Morphological and functional analysis of rat hepatocyte spheroids generated on poly(L-lactic acid) polymer in a pulsatile flow bioreactor.
Liver neo-tissue suitable for transplantation has not been established. Primary rat hepatocytes were cultured on three-dimensional biodegradable polymer matrices in a pulsatile flow bioreactor with the intention of inducing tissue formation and improving cell survival. Functional and structural analysis of the hepatocytes forming liver neo-tissue was performed. Biodegradable poly(L-lactic acid) (PLLA) polymer discs were seeded with 4 x 10(6) primary rat hepatocytes each, were exposed to a pulsatile medium flow of 24 mL/min for 1, 2, 4, or 6 days and were investigated for monoethylglycinexylidine (MEGX) formation, ammonia detoxification, Cytokeratin 18 (CK18) expression, and preserved glycogen storage. Fine structural details were obtained using scanning and transmission electron microscopy. Spheroids of viable hepatocytes were formed. MEGX-specific production was maintained and ammonia removal capacity remained high during the entire flow-culture period of 6 days. CK18 distribution was normal. Periodic-acid- Schiff reaction demonstrated homogenous glycogen storage. The hepatocytes reassembled to form intercellular junctions and bile canaliculi. Functional and morphological analysis of rat hepatocytes forming spheroids in a pulsatile flow bioreactor indicated preserved and intact hepatocyte morphology and specific function. Pulsatile flow culture on PLLA scaffolds is a promising new method of hepatic tissue engineering leading to liver neo-tissue formation.


Association of Parathyroid Gland Biopsy Excision Technique With Ex Vivo Radiation Counts During Radioguided Parathyroid Surgery.
Parathyroid biopsy represents a means for normal and hyperfunctional glands to be distinguished intraoperatively. However, no data exist to guide surgeons regarding how much of a parathyroid gland must be biopsied to satisfy the 20% rule. To quantify the relative proportion of a hyperfunctional parathyroid gland that must be evaluated with the gamma probe to satisfy the 20% rule. A retrospective review of surgical data for 24 consecutive patients (16 women, 18 men; mean [SD] age, 66.6 [10] years; range, 51-83 years) who underwent surgery for primary hyperparathyroidism between May and October, 2015, in a tertieary academic medical center. Extirpated parathyroid glands were sectioned into parallel or pie-shaped biopsies and evaluated ex vivo with a gamma probe to determine what percentage of a hyperfunctional gland must be sampled to meet the Norman 20% rule. The hypothesis was formulated during data collection. In total, 253 ex vivo biopsy specimens were obtained from 33 surgically removed parathyroid glands. Parathyroid biopsies satisfied the 20% rule with an accuracy that depended on the relative proportion of the parent gland represented: half or more (96.6%; 95% CI, 91.7%-100.0%), a quarter to one-half (87.0%; 95% CI, 79.3%-94.7%), less than a quarter (63.6%; 95% CI, 54.5%-72.8%). When less than a quarter of the gland was removed, pie-shaped biopsies were more likely to satisfy the 20% rule compared with parallel biopsies of the same weight (78.4% vs 56.2%; absolute difference, 22.2%; 95% CI, 4.7%-39.7%). Unless half of a parathyroid gland is biopsied during radioguided parathyroidectomy, the 20% rule cannot reliably rule out the presence of a hyperfunctional parathyroid lesion. Pie-shaped biopsies originating from the center of the gland are associated with a lower rate of false-negative results compared with peripheral biopsies of similar size. Pie-shaped biopsies and biopsy of half or more of each nonexcised parathyroid gland for ex vivo counts may increase the risk of remnant devascularization and resultant hypoparathyroidism.


Nonselective beta-blockers and development of portal vein thrombosis in liver cirrhosis: a systematic review and meta-analysis.
Portal vein thrombosis (PVT), which is associated with reduced portal vein velocity, is considered to be an indicator for worse outcomes in liver cirrhosis. Nonselective beta-blockers (NSBBs), which are widely used for primary and secondary prophylaxis of esophageal variceal bleeding in liver cirrhosis, can significantly decrease the portal vein velocity. We proposed a hypothesis that the use of NSBBs might facilitate the development of PVT in cirrhotic patients. The PubMed, EMBASE, and Cochrane Library databases were searched. Major meeting abstracts and randomized-controlled trials regarding the use of NSBBs in liver cirrhosis were also hand-searched. The number of patients who developed PVT in groups treated with or without NSBBs was pooled. Odds ratios (ORs) or risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. Subgroup meta-analyses were performed according to the type of studies, region, and study quality. Meta-regression and sensitivity analyses were performed to explore the source of heterogeneity. Nine of the 6416 retrieved papers were finally included. Overall, meta-analysis demonstrated that NSBBs were significantly associated with the development of PVT (OR 4.62, 95% CI 2.50-8.53; p < 0.00001). The heterogeneity was statistically significant (I2 = 80%; p < 0.00001). Subgroup meta-analyses still demonstrated a significantly positive association of NSBBs with the development of PVT in cohort studies (RR 2.57, 95% CI 1.46-4.51; p = 0.001) and case-control studies (OR 8.17, 95% CI 2.46-27.06; p = 0.0006). Sensitivity analyses based on subgroups find the source of heterogeneity. Based on the systematic review and meta-analysis, we found that the use of NSBBs increased a 4.62-fold risk of PVT in cirrhotic patients.


Eating disorder-induced dental complications: a case report.
Eating disorders are potentially life threatening and have not lost their relatively poor prognosis in the last decades. Whereas the increase in incidence and prevalence rates of anorexia nervosa over time are questionable, an increasing trend in incidence and prevalence of bulimia nervosa has been reported. Dentists are often involved in treating teeth of patients with both anorexia nervosa and bulimia nervosa because the teeth of these patients are regularly affected by erosion and caries. Without identification of the underlying evidence of psychological problems and consequent treatment, a patient's medical and dental health will deteriorate as the eating disorder progresses. The dentition of the patient with an eating disorder may offer specific signs and characteristics to alert the dentist.


The impact of delayed surgery on radiotherapy dose and local control of rhabdomyosarcoma.
To determine if delayed surgery permits the modification of radiotherapy dose while maintaining local control in children with localized, unresectable rhabdomyosarcoma, a prospective study was launched in 1981 to test this objective. Treatment consisted of 16 weeks of preoperative chemotherapy, with or without delayed surgery, and radiotherapy using 35 to 40 Gy (3500 to 4000 rad) for microscopic and 50 to 55 Gy (5000 to 5500 rad) for gross residual tumor, plus 14 months of chemotherapy. Among 22 patients treated, surgery was feasible in 11 of 14 patients with residual tumor after chemotherapy and was performed in eight (avoiding radical surgery in three), leaving microscopic (seven patients) or gross residual (one patient) tumor. Progressive disease or amputation precluded radiotherapy in two patients. After radiotherapy local control was sustained in 12 of 14 patients with microscopic lesions vs none of six patients with gross tumor. Delayed surgery may permit the use of lower-dose radiotherapy and should be considered in the treatment plan for this subset of patients.


The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain.
To determine the mechanisms by which multiple forms of fibroblast growth factor (FGF) receptors are generated, we have mapped the arrangement of exons and introns in the human FGF receptor 1 (FGFR 1) gene (flg). We found three alternative exons encoding a portion of the third immunoglobulin (Ig)-like domain of the receptor. One of these alternatives encodes a sequence that is part of a secreted form of FGFR 1. The other two encode sequences that are likely part of transmembrane forms of FGFR 1. One of these forms has not been previously reported in published cDNAs. Also, we have determined the structural organization of a portion of the human FGFR 2 gene (bek) and found a similar arrangement of alternative exons for the third Ig-like domain. The arrangement of these genes suggests that there are conserved mechanisms governing the expression of secreted FGF receptors as well as the expression of at least two distinct membrane-spanning forms of the FGF receptors. The diverse forms appear to be generated by alternative splicing of mRNA and selective use of polyadenylation signals.


