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy.


Imaging of evoked dense-core-vesicle exocytosis in hippocampal neurons reveals long latencies and kiss-and-run fusion events.
Evoked neuropeptide secretion in the central nervous system occurs slowly, but the basis for slow release is not fully understood. Whereas exocytosis of single synaptic vesicles in neurons and of dense-core vesicles (DCVs) in endocrine cells have been directly visualized, single DCV exocytic events in neurons of the central nervous system have not been previously studied. We imaged DCV exocytosis in primary cultured hippocampal neurons using fluorescent propeptide cargo and total internal reflectance fluorescence microscopy. The majority of Ca(2+)-triggered exocytic events occurred from immobile plasma-membrane-proximal DCVs in the cell soma, whereas there were few events in the neurites. Strikingly, DCVs in the cell soma exhibited 50-fold greater release probabilities than those in neurites. Latencies to depolarization-evoked fusion for DCVs were surprisingly long, occurring with an average time constant (tau) of 16 seconds for DCVs in the soma and even longer for DCVs in neurites. All of the single DCV release events exhibited rapid fusion-pore openings and closures, the kinetics of which were highly dependent upon Ca(2+) levels. These ;kiss-and-run' events were associated with limited cargo secretion. Thus, the slow evoked release of neuropeptides could be attributed to very prolonged latencies from stimulation to fusion and transient fusion-pore openings that might limit cargo secretion.


Relationship Agreements and Willingness to Participate in Couples HIV Testing and Counseling Among Heterosexuals in the U.S.
Couples HIV testing and counseling (CHTC) has been used for more than 20 years in African settings and more recently among men who have sex with men in the United States, but little is known about willingness of heterosexuals in the U.S. to use CHTC. We conducted an online survey of heterosexuals in sexual relationships to assess willingness to use CHTC and willingness to discuss relationship agreements within a couples counseling session. We found moderate levels of willingness to use CHTC and somewhat higher levels of willingness to discuss relationship agreements in a couples counseling session. The most frequently cited reason people were not willing was that they did not perceive themselves or their partners to be at risk for HIV. These results will be useful in planning for CHTC implementation for heterosexuals in the U.S.


Anatomy and function of the posterior cruciate ligament.
At the present time, our understanding of the PCL still lags behind that of the ACL. This knowledge gap has narrowed over the past few years, however, as more basic research has shed new light on the complex anatomy and functional mechanical behavior of the PCL and the nearby capsuloligamentous structures. Recent insights have included recognition that the PCL is composed of a fiber continuum rather than morphologically separate bands or bundles, a better appreciation of the predominantly nonisometric behavior of the intact PCL, and a greater awareness of the PCLs importance in preserving normal articular kinematics. Continued advances in the basic science of the PCL are a prerequisite for improvements in the treatment and rehabilitation of its injury.


Sonographic diagnosis of complete mole and co-existent fetus: case report.
Coexistence of a complete mole and a normal fetus is a rare event. First trimester sonographic appearance of a complete molar pregnancy with a coexistent fetus and its sonographic differentiation from entities that may simulate a hydatidiform mole in its early stages is discussed. The reported case is one of a 19 y/o woman G2P1001 who was hospitalized several times for abnormal uterine bleeding. Characteristically, the sonographic appearance of a hydatidiform mole is of a moderately echogenic, multicystic intrauterine soft tissue mass. In this particular case, the initial presentation was that of a complex intrauterine fundal mass adjacent to a normal embryo, thus molar pregnancy was considered as part of the differential diagnosis. Doppler evaluation of the echogenic intrauterine mass has been proposed in addition to HCG evaluation, in order to differentiate from trophoblastic and non-trophoblastic disease. In differentiating between a partial and a complete molar pregnancy it is most important to realize that the diagnosis is difficult by ultrasonography because both present with the same multicystic or vesicular pattern. However, if there is a coexistent fetus such as in our reported case, the differentiation would be possible on basis of the presence of a sonographically normal placenta separated from the degenerated placenta.


Bleeding in cardiac surgery: its prevention and treatment--an evidence-based review.
Expected and unexpected bleeding occur frequently in patients undergoing cardiac surgery. Bleeding after cardiac surgery can be broadly divided into two groups: surgical (unrecognized bleeding vessel, anastomosis, or other suture line) or nonsurgical bleeding (caused by coagulopathy). Factors influencing both surgical and nonsurgical bleeding can be further broken down into those occurring preoperatively and those that occur intraoperatively and postoperatively. A thorough understanding of these factors is necessary to reduce bleeding. This is a desirable clinical goal, because excessive bleeding is associated with adverse outcomes.


Phase II clinical trial of h-R3 combined with radiotherapy in locally advanced nasopharyngeal carcinoma.
The purpose of this study was to evaluate the short- and long-term efficacy and toxicity of the humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody h-R3 when combined with radiotherapy for the treatment of locally advanced nasopharyngeal carcinoma (NPC). 35 patients with stage III-IVb NPC with moderate- or strong-intensity EGFR expression were randomly divided into either a radiotherapy alone group or a group receiving radiotherapy combined with h-R3. The complete remission (CR) rates of the combination group at three time points were significantly higher (p<0.05) than those of the radiotherapy alone group. Overall survival, 3-year local control rate, and no distant metastasis rate did not differ between the two groups. No severe toxicity was noticed. h-R3 is an agent with good safety profile which could help enhance the radiation antitumor effect in locally advanced NPC, but it did not seem to exhibit significant long-term efficacy.


Automated estimation of initial and terminal contact timing using accelerometers; development and validation in transtibial amputees and controls.
The aim of this study was to develop and validate an automated accelerometry-based system for estimating initial contact (IC) and terminal contact (TC) timing information from walking patterns of healthy control subjects and transtibial amputees that can be used in daily life with minimal interference of researchers. Subjects were instrumented with two uniaxial accelerometers just below the knee while synchronized ground reaction force (GRF) recordings were used as reference measurements. An automated multiphase algorithm was developed to estimate the time of IC and TC in the acceleration signals of five healthy subjects and two transtibial amputees walking at different walking speeds. The accuracy of the detection algorithm in ten control subjects and eight transtibial amputees indicated mean errors ranging between 0.013 and 0.034 s for the TC and IC timing, with 95 % confidence interval of the individual step errors ranging between -0.062 and 0.115 s. Correlation coefficients between the estimated stance phase duration and GRF data were 0.98 and 0.97 for controls and amputees, respectively. We concluded that IC and TC can be accurately and easily measured using this system in both healthy subjects and transtibial amputees walking at different walking speeds. The system can be used in clinical situations or gait labs as well as during daily life.


Impact of multiple Alcohol Dehydrogenase gene polymorphisms on risk of laryngeal, esophageal, gastric and colorectal cancers in Chinese Han population.
Alcohol intake is positively associated with the risk of upper aerodigestive tract (UADT) cancers; but its effect on gastric or colorectal cancer is controversial. Previous study had identified several single nucleotide polymorphisms (SNPs) of Alcohol Dehydrogenase (ADH) genes associated with UADT cancers in European and Japanese populations. We sought to determine if these SNPs associated with laryngeal, esophageal, gastric or colorectal cancer in Chinese population. We conducted a case-control study among 1577 cases and 1013 healthy controls from northwest China. Five SNPs associated with UADT cancers risk were selected from previous genome-wide association studies and genotyped using Sequenom Mass-ARRAY technology. Odds ratios and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusting for age and gender. We identified that the minor alleles of rs1789924 and rs971074 were associated with decreased risk of laryngeal cancer (OR = 0.311; 95% CI = 0.161-0.602; P < 0.001) and esophagus cancer (OR = 0.711; 95% CI = 0.526-0.962; P = 0.027) in allelic model analysis, respectively. In the genetic model analysis, we found the "C/T" genotype of rs1789924 was associated with decreased laryngeal cancer risk in codominant model (P = 0.046) and overdominant model (P = 0.013); the "C/T-T/T" genotype of rs1789924 was associated with reduced risk of laryngeal cancer under dominant model (P = 0.013). Additionally, none of the SNPs was associated with gastric or colorectal cancer in our study. Our data shed new light on the association between ADH SNPs and respiratory and digestive tract cancers susceptibility in the Han Chinese population.


The Efficacy and Toxicity of Using the Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), and Its Products in Chemotherapy (Review).
Around the world, cancer patients often combine conventional anticancer treatment with complementary alternative medicines derived from natural sources such as fungi and mushrooms, including the popular lingzhi or reishi medicinal mushroom Ganoderma lucidum. Many studies to date have described the anticancer properties of G. lucidum, which are attributed to its major pharmacologically bioactive compounds, such as terpenoids and polysaccharides. Moreover, several scientific observations have suggested a potential beneficial therapeutic strategy using G. lucidum in combination with chemotherapeutic agents to improve therapeutic outcome. However, to my knowledge, no systematic review has been conducted in this area. Therefore, this review summarizes the current knowledge on G. lucidum or its individual components in relation to chemotherapeutic efficacy, ability to reverse multidrug resistance, and chemotherapeutic toxicity.


Secondary oesophageal peristalsis in patients with non-obstructive dysphagia.
Secondary peristalsis was investigated in 30 patients with non-obstructive dysphagia and 20 age matched controls. Oesophageal motility was recorded at 3 cm intervals along the oesophageal body. Primary peristalsis was tested with 5 ml water swallows. Secondary peristalsis was stimulated with 10 ml boluses of air and water injected in the mid-oesophagus and by distensions (5 seconds duration) with a 3 cm balloon at the same level. Primary peristalsis was normal in 19 of the 20 control subjects and in nine of the 30 patients with dysphagia; 11 patients had diffuse spasm and 10 had non-specific abnormalities of primary peristalsis. Secondary peristalsis was triggered significantly less frequently by air and water distension in dysphagia patients (median success rate of 10% for the air boluses and 0% for the water boluses) than in control subjects (50% and 30% respectively, p < 0.005), and was abnormal in six of nine patients with normal primary peristalsis, nine of 11 patients with diffuse spasm and eight of 10 patients with non-specific motor abnormalities. The median frequency of balloon induced secondary peristalsis, however, was not significantly different in the two groups (0% controls, 40% non-obstructive dysphagia, p = 0.22). For each stimulus, there were no significant differences in the response rate in the three subgroups of patients. The major pattern of failure of secondary peristalsis in response to the air and water boluses was the complete absence of any oesophageal response. The amplitude of complete secondary peristalsis triggered by the water boluses and the balloon was greater in the patients with dysphagia (p = 0.03) than in normal subjects, while the amplitude of the secondary peristaltic responses triggered by the air boluses was similar in the two groups. Secondary peristaltic velocity was also similar in normal subjects and patients with non-obstructive dysphagia. Patients with non-obstructive dysphagia show a noticeable defect in the triggering of secondary peristalsis which may make an important contribution to the delayed oesophageal bolus transit and dysphagia seen in this condition.


Emerging issues in public health genomics.
This review highlights emerging areas of interest in public health genomics. First, we describe recent advances in newborn screening (NBS), with a focus on the practice and policy implications of current and future efforts to expand NBS programs (e.g., via next-generation sequencing). Next, we detail research findings from the rapidly progressing field of epigenetics and epigenomics, highlighting ways in which our emerging understanding in these areas could guide future intervention and research efforts in public health. We close by considering various ethical, legal, and social issues posed by recent developments in public health genomics; these include policies to regulate access to personal genomic information, the need to enhance genetic literacy in both health professionals and the public, and challenges in ensuring that the benefits (and burdens) of genomic discoveries and applications are equitably distributed. We also note needs for future genomic research that integrates across basic and social sciences.