Reclassification of the Penicillium roqueforti group into three species on the basis of molecular genetic and biochemical profiles.
Penicillium roqueforti is currently divided into two varieties, one used for cheese starter cultures, P. roqueforti var. roqueforti, and one ubiquitous patulin-producing variety, P. roqueforti var. carneum. The ribosomal regions comprising the 5.8S gene and the internal transcribed spacers, ITS I and ITS II, have been analysed from 10 isolates belonging to each variety. The 10 P. roqueforti var. carneum isolates were separated into two groups of five on the basis of 12 base-pair differences in the ITS regions. One of the groups of P. roqueforti var. carneum, in the following designated P. carneum, differed from P. roqueforti var. roqueforti, here designated P. roqueforti, in just two positions, while the other group, here called P. paneum, differed from P. roqueforti in 12 positions. Random Amplified Polymorphic DNA (RAPD) analysis substantiated these findings, and a comparison of secondary metabolites produced by the three groups showed that the P. roqueforti isolates all produce Penicillium Roqueforti (PR) toxin, marcfortines and fumigaclavine A, while the P. carneum isolates produce patulin, penitrem A and mycophenolic acid, as well as unidentified metabolites. P. paneum produces secondary metabolites in five chromophore families including the known mycotoxins patulin and botryodiploidin. On the basis of these findings it is proposed that P. roqueforti is reclassified into three species named P. roqueforti, P. carneum and P. paneum.


Social contact networks and disease eradicability under voluntary vaccination.
Certain theories suggest that it should be difficult or impossible to eradicate a vaccine-preventable disease under voluntary vaccination: Herd immunity implies that the individual incentive to vaccinate disappears at high coverage levels. Historically, there have been examples of declining coverage for vaccines, such as MMR vaccine and whole-cell pertussis vaccine, that are consistent with this theory. On the other hand, smallpox was globally eradicated by 1980 despite voluntary vaccination policies in many jurisdictions. Previous modeling studies of the interplay between disease dynamics and individual vaccinating behavior have assumed that infection is transmitted in a homogeneously mixing population. By comparison, here we simulate transmission of a vaccine-preventable SEIR infection through a random, static contact network. Individuals choose whether to vaccinate based on infection risks from neighbors, and based on vaccine risks. When neighborhood size is small, rational vaccinating behavior results in rapid containment of the infection through voluntary ring vaccination. As neighborhood size increases (while the average force of infection is held constant), a threshold is reached beyond which the infection can break through partially vaccinated rings, percolating through the whole population and resulting in considerable epidemic final sizes and a large number vaccinated. The former outcome represents convergence between individually and socially optimal outcomes, whereas the latter represents their divergence, as observed in most models of individual vaccinating behavior that assume homogeneous mixing. Similar effects are observed in an extended model using smallpox-specific natural history and transmissibility assumptions. This work illustrates the significant qualitative differences between behavior-infection dynamics in discrete contact-structured populations versus continuous unstructured populations. This work also shows how disease eradicability in populations where voluntary vaccination is the primary control mechanism may depend partly on whether the disease is transmissible only to a few close social contacts or to a larger subset of the population.


Non-spreading Bessel spatiotemporal optical vortices.
Non-spreading nature of Bessel spatiotemporal wavepackets is theoretically and experimentally investigated and orders of magnitude improvement in the spatiotemporal spreading has been demonstrated. The spatiotemporal confinement provided by the Bessel spatiotemporal wavepacket is further exploited to transport transverse orbital angular momentum through embedding spatiotemporal optical vortex into the Bessel spatiotemporal wavepacket, constructing a new type of wavepacket: Bessel spatiotemporal optical vortex. Both numerical and experimental results demonstrate that spatiotemporal vortex structure can be well maintained and confined through much longer propagation. High order spatiotemporal optical vortices can also be better confined in the spatiotemporal domain and prevented from further breaking up, overcoming a potential major obstacle for future applications of spatiotemporal vortex.


Evaluation of spin in the abstracts of emergency medicine systematic reviews and meta-analyses.
The objective of this study was to assess for spin - a form of reporting that overemphasizes benefits or downplay harms - within abstracts of systematic reviews and meta-analyses related to the clinical practice of emergency medicine (EM). PubMed was searched for systematic reviews and meta-analyses published since 2015 in either EM or general medical journals that examined an aspect of emergency medical care. In a duplicate, masked fashion, article titles and abstracts were screened to determine eligibility based on predetermined inclusion criteria. The included full-text studies were read and evaluated for spin using a previously determined search strategy. Two authors further evaluated study quality using the AMSTAR-2 tool. Our PubMed search identified 478 systematic reviews and meta-analyses, of which a random sample of 200 was selected for data extraction. Spin within the abstract of the manuscript was identified in 34.5% (69/200) of the included reviews. We identified seven of the nine spin types, with two types being most common: (1) conclusion claiming a benefit despite high risk of bias among studies reviewed (19.5% of abstracts), and (2) conclusion claiming a benefit despite reporting bias (14.5%). No significant associations were found between the presence of spin and any of the evaluated study characteristics, the AMSTAR-2 appraisal, or the journal of publication. Spin is commonly present in abstracts of EM systematic reviews. The reporting quality for EM systematic reviews requires improvement. Measures should be taken to improve the overall review process and way information is conveyed through abstracts.


Utilizing health information technology to improve the recognition and management of life-threatening adrenal crisis in the pediatric emergency department: medical alert identification in the 21st century.
Background Many barriers exist to the appropriate recognition and management of life-threatening adrenal crisis in the emergency department (ED). Clinical decision support (CDS) is a health information technology (IT) component that provides useful information to providers as healthcare is being delivered. We hypothesized that CDS incorporated into the electronic health record (EHR) could improve the recognition and management of adrenal crisis within the pediatric ED. Methods We retrospectively analyzed the impact of electronic CDS on the management of patients with known adrenal insufficiency (AI) presenting to two pediatric ED locations over a 19-month period with symptoms suggestive of adrenal crisis. Outcome variables assessed included the frequency of hydrocortisone (HC) administration, appropriateness of HC dosing, and timing to HC order placement and administration. Results A total of 145 encounters were reviewed. When the electronic CDS was in place at the time of the ED visit, patients were nearly 3 times as likely to receive HC (p = 0.002). Among those patients who received HC, the presence of the CDS increased the likelihood of an appropriate 50-mg/m2 dose of HC being given from 20 to 53% (p = 0.02). However, the CDS did not significantly reduce the time from ED arrival to HC order placement (p = 0.36) or administration (p = 0.59). Conclusions The use of innovative health IT strategies, such as the electronic CDS, can improve the recognition and management of adrenal crisis among patients with AI presenting to the pediatric ED.