The performance of phylogenetic algorithms in estimating haplotype genealogies with migration.
Genealogies estimated from haplotypic genetic data play a prominent role in various biological disciplines in general and in phylogenetics, population genetics and phylogeography in particular. Several software packages have specifically been developed for the purpose of reconstructing genealogies from closely related, and hence, highly similar haplotype sequence data. Here, we use simulated data sets to test the performance of traditional phylogenetic algorithms, neighbour-joining, maximum parsimony and maximum likelihood in estimating genealogies from nonrecombining haplotypic genetic data. We demonstrate that these methods are suitable for constructing genealogies from sets of closely related DNA sequences with or without migration. As genealogies based on phylogenetic reconstructions are fully resolved, but not necessarily bifurcating, and without reticulations, these approaches outperform widespread 'network' constructing methods. In our simulations of coalescent scenarios involving panmictic, symmetric and asymmetric migration, we found that phylogenetic reconstruction methods performed well, while the statistical parsimony approach as implemented in TCS performed poorly. Overall, parsimony as implemented in the PHYLIP package performed slightly better than other methods. We further point out that we are not making the case that widespread 'network' constructing methods are bad, but that traditional phylogenetic tree finding methods are applicable to haplotypic data and exhibit reasonable performance with respect to accuracy and robustness. We also discuss some of the problems of converting a tree to a haplotype genealogy, in particular that it is nonunique.


Developing Augmentative and Alternative Communication Systems in Languages Other Than English: A Scoping Review.
Access to augmentative and alternative communication (AAC) systems in languages other than English and multilingual AAC systems remains limited for many people with complex communication needs, despite a growing interest in this field, and an acknowledged need for culturally responsive AAC practice. The purpose of this scoping review was to identify published research that has reported on the development of components or whole AAC systems in languages other than English, and the linguistic and cultural factors that influenced research methods and AAC system development. Nine databases were systematically searched for published research that presented development of components or whole AAC systems in languages other than English. The Mixed Methods Appraisal Tool was used to assess the quality of studies. Charted data from studies included journal and publication date, research team, language of AAC system, aims of the study, study methodologies, study participants, and type of AAC systems developed. An analytical framework was developed to identify the cultural and linguistic factors that influenced research methods and or AAC system outcomes. A total of 22 studies were included (13 qualitative, one quantitative nonrandomized, six quantitative descriptive, and two mixed-methods studies). Overall quality of studies was high. Some qualitative studies were of lower quality due to limited analysis or interpretation of results. Linguistic factors were extensively reported in the existing literature, whereas cultural factors were rarely explicitly reported. Factors contributing to lack of reporting of cultural considerations are posited with suggestions for future research. https://doi.org/10.23641/asha.21482607.


[Neuro-ultrasonography in the assessment of perinatal lesions of the brain in high-risk children at birth and at 3 months of age].
As many as 135 children belonging to the group at high risk underwent neurosonography to assess the neuropsychic status in the early neonatal period and at an age of three months. A high rate of perinatal brain injuries was established as was a close relationship between the gestation age of the child, on the one hand and the character and intensity of the injury, on the other one. It has been revealed that the combination of deep immaturity and severe ante-intranatal hypoxia predetermines almost 100% injury of the brain structures, bringing about the formation of organic pathology and impairment of the psychoneurologic development of these children by the age of 3 months.


Influence of tissue fixation on depth-resolved birefringence of oral cavity tissue samples.
To advance our understanding of the contrast observed when imaging with polarization-sensitive optical coherence tomography (PS-OCT) and its correlation with oral cancerous pathologies, a detailed comparison with histology provided via ex vivo fixed tissue is required. The effects of tissue fixation, however, on such polarization-based contrast have not yet been investigated. A study was performed to assess the impact of tissue fixation on depth-resolved (i.e., local) birefringence measured with PS-OCT. A PS-OCT system based on depth-encoded polarization multiplexing and polarization-diverse detection was used to measure the Jones matrix of a sample. A wide variety of ex vivo samples were measured freshly after excision and 24 h after fixation, consistent with standard pathology. Some samples were also measured 48 h after fixation. The tissue fixation does not diminish the birefringence contrast. Statistically significant changes were observed in 11 out of 12 samples; these changes represented an increase in contrast, overall, by 11% on average. We conclude that the fixed samples are suitable for studies seeking a deeper understanding of birefringence contrast in oral tissue pathology. The enhancement of contrast removes the need to image immediately postexcision and will facilitate future investigations with PS-OCT and other advanced polarization-sensitive microscopy methods, such as mapping of the local optic axis with PS-OCT and PS-optical coherence microscopy.


Multidisciplinary teamwork improves use of the operating room: a multicenter study.
Poor inter-professional collaboration might negatively influence adequate planning of operative procedures. Interventions capable of improving inter-professional collaboration will positively impact professional practice and health care outcomes. Radboud University Medical Center (UMC) redesigned their operating room (OR) scheduling method by implementing cross-functional teams (CFTs). In this center, positive effects of CFTs were already demonstrated in a mono-center study. This study aims to confirm these effects by comparing the Radboud data with data from 6 other similar centers using a nationwide OR benchmark collaborative. The effect of CFTs was measured by the performance indicator "raw utilization." The Kruskal-Wallis one-way ANOVA was applied to compare OR performance among all 7 centers. The Wilcoxon-Mann-Whitney test was used to determine differences in OR performance between Radboud UMC and the control group. Operating room performance differed significantly among all 7 centers (p<0.0005). Radboud UMC demonstrated the highest median raw utilization of 94% vs 85% in the control group (p<0.0005). Box-and-whisker plots validated the reduced variation during the years, indicating an organizational learning effect. Therefore, not only a better performance than the control group, but also a gradual improvement of this performance during the years. This study shows that multidisciplinary collaboration in CFTs during the perioperative phase has a positive influence on OR scheduling and use of OR time. Other national databases considering mortality rates also support the idea that introducing CFTs is not only an important condition for improving OR performance, but also for improving quality of care.


Use of audiovisual devices in transnasal endoscopy without sedation to improve tolerance. A prospective clinical trial.
Transnasal endoscopy (TNE) has proven its diagnostic utility, but it has not been widely accepted given that it is performed without sedation. There are no previous studies on the use of methods to improve its tolerability. Our aim was to evaluate the tolerability of TNE, when simultaneously performed with an audiovisual device as a distractor. We evaluated 50 patients, 10 of whom did not agree to participate. The performance of the procedure was explained, using an audiovisual device. Before randomization, we applied anxiety and depression scores. Patients were divided into 2 groups: Group I (using an audiovisual device during the procedure) and Group II (without a device). Anxiety and numeric pain rating scales were used, and vital signs were monitored and recorded before, during, and after the endoscopy. An overall procedure satisfaction score was applied at the end of the study and 24 h later. Mean age was 41.6 years and 35 of the patients were women (87.5%). The most frequent indication for TNE was refractory gastroesophageal reflux disease. There were no severe comorbidities, and none of the patients had a significant anxiety or depression score. One patient in Group II did not tolerate TNE due to nasal pain. There was no statistically significant difference between groups, regarding anxiety, pain, vital signs, and satisfaction scale. Our study showed that TNE was well tolerated and had a high acceptance rate in our patients. The use of distracting audiovisual devices did not increase tolerance to the endoscopic procedure.


A cloned cDNA encoding MAP1 detects a single copy gene in mouse and a brain-abundant RNA whose level decreases during development.
Screening of a bacteriophage lambda gt11 cDNA expression library with a polyclonal anti-microtubule associated protein (MAP) antiserum resulted in the isolation of two non-cross-hybridizing sets of cDNA clones. One set was shown to encode MAP2 (Lewis, S. A., A. Villasante, P. Sherline, and N. J. Cowan, 1986, J. Cell Biol., 102:2098-2105). To determine the specificity of the second set, three non-overlapping fragments cloned from the same mRNA molecule via a series of "walking" experiments were separately subcloned into inducible plasmid expression vectors in the appropriate orientation and reading frame. Upon induction and analysis by immunoblotting, two of the fusion proteins synthesized were shown to be immunoreactive with an anti-MAP1-specific antibody, but not with an anti-MAP2-specific antibody. Since these MAP1-specific epitopes are encoded in non-overlapping cDNAs cloned from a single contiguous mRNA, these clones cannot encode polypeptides that contain adventitiously cross-reactive epitopes. Furthermore, these cDNA clones detected an abundant mRNA species of greater than 10 kb in mouse brain, consistent with the coding requirement of a 350,000-D polypeptide and the known abundance of MAP1 in that tissue. The MAP1-specific cDNA probes were used in blot transfer experiments with RNA prepared from brain, liver, kidney, stomach, spleen, and thymus. While detectable quantities of MAP1-specific mRNA were observed in these tissues, the level of MAP1 expression was approximately 500-fold lower than in brain. The levels of both MAP1-specific and MAP2-specific mRNAs decline in the postnatal developing brain; the level of MAP1-specific mRNA also increases slightly in rat PC12 cells upon exposure to nerve growth factor. These surprising results contrast sharply with reported dramatic developmental increases in the amount of MAP1 in brain and in nerve growth factor-induced PC12 cells. The cDNA clones encoding MAP1 detect a single copy sequence in mouse DNA, even under conditions of low stringency that would allow the detection of related but mismatched sequences. The cDNAs cross-hybridize with genomic sequences in rat, human, and chicken DNA, but not with DNA from frog, Drosophila, or sea urchin. These data are discussed in terms of the evolution and possible biological role of MAP1.


The Benefits and Limitations of Targeted Training in Flexible Transnasal Laryngoscopy Diagnosis.
Targeted laryngoscopy training can be used successfully in de novo learners. To determine the value of targeted laryngoscopy education in interns. This prospective study of fiberoptic laryngoscopy interpretations enrolled 13 participants in an academic hospital setting from August 1 to December 31, 2015. Participants included 10 postgraduate year 1 emergency and otolaryngology interns and 3 board-certified otolaryngology attending physicians. Participants viewed 25 selected and digitally recorded fiberoptic laryngoscopies and were asked to rate 13 items relating to abnormalities in the pharynx, hypopharynx, larynx, and subglottis; the level of concern; and confidence with the diagnosis. A laryngoscopy teaching video was then administered to the interns before rating a second set of 25 videos. Improvement in diagnosis and intraclass correlation coefficients (ICC) were calculated for each question and compared between the first and second administration. Improvement in correct diagnosis of abnormalities in recorded laryngoscopies. All 13 participants completed the interventions. The ICCs for all questions were generally low for the intern groups and higher for the attending group. For vocal cord mobility, a preintervention ICC of 0.25 (95% CI, 0.16-0.37) improved to 0.47 (95% CI, 0.36-0.59) among interns after the intervention. The ICCs for vocal cord mobility were higher among attendings for the preintervention (0.89; 95% CI, 0.84-0.93) and postintervention (0.89; 95% CI, 0.83-0.93) assessments. Minimal improvement was observed in intern scores for base of tongue abnormalities, subglottic stenosis, vocal cord abnormalities, level of comfort, level of concern, pharyngeal abnormalities, or laryngeal, pharyngeal, and hypopharyngeal masses. Learning of flexible laryngoscopy can be improved with the use of a teaching video; however, additional interventions are needed to attain competence in accurately diagnosing upper airway lesions. Clinicians who seek to perform flexible laryngoscopy require robust training.


Supported Independence: The Role of Supervision to Help Trainees Manage Uncertainty.
Safe and effective supervised practice requires a negotiated partnership between trainees and their supervisors. Substantial work has explored how supervisors make judgments about trainees' readiness to safely engage in critical professional activities, yet less is known about how trainees leverage the support of supervisors when they perceive themselves to be at the limits of their abilities. The purpose of this study is to explore how trainees use supervisory support to navigate experiences of clinical uncertainty. Using a constructivist grounded theory approach, the authors explored how novice emergency medicine trainees conceptualized the role of their supervisors during experiences of clinical uncertainty. They employed a critical incident technique to elicit stories from participants immediately following clinical shifts between July and September 2020, and asked participants to describe their experiences of uncertainty within the context of supervised practice. Using constant comparison, 2 investigators coded line-by-line and organized these stories into focused codes. The relationships between these codes were discussed by the research team, and this enabled them to theorize about the relationships between the emergent themes. Participants reported a strong desire for supported independence, where predictable and accessible supervisory structures enabled them to work semiautonomously through challenging clinical situations. They described a process of borrowing their supervisors' comfort during moments of uncertainty and mechanisms to strategically broadcast their evolving understanding of a situation to implicitly invoke (the right level of) support from their supervisors. They also highlighted challenges they faced when they felt insufficiently supported. By borrowing comfort from-or deliberately projecting their thinking to-supervisors, trainees aimed to strike the appropriate balance between independence for the purposes of learning and support to ensure safety. Understanding these strategic efforts could help educators to better support trainees in their growth toward self-regulation.