Genes for the alpha and beta subunits of the phenylalanyl-transfer ribonucleic acid synthetase of Escherichia coli.
The phenylalanyl-transfer ribonucleic acid synthetase of Escherichia coli is a tetramer that contains two different kinds of polypeptide chains. To locate the genes for the two polypeptides, we analyzed temperature-sensitive mutants with defective phenylalanyl-transfer ribonucleic acid synthetases to see which subunit was altered. The method was in vitro complementation; mutant cell extracts were mixed with purified separated alpha or beta subunits of the wild-type enzyme to generate an active hybrid enzyme. With three mutants, enzyme activity appeared when alpha was added, but not when beta was added: these are, therefore, assumed to carry lesions in the gene for the alpha subunit. Two other mutants gave the opposite response and are presumably beta mutants. Enzyme activity is also generated when alpha and beta mutant extracts are mixed, but not when two alpha or two beta mutant extracts are mixed. The inactive mutant enzymes appear to be dissociated, as judged by their sedimentation in sucrose density gradients, but the dissociation may be only partial. The active enzyme generated by complementation occurred in two forms, one that resembled the native wild-type enzyme and one that sedimented more slowly. Both alpha and beta mutants are capable of generating the native form, although alpha mutants require prior urea denaturation of the defective enzyme. With the mutants thus characterized, the genes for the alpha and beta subunits (designated pheS and heT, respectively) were mapped. The gene order, as determined by transduction is aroD-pps-pheT-pheS. The pheS and pheT genes are close together and may be immediately adjacent.


EBV Latency III-Transformed B Cells Are Inducers of Conventional and Unconventional Regulatory T Cells in a PD-L1-Dependent Manner.
EBV infects and immortalizes B cells in vitro and in vivo. It is the causative agent of most immune deficiency-related lymphoproliferative disorders and is associated with various lymphomas. EBV latency III-transformed B cells are known to express two immunosuppressive molecules, IL-10 and PD-L1, two characteristics of regulatory B cells (Bregs). In this study, we show that, in addition to secretion of the Breg immunosuppressive cytokines IL-10, IL-35, and TGF-β1, EBV latency III-transformed B cells were able to repress proliferation of their autologous T cells preactivated by CD2, CD3, and CD28. This inhibitory effect was likely caused by CD4+ T cells because EBV latency III-transformed B cells induced a strong proliferation of isolated autologous CD8 T cells. Indeed, EBV was able to promote expansion of autologous FOXP3+ CD39high CTLA4+, Helios+, GITR+, LAG3+ CD4 T cells (i.e., regulatory T cells [Tregs]). Two types of Tregs were induced: unconventional CD25neg and conventional CD25pos Tregs. These Tregs expressed both the latency-associated peptide (LAP) and the PD-1 receptor, two markers of functional Tregs. Expansion of both Treg subtypes depended on PD-L1, whose expression was under the control of LMP1, the main EBV oncogene. These results demonstrate that, like Bregs, EBV latency III-transformed B cells exhibit strong immunoregulatory properties. These data provide clues to the understanding of how after EBV primo-infection, EBV-proliferating B cells can survive in an aggressive immunological environment and later emerge to give rise to EBV-associated B cell lymphomas such as in elderly patients.


Selective phosphodiesterase inhibitors: a promising target for cognition enhancement.
One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer's disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or cAMP. The aim of this review was to provide an overview of the effects of phosphodiesterase inhibitors (PDE-Is) on cognition, the possible underlying mechanisms, and the relationship to current theories about memory formation. Studies of the effects of inhibitors of different PDE families (2, 4, 5, 9, and 10) on cognition were reviewed. In addition, studies related to PDE-Is and blood flow, emotional arousal, and long-term potentiation (LTP) were described. PDE-Is have a positive effect on several aspects of cognition, including information processing, attention, memory, and executive functioning. At present, these data are likely to be explained in terms of an LTP-related mechanism of action. PDE-Is are a promising target for cognition enhancement; the most suitable candidates appear to be PDE2-Is or PDE9-Is. The future for PDE-Is as cognition enhancers lies in the development of isoform-specific PDE-Is that have limited aversive side effects.


Recent advances in curcumin nanoformulation for cancer therapy.
Natural compounds are emerging as effective agents for the treatment of malignant diseases. Curcumin (diferuloylmethane), the active constituent of turmeric extract, has gained significant interest as a plant-based compound with anti-cancer properties. Curcumin is physiologically very well tolerated, with negligible systemic toxicity observed even after high oral doses administration. Despite curcumin's superior properties as an anti-cancer agent its applications are limited due to its low solubility and physico-chemical stability, rapid systemic clearance and low cellular uptake. This review focuses on the development of curcumin nano-particle formulation to improve its therapeutic index through enhanced cellular uptake, localization to targeted areas and improved bioavailability. The feasibility of nano-formulation in delivering curcumin and the limitations and challenges in designing and administrating the nano-sized curcumin particles are also covered in this review. Nanotechnology is a promising tool to enhance efficacy and delivery of drugs. In this context, formulation of curcumin as nano-sized particles could reduce the required therapeutic dosages and subsequently reduced its cell toxicity. These nanoparticles are capable to provide local delivery of curcumin targeted to specific areas and thereby preventing systemic clearance. In addition, using specific coating, better pharmacokinetic and internalization of nano-curcumin could be achieved. However, the potential toxicity of nano-carriers for curcumin delivery is an important issue, which should be taken into account in curcumin nano-formulation.


[Osteopenia in workers engaged into mining industry].
The study was aimed to evaluate prevalence of osteopenia in miners engaged into deep-mined output of copper-zinc pyrite. The examinees were 130 males with clinical manifestations of bone and joint disorders, including 85 drifters engaged into underground mining (main group) and 45 individuals of surface occupations. Hazardous work conditions (4 degree of 3 class) cause in workers engaged into deep-mined output of copper-zinc pyrite risk of osteopenia that is more prevalent than in the surface occupations workers and is highly related with the occupation.


The N-terminal amino acid sequences of the heavy and light chains of human cathepsin L. Relationship to a cDNA clone for a major cysteine proteinase from a mouse macrophage cell line.
Human liver cathepsin L consists of a heavy chain and a light chain with Mr values of 25,000 and 5000 respectively. The chains have been purified and their N-terminal amino acid sequences have been determined. The 40 amino acids determined from the heavy chain and 42 amino acids sequenced in the light chain are homologous with the N-terminal and C-terminal regions respectively of the superfamily of cysteine proteinases. Therefore it is likely that the two chains of cathepsin L are derived by proteolysis of a single polypeptide precursor. Of the amino acids sequenced, 81% are identical with the homologous portions of a protein sequence for a major cysteine proteinase predicted from a cDNA clone from a mouse macrophage cell line. This is the closest relative amongst the known sequences in the superfamily and strongly indicates that the protein encoded by this mRNA is cathepsin L. The mouse protein is also probably the major excreted protein of a transformed cell line [Gal & Gottesman (1986) Biochem. Biophys. Res. Commun. 139, 156-162]. The heavy chain is identical in only 71% of its residues with the sequence of ox cathepsin S, providing further evidence that this latter enzyme is probably not a species variant of cathepsin L. The relationship with a second unidentified cathepsin cDNA clone from a bovine library is much weaker (41% identity), and so this clone remains unidentified.


Asthma management: Part 1: An overview of the problem and current trends.
Death rates from asthma have increased or remained stable over the past decade despite increased knowledge about the pathophysiology and improved treatment of the disease, a fact that is both puzzling and disconcerting. Some children with asthma experience severe and life-interfering exacerbations separated by long periods of normal lung function and no symptoms. Asthma management plans are developed by primary care providers and the family. School nurses implement and monitor the child's response to the plan. Therefore, the school nurse needs current information about asthma management. Part I of this two-part series describes the pathophysiology of asthma and the types, risk factors, and current trends in management of the disease. The role of the school nurse in asthma management is outlined, including how he or she can influence environmental factors that precipitate asthma symptoms or exacerbations. Part II will discuss the role of the school nurse in pharmacologic management of asthma. Complementary alternative medicine for asthma management will be described, as well as health teaching for the child with asthma and their family.