Health-Related Everyday Functioning in the Internet Age: HIV-Associated Neurocognitive Disorders Disrupt Online Pharmacy and Health Chart Navigation Skills.
This study evaluated the effects of HIV-associated Neurocognitive Disorders (HAND) on 2 Internet-based tests of healthcare management. Study participants included 46 individuals with HIV infection, 19 of whom were diagnosed with HAND, and 21 seronegatives. Participants were administered Internet-based tests of online pharmacy and health records navigation skills in which they used mock credentials to log in to an experimenter-controlled website and independently perform a series of typical online health-related behaviors (e.g., refill a prescription, read and interpret an electronic chart note). HAND was associated with significantly lower accuracy on both the online pharmacy and health records navigation tasks. Among the HIV+ participants, poorer performance on the online healthcare navigation tasks was associated with fewer years of education, higher plasma viral load, less frequent Internet use, and lower health literacy. Findings indicate that individuals with HAND may have marked difficulties navigating the Internet to complete important health-related behaviors.


Routine administration of the Canadian Occupational Performance Measure: effect on functional outcome.
Routinely using outcome measures as an integral component of practice has been encouraged for decades yet has not been widely adopted. There are many reasons to measure outcomes yet any positive effect of measurement on our programs or clients has not been substantiated. If the time-consuming nature of outcome measurement is to be encouraged, we need to begin addressing larger questions of the value of outcome measurement on care and outcomes. This cohort study evaluated the impact of routinely administering the Canadian Occupational Performance Measure on client outcomes on a geriatric rehabilitation unit. Changes in Functional Independence Measure™ scores between an experimental group (n = 45) that received the routine use of the Canadian Occupational Performance Measure for evaluation/planning versus a historical comparison group (n = 58) that received 'usual' care were analysed using generalised linear modeling. Both groups had significant changes in Functional Independence Measure™ scores over time. Results for differences between groups were inconclusive with a significantly underpowered analysis; however, results suggest that a medium to large effect of this intervention cannot be expected. Results are significant for the field of routine outcome measurement, suggesting that when adding the Canadian Occupational Performance Measure to routine assessment within an inpatient rehabilitation setting, substantially improved Functional Independence Measure™ score outcomes should not be expected. The value of routine outcome measurement on client outcomes remains largely unexplored. Routinely, using outcome measures requires additional research to determine the specific benefits to our programs and client outcomes.


[Spinal cord injuries: comments on preventive and curative strategy].
Research for the cure for paralysis caused by spinal cord injury has followed three complementary lines: Limitation of secondary lesions; the use of antagonists of excitatory amino acids has proven affective in reducing the extent of the lesions. Control of the glial scar; an oxygenated derivative of cholesterol can reduce the proliferation of reactive astrocytes and their hypertrophy, and permit the regrowth of axons in a denervated territory. Transplantation of embryonic neurons below the lesion allows to reinnervate denervated sites and reestablish reflex functions.


Cardiopulmonary consequences of gestational toxicant exposure: Symposium overview at the 56th annual SOT meeting, Baltimore, MD.
Xenobiotic exposures affect the maternal and/or in utero environment resulting in impairments in fetal development. During the period of rapid fetal growth, developing cardiovascular systems are especially vulnerable to their environment. Furthermore, fetal exposures can evoke changes in epigenetic signatures that result in permanent modifications in gene expression. This symposium focused on the intersection between maternal and fetal exposure and the developing cardiovascular system. The impact of maternal exposures on prenatal development is of major concern for regulatory agencies given the unique vulnerability of the embryo/fetus to environmental factors, the importance of vascular biology to maternal-fetal interactions, and the adverse consequences of vascular disruption to children's health. Speakers provided data from diverse exposures: nanomaterials, particulate matter or air pollution (PM2.5), nicotine, and environmental chemicals. The current findings related to susceptible gestational windows for cardiovascular development and epigenetic, transcriptomic, toxicokinetic, and toxicodynamic changes in vascular physiology and cardiac function. In response to these concerns, new concepts in predictive modeling and risk assessment associated with in utero exposures were presented as future avenues of research within developmental toxicology. Finally, current applications using an Adverse Outcome Pathway framework for developmental toxicity were presented to integrate data from in vitro profiling of chemical libraries (e.g. ToxCast™) with computational models for in silico toxicology. In summary, this symposium addressed the significant threats to cardiovascular health that are associated with fetal/perinatal exposures, and offered new insights into the predictive, mechanistic, and risk assessment strategies in developmental toxicology.


Pediatric pain management.
Regional anesthesia has become an integral part of adult anesthesia. Although not routinely used in children because of the need for general anesthesia that is necessary to keep the patients from moving and cooperating with the operator, regional anesthesia has been gaining immense popularity in the last decade. Although there is not much objective evidence, large prospective databases and expert opinion have favored administering regional anesthesia in the asleep child safely because major neural damage has not been reported in children. This review discusses a comprehensive approach to acute pain management in infants, children, and adolescents using regional anesthesia.


The perceived life stressors among elderly Chinese immigrants: are they different from those of other elderly Americans?
This is a descriptive study examining the perceived life stressors among elderly Chinese immigrants and comparing their stressors to those experienced by other elderly Americans. Lazarus and Folkman's stress theory and Roy's adaptation model were used as the theoretical basis for this study. Based on this framework, it was predicted that elderly Chinese immigrants would report more life stressors than elderly Americans, because they experience a changing cultural environment along with the aging process. The sample was a convenience sample of 30 elderly people from two Chinese churches in one northeastern metropolitan city. Participants were asked to describe a stressful event that they had experienced within the past month. Data were collected by a bilingual (Chinese and English) interviewer using open-ended questions. The research design was based on Manfredi and Pickett's (1987) research exploring the stressors among elderly Americans, and those research results provide the comparison data for this study. The findings suggest that the amount and sources of stress reported by elderly Chinese immigrants are different from those reported by other elderly Americans. Additional studies are needed to identify the coping strategies used by elderly Chinese immigrants. These findings have implications for gerontologists, policy makers, community healthcare providers, and the Chinese immigrant population.


IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis type 6 (ALS6) is a familial subtype of ALS linked to Fused in Sarcoma (FUS) gene mutation. FUS mutations lead to decreased global protein synthesis, but the mechanism that drives this has not been established. Here, we used ALS6 patient-derived induced pluripotent stem cells (hIPSCs) to study the effect of the ALS6 FUSR521H mutation on the translation machinery in motor neurons (MNs). We find, in agreement with findings of others, that protein synthesis is decreased in FUSR521H MNs. Furthermore, FUSR521H MNs are more sensitive to oxidative stress and display reduced expression of TGF-β and mTORC gene pathways when stressed. Finally, we show that IFNγ treatment reduces apoptosis of FUSR521H MNs exposed to oxidative stress and partially restores the translation rates in FUSR521H MNs. Overall, these findings suggest that a functional IFNγ response is important for FUS-mediated protein synthesis, possibly by FUS nuclear translocation in ALS6.


Sub-Poissonian Statistics of Jamming Limits in Ultracold Rydberg Gases.
Several recent experiments have established by measuring the Mandel Q parameter that the number of Rydberg excitations in ultracold gases exhibits sub-Poissonian statistics. This effect is attributed to the Rydberg blockade that occurs due to the strong interatomic interactions between highly excited atoms. Because of this blockade effect, the system can end up in a state in which all particles are either excited or blocked: a jamming limit. We analyze appropriately constructed random-graph models that capture the blockade effect, and derive formulae for the mean and variance of the number of Rydberg excitations in jamming limits. This yields an explicit relationship between the Mandel Q parameter and the blockade effect, and comparison to measurement data shows strong agreement between theory and experiment.


Self-healing materials.
Self-healing materials are able to partially or completely heal damage inflicted on them, e.g., crack formation; it is anticipated that the original functionality can be restored. This article covers the design and generic principles of self-healing materials through a wide range of different material classes including metals, ceramics, concrete, and polymers. Recent key developments and future challenges in the field of self-healing materials are summarised, and generic, fundamental material-independent principles and mechanism are discussed and evaluated.


In vitro production of anti-histone antibodies by spleen cells from young autoantibody negative NZB/NZW mice.
Anti-histone antibodies (AHA) are spontaneously produced in NZB/NZW mice as part of their autoimmune disease. IgM AHA are usually not detected until after 4 mo of age, and older female mice switch to the production of IgG AHA. We studied the in vitro production of AHA by spleen cells from young (less than or equal to 12-wk-old) NZB/NZW mice. Despite the absence of elevated serum AHA activity, spleen cells from these mice demonstrated marked spontaneous autoantibody production in culture. In kinetic studies, little in vitro production was detectable after 1 day of culture, and maximal accumulation occurred on day 5. Elevated AHA production was apparent by cells from 2-wk-old NZB/NZW mice, and an age-dependent increase in autoantibody production was also noted. Only AHA of the IgM class were detected in cultures of young spleen cells. The in vitro production of IgM AHA in culture was T cell dependent, depletion of T cells resulting in a 70 to 90% reduction in production, which was corrected by the readdition of T cells. In cultures where both IgM AHA and total IgM secretion were measured, a much greater T cell dependence for AHA production was apparent. The requirement for T cells could also be partially replaced by factors present in concanavalin A supernatant. AHA secretion was induced by lipopolysaccharide by using cells from both NZB/NZW and non-autoimmune mice. Although production was greater with NZB/NZW cells, the difference was much less than that for spontaneous production. Thus, AHA-secreting cells that are dependent on in vitro T cell help are present in young NZB/NZW mice. These studies may help define the mechanisms responsible for selective autoantibody secretion in lupus-like disease.


XLOS-observed mutations of MID1 Bbox1 domain cause domain unfolding.
MID1 catalyzes the ubiquitination of the protein alpha4 and the catalytic subunit of protein phosphatase 2A. Mutations within the MID1 Bbox1 domain are associated with X-linked Opitz G syndrome (XLOS). Our functional assays have shown that mutations of Ala130 to Val or Thr, Cys142 to Ser and Cys145 to Thr completely disrupt the polyubiquitination of alpha4. Using NMR spectroscopy, we characterize the effect of these mutations on the tertiary structure of the Bbox1 domain by itself and in tandem with the Bbox2 domain. The mutation of either Cys142 or Cys145, each of which is involved in coordinating one of the two zinc ions, results in the collapse of signal dispersion in the HSQC spectrum of the Bbox1 domain indicating that the mutant protein structure is unfolded. Each mutation caused the coordination of both zinc ions, which are ∼ 13 Å apart, to be lost. Although Ala130 is not involved in the coordination of a zinc ion, the Ala130Thr mutant Bbox1 domain yields a poorly dispersed HSQC spectrum similar to those of the Cys142Ser and Cys145Thr mutants. Interestingly, neither cysteine mutation affects the structure of the adjacent Bbox2 domain when the two Bbox domains are engineered in their native tandem Bbox1-Bbox2 protein construct. Dynamic light scattering measurements suggest that the mutant Bbox1 domain has an increased propensity to form aggregates compared to the wild type Bbox1 domain. These studies provide insight into the mechanism by which mutations observed in XLOS affect the structure and function of the MID1 Bbox1 domain.


Reconfigurable microfluidics.
Lab-on-a-chip devices leverage microfluidic technologies to enable chemical and biological processes at small scales. However, existing microfluidic channel networks are typically designed for the implementation of a single function or a well-defined protocol and do not allow the flexibility and real-time experimental decision-making essential to many scientific applications. In this Perspective, we highlight that reconfigurability and programmability of microfluidic platforms can support new functionalities that are beyond the reach of current lab-on-a-chip systems. We describe the ideal fully reconfigurable microfluidic device that can change its shape and function dynamically, which would allow researchers to tune a microscale experiment with the capacity to make real-time decisions. We review existing technologies that can dynamically control microscale flows, suggest additional physical mechanisms that could be leveraged towards the goal of reconfigurable microfluidics and highlight the importance of these efforts for the broad scientific community.