Distributed and selective auditory representation of song repertoires in the avian song system.
For many songbirds, the vocal repertoire constitutes acoustically distinct songs that are flexibly used in various behavioral contexts. To investigate how these different vocalizations are represented in the song neural system, we presented multiple song stimuli while performing extracellular recording in nucleus HVC in adult male song sparrows Melospiza melodia, a species known for its complex vocal repertoire and territorial use of song. We observed robust auditory responses to natural song stimuli in both awake and anesthetized animals. Auditory responses were selective for multiple songs of the bird's own repertoire (BOR) over acoustically modified versions of these stimuli. Selectivity was evident in both awake and anesthetized HVC, in contrast to auditory selectivity in zebra finch HVC, which is apparent only under anesthesia. Presentation of multiple song stimuli at different recording locations demonstrated that stimulus acoustic features and local neuronal tuning both contribute to auditory responsiveness. HVC auditory responsiveness was broadly distributed and nontopographic. Variance in auditory responsiveness was greater among than within HVC recording locations in both anesthetized and awake birds, in contrast to the global nature of auditory representation within zebra finch HVC. To assess the spatial consistency of auditory representation within HVC, we measured the repeatability with which ensembles of BOR songs were represented across the nucleus. Auditory response ranks to different songs were more consistent across recording locations in awake than in anesthetized animals. This spatial reliability of auditory responsiveness suggests that sound stimulus acoustic features contribute relatively more to auditory responsiveness in awake than in anesthetized animals.


Management of Complications in Neuro-oncology Patients.
The purpose of this article is to familiarize the reader with the spectrum of neurologic and medical complications relevant to the care of patients with neurologic cancer while highlighting best practices to prevent morbidity and mortality. Topics include tumor-related epilepsy, vasogenic edema, complications of corticosteroid use, disruption of the hypothalamic-pituitary axis, venous thromboembolism, and opportunistic infection. In 2021, a joint guideline from the Society for Neuro-Oncology and the European Association of Neuro-Oncology reaffirmed recommendations first established in 2000 that patients with newly diagnosed brain tumors should not be prescribed an antiseizure medication prophylactically. For those with tumor-related epilepsy, monotherapy with a non-enzyme-inducing anticonvulsant is the preferred initial treatment, and levetiracetam remains the preferred first choice. Surveys of physician practice continue to demonstrate excessive use of glucocorticoids in the management of patients with both primary and metastatic central nervous system malignancy. This is particularly concerning among patients who require checkpoint inhibitors as the efficacy of these agents is blunted by concomitant glucocorticoid use, resulting in a reduction in overall survival. Finally, direct oral anticoagulants have been shown to be safe in patients with brain tumors and are now favored as first-line treatment among those who require treatment for venous thromboembolism. Medical care for patients impacted by primary and secondary central nervous system malignancy is complex and requires a committed team-based approach that routinely calls upon the expertise of physicians across multiple fields. Neurologists have an important role to play and should be familiar with the spectrum of complications impacting these patients as well as the latest recommendations for management.


Synthesis of Novel 7-Substituted-5-phenyl-[1,2,4]triazolo[1,5-a] Pyrimidines with Anticonvulsant Activity.
Considerable interest has been focused on the triazole structure, which has been known to possess a broad spectrum of biological activities such as antitumor, anti-inflammatory, antimicrobial, antiviral, and anticonvulsant activities. Before this, several heterocyclic compounds containing triazole were synthesized that had shown considerable anticonvulsant activity. As part of our continuous research in this area, we have synthesized several new 7-substituted-5-phenyl-[1,2,4] triazolo[1,5-a] pyrimidines (compounds 3a-3i, 5a-5j) through incorporating triazole moiety into the pyrimidine ring, which are expected to have the synergistic effect in dealing with the epilepsy. Their anticonvulsant activities were measured through the Maximal electroshock (MES) test. Carbamazepine and valproate were considered as positive control drugs with anticonvulsant effects [ED50 = 11.8 and 272 mg/Kg]. Amongst the compounds tested, compound 3f, 7-(heptyloxy)-5-phenyl-[1,2,4] triazolo[1,5-a] pyrimidine, showed potent anticonvulsant activity with ED50 84.9 mg/Kg, which was weaker than carbamazepine, but better than valproate.


On the structure of biomedical silver-doped phosphate-based glasses from molecular dynamics simulations.
First-principles and classical molecular dynamics simulations of undoped and silver-doped phosphate-based glasses with 50 mol% P2O5, 0-20 mol% Ag2O, and varying amounts of Na2O and CaO have been carried out. Ag occupies a distorted local coordination with a mean Ag-O bond length of 2.5 Å and an ill-defined first coordination shell. This environment is shown to be distorted octahedral/trigonal bipyramidal. Ag-O coordination numbers of 5.42 and 5.54-5.71 are calculated for first-principles and classical methodologies respectively. A disproportionation in the medium-range phosphorus Q(n) distribution is explicitly displayed upon silver-doping via CaO substitution, approximating 2Q(2)→Q(1) + Q(3), but not on silver-doping via Na2O substitution. An accompanying increase in FWHM of the phosphorus to bridging oxygen partial pair-correlation function is strong evidence for a bulk structural mechanism associated with decreased dissolution rates with increased silver content. Experimentally, Ag2O ↔ Na2O substitution is known to decrease dissolution and we show this to be a result of Ag's local bonding.


Effect of tocolysis on incidence of low birth weight.
Tocolysis was attempted in only 2.5% of 570 consecutive low birth weight deliveries in the years 1980 through 1981. The reasons for rejecting therapy in the majority of cases are discussed. Prospectively, tocolysis was attempted in only 13.8% of all patients in preterm labor, with an 82% success rate. If tocolytic therapy were not used, and a calculation made with allowance for usually acceptable false diagnosis and failure rate, the general low birth weight rate would rise minimally and insignificantly (P = 1.4). It is concluded that availability of tocolytic agents must not be expected to lower the overall low birth weight rate, although it will benefit the appropriately selected individual patient.


Nephrogenic syndrome of inappropriate antidiuresis.
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. We describe two infants whose clinical and laboratory evaluations were consistent with the presence of SIADH, yet who had undetectable arginine vasopressin (AVP) levels. We hypothesized that they had gain-of-function mutations in the V2 vasopressin receptor (V2R). DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations in both, with resultant changes in codon 137 from arginine to cysteine or leucine. These novel mutations cause constitutive activation of the receptor and are the likely cause of the patients' SIADH-like clinical picture, which we have termed "nephrogenic syndrome of inappropriate antidiuresis."


Mechanisms of lysosomal enzyme release from human polymorphonuclear leukocytes. Effects of phorbol myristate acetate.
PMA enhanced release of the azurophil granule enzyme, beta-glucuronidase, as well as lysozyme, from cytochalasin B-treated PMN's exposed to either zymosan particles or C5a. PMA was active at nanomolar concentrations, was not toxic to the cells, and was most effective when present for brief durations (0-1 min) before exposure of the cells to the stimuli. Beta-glucuronidase was not released in significant amounts from PMN's exposed to PMA alone, in the absence of stimuli such as zymosan or C5a. In contrast, only the specific granule enzyme, lysozyme, was released from unstimulated cells. Electron micrographs of cells exposed to PMA revealed an increase in the number of visible cytoplasmic microtubules as compared to control cells. Enhancement of lysosomal enzyme (beta-glucuronidase) release by PMA appears to be independent of effects on release of specific granule enzymes (lysozyme), but rather is likely due to PMA-induced elevations of cellular cGMP.


Variability in Contemporary Heparin Prescription and Activated Clotting Time Monitoring During Percutaneous Coronary Intervention: Call for Up-To-Date Evidence-Based Guidelines.
Unfractionated heparin (UFH) is the preferred anticoagulant agent in percutaneous coronary intervention (PCI) procedures for minimising the risk of thrombotic complications. Because of the narrow therapeutic range of UFH, some society guidelines have advocated the use of the activated clotting time (ACT) test to monitor anticoagulation intensity during PCI to reduce thrombotic and bleeding complications. We aimed to assess the current practice of UFH prescription and its monitoring in Australia and New Zealand (ANZ). We conducted an anonymous voluntary cross-sectional survey of interventional cardiologists (ICs) who were members of the Cardiac Society of Australia and New Zealand in 2022. The survey included 10 questions pertaining to the current practice of anticoagulation during PCI. Of 430 ICs surveyed, 148 responded (response rate, 34.4%). Most ICs (84.4%) prescribed 70-100 IU/kg of UFH for PCI. Over half of ICs (58.7%) routinely measured ACT during PCI, whereas only 22.2% routinely measured ACT after PCI to guide additional UFH prescription. Among ICs who prescribed additional UFH, approximately half (48%) aimed for ACT ≥250 seconds. Factors that influenced post-PCI UFH prescription included vascular access site and concomitant antiplatelet or anticoagulant therapy. The contemporary practice of UFH prescription during PCI and ACT monitoring in ANZ is variable and based on outdated evidence preceding current drug-eluting stents, antiplatelet therapies, and radial-first practice. Current society guideline recommendations lack clarity and agreement, reflecting the quality of the available evidence. Up-to-date clinical trials evaluating UFH prescription and ACT monitoring are needed to optimise clinical outcomes in contemporary PCI procedures.


Mesenchymal stem cell fate following non-viral gene transfection strongly depends on the choice of delivery vector.
Controlling the phenotype of mesenchymal stem cells (MSCs) through the delivery of regulatory genes is a promising strategy in tissue engineering (TE). Essential to effective gene delivery is the choice of gene carrier. Non-viral delivery vectors have been extensively used in TE, however their intrinsic effects on MSC differentiation remain poorly understood. The objective of this study was to investigate the influence of three different classes of non-viral gene delivery vectors: (1) cationic polymers (polyethylenimine, PEI), (2) inorganic nanoparticles (nanohydroxyapatite, nHA) and (3) amphipathic peptides (RALA peptide) on modulating stem cell fate after reporter and therapeutic gene delivery. Despite facilitating similar reporter gene transfection efficiencies, these nanoparticle-based vectors had dramatically different effects on MSC viability, cytoskeletal morphology and differentiation. After reporter gene delivery (pGFP or pLUC), the nHA and RALA vectors supported an elongated MSC morphology, actin stress fibre formation and the development of mature focal adhesions, while cells appeared rounded and less tense following PEI transfection. These changes in MSC morphology correlated with enhanced osteogenesis following nHA and RALA transfection and adipogenesis following PEI transfection. When therapeutic genes encoding for transforming growth factor beta 3 (TGF-β3) and/or bone morphogenic protein 2 (BMP2) were delivered to MSCs, nHA promoted osteogenesis in 2D culture and the development of an endochondral phenotype in 3D culture, while RALA was less osteogenic and appeared to promote a more stable hyaline cartilage-like phenotype. In contrast, PEI failed to induce robust osteogenesis or chondrogenesis of MSCs, despite effective therapeutic protein production. Taken together, these results demonstrate that the differentiation of MSCs through the application of non-viral gene delivery strategies depends not only on the gene delivered, but also on the gene carrier itself. Nanoparticle-based non-viral gene delivery vectors have been extensively used in regenerative medicine, however their intrinsic effects on mesenchymal stem cell (MSC) differentiation remain poorly understood. This paper demonstrates that different classes of commonly used non-viral vectors are not inert and they have a strong effect on cell morphology, stress fiber formation and gene transcription in MSCs, which in turn modulates their capacity to differentiate towards osteogenic, adipogenic and chondrogenic lineages. These results also point to the need for careful and tissue-specific selection of nanoparticle-based delivery vectors to prevent undesired phenotypic changes and off-target effects when delivering therapeutic genes to damaged or diseased tissues.


Inelastic transport: a pseudoparticle approach.
We discuss a pseudoparticle NEGF approach as a tool to describe transport in molecular junctions in the language of many-body states of the molecule. A method developed by Oh et al. [Phys. Rev. B, 2011, 83, 205302] is applied to inelastic transport in the case of strong electron-vibron interaction. The approach can be seen as a generalization of the exact mapping developed by Bonca and Trugman [Phys. Rev. Lett., 1995, 75, 2566] which includes information on the Pauli exclusion principle and Fermi electron distribution in the leads. Within simple model calculations of inelastic transport in junctions, we compare the pseudoparticle approach to other approximate NEGF schemes.


Ventricular fibrillation in pediatric cardiac arrest.
After activating 9-1-1 for out-of-hospital cardiac arrest (CA), guidelines for children 1 year and older have evolved to include immediate automated external defibrillator (AED) use for witnessed arrest, and two minutes of cardiopulmonary resuscitation (CPR) followed by AED use for unwitnessed arrests. The best approach to resuscitation in a two-tiered emergency medical services (EMS) system depends in part on how likely the patient is to present with ventricular fibrillation (VF). Therefore, the authors evaluated the frequency of VF with respect to age and other characteristics to further elucidate the role of the AED among pediatric CAs. The investigation was a retrospective cohort study of EMS-treated, nontraumatic, out-of-hospital CA among persons aged 1-18 years in King County, Washington, between April 1, 1976, and December 31, 2003. The primary goal was to identify the proportion of patients presenting to EMS in VF, according to age. The association between other characteristics and the likelihood of VF was also evaluated. Finally, hospital survival according to cardiac rhythm at EMS arrival was evaluated. Ventricular fibrillation was the presenting rhythm in 17.6% of cases (48/272). The proportion presenting with VF was 7.6% (10/131) among children aged 1-7 years and 27.0% (38/141) among children aged 8-18 years (p < 0.001). In multivariable models, VF was independently associated with age 8 years and older compared with 1-7 years (odds ratio, 3.19; 95% confidence interval [CI] = 1.46 to 6.97), witnessed arrest (odds ratio, 3.33; 95% CI = 1.63 to 6.82), and cardiac etiology (odds ratio, 2.89; 95% CI = 1.32 to 6.34). Survival was 31.3% (15/48) for VF and 10.7% (24/224) for nonshockable rhythm CAs. The proportion of children aged younger than 8 years presenting with VF is low compared with older children. The greatest increase in VF proportion occurs in children older than 12 years. Based on these results, the best approach for initial EMS resuscitation in a two-tiered EMS system, CPR versus AED use, is uncertain among younger children. Inclusion of witness status into the decision process for younger children may more efficiently allocate AED use, a finding in accordance with 2005 guidelines.


Quantitative surface-enhanced Raman spectroscopy of dipicolinic acid--towards rapid anthrax endospore detection.
Dipicolinic acid (DPA) is an excellent marker compound for bacterial spores, including those of Bacillus anthracis (anthrax). Surface-enhanced Raman spectroscopy (SERS) potentially has the sensitivity and discrimination needed for trace DPA analysis, but mixing DPA solutions with citrate-reduced silver colloid only yielded measurable SERS spectra at much higher (>80 ppm) concentrations than would be desirable for anthrax detection. Aggregation of the colloid with halide salts eliminated even these small DPA bands but aggregation with Na2SO4(aq) resulted in a remarkable increase in the DPA signals. With sulfate aggregation even 1 ppm solutions gave detectable signals with 10 s accumulation times, which is in the sensitivity range required. Addition of CNS- as an internal standard allowed quantitative DPA analysis, plotting the intensity of the strong DPA 1010 cm(-1) band (normalised to the ca. 2120 cm(-1) CNS- band) against DPA concentration gave a linear calibration (R2 = 0.986) over the range 0-50 ppm DPA. The inclusion of thiocyanate also allows false negatives due to accidental deactivation of the enhancing medium to be detected.