Elastic, plastic, and fracture mechanisms in graphene materials.
In both research and industry, materials will be exposed to stresses, be it during fabrication, normal use, or mechanical failure. The response to external stress will have an important impact on properties, especially when atomic details govern the functionalities of the materials. This review aims at summarizing current research involving the responses of graphene and graphene materials to applied stress at the nanoscale, and to categorize them by stress-strain behavior. In particular, we consider the reversible functionalization of graphene and graphene materials by way of elastic deformation and strain engineering, the plastic deformation of graphene oxide and the emergence of such in normally brittle graphene, the formation of defects as a response to stress under high temperature annealing or irradiation conditions, and the properties that affect how, and mechanisms by which, pristine, defective, and polycrystalline graphene fail catastrophically during fracture. Overall we find that there is significant potential for the use of existing knowledge, especially that of strain engineering, as well as potential for additional research into the fracture mechanics of polycrystalline graphene and device functionalization by way of controllable plastic deformation of graphene.


Nutrient dietary patterns and the risk of breast and ovarian cancers.
The issue of diet and breast and ovarian cancers has been considered in terms of foods and nutrients, but rarely in terms of dietary patterns. We examined the associations between dietary patterns and breast and ovarian cancers in 2 Italian multicentric case-control studies. Cases were 2,569 breast cancers and 1,031 ovarian cancers hospitalized in 4 Italian areas between 1991 and 1999. Controls were 3,413 women from the same hospital network. Dietary habits were investigated through a validated food-frequency questionnaire. Dietary patterns were identified on a selected set of nutrients through principal component factor analysis. Odds ratios (OR) and 95% confidence intervals (CI) for both cancers were estimated using unconditional multiple logistic regression models on quartiles of factor scores and continuous factor scores. We identified 4 major dietary patterns named Animal products, Vitamins and fiber, Unsaturated fats and Starch-rich. The animal products pattern and the unsaturated fats pattern were inversely associated with breast cancer (OR = 0.74, 95% CI: 0.61-0.91 and OR = 0.83, 95% CI: 0.68-1.00, respectively, for the highest consumption quartile), whereas the starch-rich pattern was directly associated with it (OR = 1.34, 95% CI: 1.10-1.65). The vitamins and fiber pattern was inversely associated with ovarian cancer (OR = 0.77, 95% CI: 0.61-0.98), whereas the starch-rich pattern was directly associated with it (OR = 1.85, 95% CI: 1.37-2.48). In conclusion, the starch-rich pattern is potentially an unfavorable indicator of risk for both breast and ovarian cancers, while the animal products and the vitamins and fiber patterns may be associated with a reduced risk of breast and ovarian cancers, respectively.


Periprandial blood glucose and insulin values during the third trimester of normal pregnancies.
In order to determine the normal periprandial blood glucose values during gravidity, we studied 17 normal pregnant women, near term of gestation, in their homes using test strips and reflectometers . Results show an initial fasting level not higher than 80 mg/dl and not lower than 45 mg/dl. In all cases but one blood glucose levels were lower than 120 mg/dl, irrespective of when the measurements were taken. Insulin determinations permitted us to recognize low and high responders, although no differences could be found between them.


[The difference of IL-28B polymorphisms between hepatitis C patients with and without cryoglobulinemia].
To determine whether patients infected with chronic hepatitis C (CHC) show a differential distribution profile of IL-28B polymorphisms according to the presence of concomitant cryoglobulinemia. Sixty-two consecutive CHC patients were enrolled in the study between December 2008 and December 2010. All patients received combination therapy of pegylated interferon alpha-2a (weekly, 180 g, subcutaneous injection) plus ribavirin (daily, 10to15 mg/kg body weight, oral) for 48 weeks, with individualized dosage adjustments according to the patient's clinical situation. Cryoglobulins were detected visibly by separation of cryoprecipitates in patient serum samples. Three IL-28B SNPs (rs8099917, rs12979860, and rs12980275) were detected by sequencing. Response to treatment was assessed by measuring serum levels of HCV RNA by quantitative PCR at baseline (prior to treatment initiation), during treatment (4 and 12 weeks after treatment initiation), end of therapy (48 weeks after treatment initiation), and post-treatment (24 weeks after end of therapy). The significance of between-group differences were assessed by the Chi-square and Fisher's exact tests. Cryoglobulinemia was detected in 43.5% (27/62) of the CHC patients and showed a female bias (59.3% vs. males: 34.3%, P = 0.05). Compared to CHC patients without cryoglobulinemia, the CHC patients with cryoglobulinemia showed significantly higher levels of HCV RNA at baseline (5.64+/-1.20 vs. 6.37+/-0.67, P less than 0.05) but lower frequencies of the IL28B rs8099917 TT genotype (94.3% vs. 63.0%, P = 0.002), rs8099917 T allele (97.1% vs. 81.5%, P = 0.003), and rs12979860 C allele (94.3% vs. 83.3%, P = 0.048). CHC patients with cryoglobulinemia and having the rs8099917 TT, rs12979860 CC, or rs12980275 AA genotype achieved a higher rate of sustained virological response. Cryoglobulinemia in CHC patients is associated with a differential distribution of IL-28B polymorphisms, and certain polymorphisms may be related to anti-viral treatment response.


Pemphigus in the Arab world.
The Arab world lies geographically between the Atlantic coasts of northern Africa and the Arabian Gulf. This area has wide latitudinal differences as well as variable environmental conditions ranging from deserts to forests. Approximately 370 million individuals who share the Arabic language live in this area. Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are the main subtypes of the pemphigus disease. Both pemphigus subtypes are present in many Arab countries; however, there is variation in the predominant subtype among countries. PV is the most common subtype in Egypt, Sudan, Morocco, Syria, Kuwait, Saudi Arabia and Yemen. On the other hand, PF is more prevalent in Libya and is endemic in Tunisia. Interestingly, there is variation in the dominant subtype in some cities within Morocco. For example, PF is more common in Marrakech which is the second largest city. The presence of anti-desmoglein 1 antibodies in the sera of normal Tunisians and the presence of anti-desmoglein 3 in normal Egyptians' sera suggested that environmental factors played a role in the disease pathogenesis in those areas. Further researches detected that traditional cosmetics were among the risk factors in Tunisia. Moreover, farming was suggested as a risk factor in Egypt, Tunisia and Sudan. Because there is no consensus for pemphigus treatment among the Arab countries, there is diversity in their pemphigus treatment regimens. Studying the demographic characteristics and the environmental conditions which caused the variations in the prevailing clinical phenotype will help us fill the gaps to understand the pathogenesis of the pemphigus disease.


Dopaminergic response to drug words in cocaine addiction.
When exposed to drug conditioned cues (stimuli associated with the drug), addicted individuals experience an intense desire for the drug, which is associated with increased dopamine cell firing. We hypothesized that drug-related words can trigger activation in the mesencephalon, where dopaminergic cells are located. During functional magnetic resonance imaging (fMRI), 15 individuals with cocaine use disorders and 15 demographically matched healthy control subjects pressed buttons for color of drug-related versus neutral words. Results showed that the drug words, but not neutral words, activated the mesencephalon in the cocaine users only. Further, in the cocaine users only, these increased drug-related mesencephalic responses were associated with enhanced verbal fluency specifically for drug words. Our results for the first time demonstrate fMRI response to drug words in cocaine-addicted individuals in mesencephalic regions as possibly associated with dopaminergic mechanisms and with conditioning to language (in this case drug words). The correlation between the brief verbal fluency test, which can be easily administered (crucial for clinical studies), and fMRI cue reactivity could be used as a biomarker of neurobiological changes in addiction.


Short- and midterm results of iliac artery stenting for flush occlusion with the assistance of an occlusive contralateral iliac artery balloon.
Endovascular treatment of flush iliac artery occlusion remains a challenge and is most often performed using open surgery. We report the outcomes of 10 cases that were successfully recanalized endovascularly with the assistance of a contralateral occlusive balloon. A retrospective review of patients undergoing iliac artery stenting was performed at a single institution. Technical success, short- and midterm patency, and 30-day complications are reported. Ten patients were identified. Technical success was 100% when a brachial approach was used. Retrograde recanalization was attempted in 3 cases. Reentry into the aorta could not be achieved in 1 case. The aorta was entered above the inferior mesenteric artery (IMA) in the other 2 cases, and the decision was made to attempt a brachial approach to avoid stenting above the IMA. There were no dissections or perforations. Two patients developed brachial access complications, but only 1 required operative repair for a pseudoaneurysm. Nine patients (90%) remained patent at a mean follow-up of 14.6 months (range 9-24 months). One patient presented 9 months later with iliac artery stent and lower extremity bypass thromboses, which resulted in an amputation. There were no deaths in this series. Iliac stenting for flush iliac artery occlusion can be achieved with this technique with encouraging short- and midterm results and minimal morbidity.


Glucose transporter-1-deficient mice exhibit impaired development and deformities that are similar to diabetic embryopathy.
The hyperglycemia of maternal diabetes suppresses the glucose transporter-1 (GLUT1) facilitative glucose transporter 49-66% in preimplantation embryos. Glucose uptake is reduced and apoptosis is activated. We hypothesized that the reduction of embryonic GLUT1 may play a key role in the malformations of diabetic embryopathy. Therefore, we produced GLUT1-deficient transgenic mice [i.e., antisense-GLUT1 (GT1AS)] to determine whether GLUT1 deficiency alone could reproduce the growth defects. Early cell division of fertilized mouse eggs injected with GT1AS was markedly impaired, P < 0.001 vs. controls. Two populations of preimplantation embryos obtained from GT1AS x GT1AS heterozygote matings exhibited reduction of the 2-deoxyglucose uptake rate: one by 50% (presumed heterozygotes, P < 0.001 vs. control) and the other by 95% (presumed homozygotes, P < 0.001 vs. heterozygotes). Embryonic GLUT1 deficiency in the range reported with maternal diabetes was associated with growth retardation and developmental malformations similar to those described in diabetes-exposed embryos: intrauterine growth retardation (31.1%), caudal regression (9.8%), anencephaly with absence of the head (6.6%), microphthalmia (4.9%), and micrognathia (1.6%). Reduced body weight (small embryos, <70% of the nontransgenic body weight) was accompanied by other malformations and a 56% reduction of GLUT1 protein, P < 0.001 vs. nonsmall embryos (body weight >or=70% normal). The heart, brain, and kidneys of embryonic day 18.5 GT1AS embryos exhibited 24-51% reductions of GLUT1 protein. The homozygous GT1AS genotype was lethal during gestation. Reduced embryonic GLUT1 was associated with the appearance of apoptosis. Therefore, GLUT1 deficiency may play a role in producing embryonic malformations resulting from the hyperglycemia of maternal diabetes. Late gestational macrosomia was absent, apparently requiring a different mechanism.


Effects of tannic acid and its related compounds on food mutagens or hydrogen peroxide-induced DNA strands breaks in human lymphocytes.
The effect of tannic acid (TA), gallic acid (GA), propyl gallate (PA) and ellagic acid (EA) on DNA damage in human lymphocytes induced by food mutagens [3-amino-1-methyl-5H-pyrido (4,3-b) indole (Trp-P-2) and 2-amino-1-methyl-6-phenylimadazo (4,5-b) pyridine (PhIP) or H2O2 was evaluated by using single-cell electrophoresis (comet assay). The toxicity of these tested compounds (0.1-100 microg/ml) on lymphocytes was not found. These compounds did not cause DNA strand breaks at lower concentrations of 0.1-10 microg/ml. At a concentration of 100 microg/ml, TA and GA exhibited slight DNA damage, whereas PA and EA showed no DNA strand breaks. TA and its related compounds decreased the DNA strand breaks induced by Trp-P-2, PhIP or H2O2 at concentrations of 0.1-10 microg/ml. DNA repair enzymes endonuclease III (Endo III) and formamidopyrimidine-DNA glycoslase (FPG)] were used to examine the levels of oxidised pyrimidines and purines in human lymphocytes induced by H2O2. All the compounds at 10 microg/ml can reduce the level of FPG sensitive sites. However, only EA inhibited the formation of EndoIII sensitive sites. The results indicated that these compounds can enhance lymphocytes resistance towards DNA strand breaks induced by food mutagens or H2O2 in vitro.