Stereotactic radiosurgical treatment of brain metastases.
In a series of 33 patients with reasonably controlled primary cancers, stereotactic radiosurgery was used to treat 52 brain metastases. After a mean radiological follow-up time of 5.5 months, six lesions (12%) had stabilized in size, 26 (50%) were significantly reduced, and 15 (29%) had disappeared. One large melanoma metastasis progressed relentlessly despite treatment. Five lesions (9%) had decreased in size slightly before enlarging. In two of these lesions, biopsy revealed only necrosis. In almost all cases, treatment was associated with decreased peritumoral edema. However, a group of patients with large metastases and extensive prior brain irradiation has been identified in whom prolonged symptomatic cerebral edema poses a problem. It is concluded that radiosurgery is a viable alternative to surgical resection for some cases of brain metastasis.


Human nerve growth factor receptor and cytosine deaminase fusion genes.
Cytosine deaminase (CD) converts 5-fluorocytosine (5-FC) to the toxic metabolite 5-fluorouracil (5-FU), and has been investigated extensively as a potential tool for selective cellular eradication. In this paper, genetic constructs were designed to express the CD enzyme fused to the transmembrane and extracellular domains of the human nerve growth factor receptor (NGFR), thus allowing for positive identification of transduced cells by flow cytometry and positive selection by magnetic bead technology. Constructs were designed to encode a [Gly(4)Ser](2) flexible linker between the nucleic acid coding sequences for the NGFR and CD genes. Retroviral vectors constructed with wild-type CD and NG/CD fusion genes were used to transduce 3T3 fibroblasts and the human T cell line CEM. The function of CD fusion genes was comparable to that of wild-type genes as determined in cytotoxicity assays. By flow cytometry, the NGFR antigen was detectable after expression of the fusion gene derived from either Escherichia coli (NG/CDe) or Saccharomyces cerevisiae (NG/CDs), but the greatest antigen density was observed in cells transduced with the NG/CDs vector. Similarly, superior 5-FC sensitivity was observed with NG/CDs fusion gene in both murine fibroblasts and human T cells. In addition, CEM cells expressing NG/CDs were more efficiently eliminated in vivo. Engineering of cells utilizing the chimeric NG/CD genes provides a new modality in gene therapy allowing positive and negative selection using a single protein-coding sequence.


[Spectophotometric method for preparing the inocula of dematiaceous fungi.].
The aim of this study was to adapt a spectrophotometric method for preparing the inocula of dematiaceous fungi used for in vitro susceptibility tests. Fifty-two isolates of 17 different species of dematiaceous fungi were used for this purpose. Homogeneous suspensions of conidia and hyphae of these isolates were obtained and adjusted for reading at 530 and 550 nm at 40% and 50% of transmittance. The suspensions were standardised to 1-5 x 10 e6 CFU/ml. Quality controls of the inocula were done by quantitative cultures on agar-Sabouraud plates. The inocula obtained by spectrophotometry showed little variability within all the isolates. This method can be useful for in vitro antifungal evaluation of dematiaceous fungi.


A molecular phylogeny of bivalve mollusks: ancient radiations and divergences as revealed by mitochondrial genes.
Bivalves are very ancient and successful conchiferan mollusks (both in terms of species number and geographical distribution). Despite their importance in marine biota, their deep phylogenetic relationships were scarcely investigated from a molecular perspective, whereas much valuable work has been done on taxonomy, as well as phylogeny, of lower taxa. Here we present a class-level bivalve phylogeny with a broad sample of 122 ingroup taxa, using four mitochondrial markers (MT-RNR1, MT-RNR2, MT-CO1, MT-CYB). Rigorous techniques have been exploited to set up the dataset, analyze phylogenetic signal, and infer a single final tree. In this study, we show the basal position of Opponobranchia to all Autobranchia, as well as of Palaeoheterodonta to the remaining Autobranchia, which we here propose to call Amarsipobranchia. Anomalodesmata were retrieved as monophyletic and basal to (Heterodonta + Pteriomorphia). Bivalve morphological characters were traced onto the phylogenetic trees obtained from the molecular analysis; our analysis suggests that eulamellibranch gills and heterodont hinge are ancestral characters for all Autobranchia. This conclusion would entail a re-evaluation of bivalve symplesiomorphies.


Mapping continuous potentials to discrete forms.
The optimal conversion of a continuous inter-particle potential to a discrete equivalent is considered here. Existing and novel algorithms are evaluated to determine the best technique for creating accurate discrete forms using the minimum number of discontinuities. This allows the event-driven molecular dynamics technique to be efficiently applied to the wide range of continuous force models available in the literature, and facilitates a direct comparison of event-driven and time-driven molecular dynamics. The performance of the proposed conversion techniques are evaluated through application to the Lennard-Jones model. A surprising linear dependence of the computational cost on the number of discontinuities is found, allowing accuracy to be traded for speed in a controlled manner. Excellent agreement is found for static and dynamic properties using a relatively low number of discontinuities. For the Lennard-Jones potential, the optimized discrete form outperforms the original continuous form at gas densities but is significantly slower at higher densities.


Differences in the association between high blood pressure and cognitive functioning among the general Japanese population aged 70 and 80 years: The SONIC study.
High blood pressure in middle age (up to 64 years) has been proposed as a predictive indicator of dementia. However, the association between hypertension and the cognitive functioning is controversial in older age groups. The aim of this study was to investigate this association in 70-80-year-old participants in the Japanese study of Septuagenarians, Octogenarians and Nonagenarians Investigation with Centenarians (SONIC). Participants aged 70 (±1) and 80 (±1) years (n=1000 and 973, respectively) were randomly recruited from the general population in Japan. Cognitive functioning was measured by the Montreal Cognitive Assessment. Blood pressure and other medical and social variables were analyzed by multiple regression analyses. High systolic blood pressure (SBP) was significantly correlated with a reduced cognitive functioning only in participants aged 70 years. Additionally, this correlation became more marked in participants with uncontrolled blood pressure at age 70 years. In contrast, SBP was not significantly correlated with the cognitive functioning at age 80 years. Nutritional status indicators such as serum albumin and frequency of going outdoors were significantly associated with cognitive functioning at age 80 years. Our findings indicate that high SBP has a significant role in cognitive functioning at age 70 years; however, blood pressure is less important as a risk factor for cognitive decline at age 80 years.


Latest Developments in Industrial Hybrid Machine Tools that Combine Additive and Subtractive Operations.
Hybrid machine tools combining additive and subtractive processes have arisen as a solution to increasing manufacture requirements, boosting the potentials of both technologies, while compensating and minimizing their limitations. Nevertheless, the idea of hybrid machines is relatively new and there is a notable lack of knowledge about the implications arisen from their in-practice use. Therefore, the main goal of the present paper is to fill the existing gap, giving an insight into the current advancements and pending tasks of hybrid machines both from an academic and industrial perspective. To that end, the technical-economical potentials and challenges emerging from their use are identified and critically discussed. In addition, the current situation and future perspectives of hybrid machines from the point of view of process planning, monitoring, and inspection are analyzed. On the one hand, it is found that hybrid machines enable a more efficient use of the resources available, as well as the production of previously unattainable complex parts. On the other hand, it is concluded that there are still some technological challenges derived from the interaction of additive and subtractive processes to be overcome (e.g., process planning, decision planning, use of cutting fluids, and need for a post-processing) before a full implantation of hybrid machines is fulfilled.


Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine.
Accumulation of triosephosphates arising from high cytosolic glucose concentrations in hyperglycemia is the trigger for biochemical dysfunction leading to the development of diabetic nephropathy-a common complication of diabetes associated with a high risk of cardiovascular disease and mortality. Here we report that stimulation of the reductive pentosephosphate pathway by high-dose therapy with thiamine and the thiamine monophosphate derivative benfotiamine countered the accumulation of triosephosphates in experimental diabetes and inhibited the development of incipient nephropathy. High-dose thiamine and benfotiamine therapy increased transketolase expression in renal glomeruli, increased the conversion of triosephosphates to ribose-5-phosphate, and strongly inhibited the development of microalbuminuria. This was associated with decreased activation of protein kinase C and decreased protein glycation and oxidative stress-three major pathways of biochemical dysfunction in hyperglycemia. Benfotiamine also inhibited diabetes-induced hyperfiltration. This was achieved without change in elevated plasma glucose concentration and glycated hemoglobin in the diabetic state. High-dose thiamine and benfotiamine therapy is a potential novel strategy for the prevention of clinical diabetic nephropathy.


Osteopathic graduate medical education 2010.
Osteopathic graduate medical education (OGME) continues to evolve. With the restructuring of the traditional osteopathic internship, which became effective July 1, 2008, for most specialties, the number of trainees in osteopathic residency programs has substantially grown. The authors detail the effects of the restructuring on OGME and provide an update on the current availability of OGME training opportunities. The present article does not, however, report data from the American Osteopathic Association Intern/Resident Registration Program (ie, the AOA "Match").


Producing HIV estimates: from global advocacy to country planning and impact measurement.
The development of global HIV estimates has been critical for understanding, advocating for and funding the HIV response. The process of generating HIV estimates has been cited as the gold standard for public health estimates. This paper provides important lessons from an international scientific collaboration and provides a useful model for those producing public health estimates in other fields. Through the compilation and review of published journal articles, United Nations reports, other documents and personal experience we compiled historical information about the estimates and identified potential lessons for other public health estimation efforts. Through the development of core partnerships with country teams, implementers, demographers, mathematicians, epidemiologists and international organizations, UNAIDS has led a process to develop the capacity of country teams to produce internationally comparable HIV estimates. The guidance provided by these experts has led to refinements in the estimated numbers of people living with HIV, new HIV infections and AIDS-related deaths over the past 20 years. A number of important updates to the methods since 1997 resulted in fluctuations in the estimated levels, trends and impact of HIV. The largest correction occurred between the 2005 and 2007 rounds with the additions of household survey data into the models. In 2001 the UNAIDS models at that time estimated there were 40 million people living with HIV. In 2016, improved models estimate there were 30 million (27.6-32.7 million) people living with HIV in 2001. Country ownership of the estimation tools has allowed for additional uses of the results than had the results been produced by researchers or a team in Geneva. Guidance from a reference group and input from country teams have led to critical improvements in the models over time. Those changes have improved countries' and stakeholders' understanding of the HIV epidemic.


Dietary arginine supplementation during early pregnancy enhances embryonic survival in rats.
Four experiments were conducted with 120 pregnant Sprague-Dawley rats to determine effects of dietary arginine supplementation on embryonic survival. Rats were fed a nonpurified diet supplemented with 1.3% (wt:wt) L-arginine-HCl or 2.2% (wt:wt) L-alanine (isonitrogenous control) throughout pregnancy (Expt. 1), between d 1 and 7 of gestation and then the nonpurified diet until parturition (Expt. 2), between d 1 and 7 of gestation for determining the number of surviving embryos on d 7 (Expt. 3), or between d 1 and 4 of pregnancy for blood sampling on d 5 after overnight food deprivation (Expt. 4). Litter size increased (P < 0.01) in response to arginine supplementation throughout pregnancy (14.5 +/- 0.62 vs. 11.3 +/- 0.61) or during the first 7 d of pregnancy (14.7 +/- 0.33 vs. 11.3 +/- 0.37). The number of surviving embryos was greater (P < 0.01) when arginine was supplemented between d 1 and 7 of pregnancy (14.7 +/- 0.39 vs. 11.4 +/- 0.66). Concentrations of nitric-oxide metabolites, arginine, proline, glutamine, and ornithine were higher (P < 0.05), but urea levels were lower (P < 0.05) in the serum of arginine-supplemented rats compared with the control group. The arginine treatment increased (P < 0.05) protein levels for inducible and constitutive nitric-oxide synthase at implantation sites by 35-37%. These results indicate that dietary arginine supplementation enhances embryonic survival, therefore increasing litter size by 30% at term birth. This novel finding has important implications for preventing early pregnancy loss and enhancing reproductive performance in mammals.


Shaping pseudoneglect with transcranial cerebellar direct current stimulation and music listening.
Non-invasive brain stimulation modulates cortical excitability depending on the initial activation state of the structure being stimulated. Combination of cognitive with neurophysiological stimulations has been successfully employed to modulate responses of specific brain regions. The present research combined a neurophysiological pre-conditioning with a cognitive conditioning stimulation to modulate behavior. We applied this new state-dependency approach to investigate the cerebellar role in musical and spatial information processing, given that a link between musical perception and visuo-spatial abilities and a clear cerebellar involvement in music perception and visuo-spatial tasks have been reported. Cathodal, anodal or sham transcranial cerebellar Direct Current Stimulation (tcDCS) pre-conditioning was applied on the left cerebellar hemisphere followed by conditioning stimulation through music or white noise listening in a sample of healthy subjects performing a Line Bisection Task (LBT). The combination of the cathodal stimulation with music listening resulted in a marked attentional shift toward the right hemispace, compensating thus the natural leftward bias of the baseline condition (pseudoneglect). Conversely, the anodal or sham pre-conditioning stimulations combined with either music and white noise conditioning listening did not modulate spatial attention. The efficacy of the combined stimulation (cathodal pre-conditioning and music conditioning) and the absence of any effect of the single stimulations provide a strong support to the state-dependency theory. They propose that tcDCS in combination with music listening could act as a rehabilitative tool to improve cognitive functions in the presence of neglect or other spatial disorders.


Comparison of macrocomplement and microcomplement fixation techniques used in fungus serology.
A comparative evaluation was performed on the micro- and macrocomplement fixation (CF) tests that are used as standard procedures in the serodiagnosis of blastomycosis, coccidioidomycosis, and histoplasmosis. Tests with 937 sera from suspected and culturally proven cases of these diseases against yeast-form antigens of Blastomyces dermatitidis and Histoplasma capsulatum and against the soluble antigens, coccidioidin and histoplasmin, revealed that the microtiters were within +/- 1 dilution of the macrotiters in 83 to 93% of the sera. Tests on randomly coded quality control sera revealed the microform of the CF test to be highly reproducible. Our studies indicate that the results obtained by the two tests have similar diagnostic and prognostic interpretations. Because of the sensitivity, reproducibility, economy, and ease of performance, the microtest is highly recommended for use in fungus serology.


Stabilized gold nanorod-dye conjugates with controlled resonance coupling create bright surface-enhanced resonance Raman nanotags.
The preparation and characterization of stable and non-aggregated colloidal suspensions of gold nanorod-molecular dye complexes which exhibit very bright surface-enhanced resonance Raman scattering (SERRS) signals is described. A systematic study was performed where both the localized surface plasmon resonance (LSPR) of the nanorod and the molecular resonance of dyes adsorbed onto the rod surface were selectively tuned with respect to the laser excitation wavelengths. Resonance coupling was found to be a significant factor in the overall SERRS enhancement. The polymer stabilized nanorod-dye conjugates were prepared without the added complexity of nanoparticle aggregation as well as having good control over the surface coverage and orientation of the dye molecules. Furthermore, we demonstrate that this new class of Raman nanotags greatly outperforms an approach based on quasi-spherical gold nanoparticles.


Factors that influence attitudes and sexual behavior among constituency youth workers in Oshana Region, Namibia.
This survey was carried out to assess attitudes and behaviour among youth within four constituencies in Oshana region, Namibia and to understand to how certain social and cultural factors inform attitudes and influence sexual behaviour among the population of young people surveyed. Using a structured questionnaire, data were collected from a random sample of eighty young men and women between the ages of 15-30 years from four constituencies in Oshana region. Survey outcomes revealed attitudes and certain factors that are linked to sexual risk behaviour such as multiple sexual partnerships. Outcomes also reveal an influence of established socio-cultural norms on gender dynamics within relationships and a culture of reserve around discussions of sex and sexuality among young people. Stakeholder interventions should be directed towards incorporating approaches that address these factors as part of efforts to curb the incidence of HIV among young people in Namibia.


Enhancement of antibody responses in DNA vaccination using a vector encoding a universal T-helper cell epitope.
DNA vaccination appears as a very promising approach to raise protective antibodies against a variety of proteins from pathogens or tumor cells, but is often hindered by the low immunogenicity of the genetic vectors used for the immunizations. To enhance the humoral response through improvement of the antigenic presentation of newly synthesized proteins upon vaccination, we engineered a plasmid coding for a low immunogenic protein (an scFv, i.e. the single-chain Fragment variable of a well-characterized antibody) fused to a small-size universal T-helper cell epitope derived from tetanus toxin, whose efficiency in classical protein-based immunization protocols has already been demonstrated. We found that immunization of C57Bl/6 mice using this vector greatly enhanced the production not only of specific antibodies recognizing essentially conformational epitopes on the undenatured scFv protein but also of antibodies against linear epitopes on the denatured protein. Since this T-epitope is known to be accommodated by several haplotypes of H-2 molecules in mice, as well as by various class II MHC molecules in humans, the results reported here allow us to conclude that this method could be of general interest for future applications of genetic immunization, including DNA-based vaccinations in humans.


Metallic nanowire networks: effects of thermal annealing on electrical resistance.
Metallic nanowire networks have huge potential in devices requiring transparent electrodes. This article describes how the electrical resistance of metal nanowire networks evolve under thermal annealing. Understanding the behavior of such films is crucial for the optimization of transparent electrodes which find many applications. An in-depth investigation of silver nanowire networks under different annealing conditions provides a case study demonstrating that several mechanisms, namely local sintering and desorption of organic residues, are responsible for the reduction of the systems electrical resistance. Optimization of the annealing led to specimens with transmittance of 90% (at 550 nm) and sheet resistance of 9.5 Ω sq(-1). Quantized steps in resistance were observed and a model is proposed which provides good agreement with the experimental results. In terms of thermal behavior, we demonstrate that there is a maximum thermal budget that these electrodes can tolerate due to spheroidization of the nanowires. This budget is determined by two main factors: the thermal loading and the wire diameter. This result enables the fabrication and optimization of transparent metal nanowire electrodes for solar cells, organic electronics and flexible displays.


Lexical neighborhood effects in phonetic processing.
Previous research on spoken word recognition has demonstrated that identification of a phonetic segment is affected by the lexical status of the item in which the segment occurs. W. F. Ganong (1980) demonstrated that a category boundary shift occurs when the voiced end of 1 voice-onset time continuum is a word but the voiceless end of another series is a word; this is known as the "lexical effect." A series of studies was undertaken to examine how lexical neighborhood; in contrast to lexical status, might influence word perception. Pairs of nonword series were created in which the voiced end of 1 series had a higher frequency-weighted neighborhood density, whereas the reverse was true for the other series. Lexical neighborhood was found to affect word recognition in much the same way as lexical status.


Intracellular entrapment of wild-type TSH receptor by oligomerization with mutants linked to dominant TSH resistance.
TSH resistance is one of the causes of congenital hypothyroidism with thyroid gland in situ. We recently identified families with dominant transmission of partial TSH resistance due to heterozygous inactivating mutations in TSH receptor (TSHR) gene. Although we documented a poor routing of TSHR mutants to the cell membrane, the mechanism responsible for dominant inheritance of partial TSH resistance remained unexplained. We therefore co-transfected Cos-7 cells with wild-type TSHR and mutant receptors found in these patients. A variable impairment of cAMP response to bTSH stimulation was observed, suggesting that inactive TSHR mutants can exert a dominant negative effect on wild-type TSHR. We then generated chimeric constructs of wild-type or inactive TSHR mutants fused to different reporters. By fluorescence microscopy and immunoblotting, we documented an intracellular entrapment, mainly in the endoplasmic reticulum, and reduced maturation of wild-type TSHR in the presence of inactive TSHR mutants. Finally, fluorescence resonance energy transfer and co-immunoprecipitation experiments were performed to study the molecular interactions between wild-type and mutant TSHRs. The results are in agreement with the presence of oligomers formed by wild-type and mutant receptors in the endoplasmic reticulum. Such physical interaction represents the molecular basis for the dominant negative effect of inactive TSHR mutants. These findings provide an explanation for the dominant transmission of partial TSH resistance. This is the first report linking dominant negative mutations of a G protein-coupled receptor to an abnormal endocrine phenotype in heterozygous patients.


Phylogenetic relationships between tuna species of the genus Thunnus (Scombridae: Teleostei): inconsistent implications from morphology, nuclear and mitochondrial genomes.
In order to infer phylogenetic relationships between tuna species of the genus Thunnus, partial sequences of the mitochondrial cytochrome b and ATPase genes were determined in all eight species. Supplemental restriction analysis on the nuclear rRNA gene was also carried out. Pacific northern bluefin tuna (Thunnus thynnus orientalis) was found to have mtDNA distinct from that of the Atlantic subspecies (T. t. thynnus) but very similar to that from the species albacore (T. alaluga). In contrast, no differentiation in nuclear genome was observed between the Atlantic and Pacific northern bluefin tunas. The Atlantic northern bluefin and southern bluefin tunas possessed mtDNA sequences very similar to species of yellowfin tuna group and not so similar to albacore and bigeye tunas which were morphologically assigned to the bluefin tuna group. The molecular data indicate that (1) mtDNA from albacore has been incorporated into the Pacific population of northern bluefin tuna and has extensively displaced the original mtDNA, and (2) albacore is the earliest offshoot, followed by bigeye tuna in this genus, which is inconsistent with the phylogenetic relationships between these tuna species inferred from morphology.


Ulnar-shortening effect on distal radioulnar joint pressure: a biomechanical study.
The ulnar-shortening procedure has been successfully used to relieve ulnar impaction syndrome and may help in stabilizing the distal radioulnar joint (DRUJ) by increasing the tension within the triangular fibrocartilage complex. This procedure, however, may increase pressure at the DRUJ and possibly induce degenerative changes in the joint. This study aimed to examine the changes in pressure at the DRUJ by simulating the ulnar-shortening procedure in intact and torn states of the triangular fibrocartilage complex. Seven fresh-frozen cadaver arms amputated at the midportion of the humerus were used. The ulna and humerus were affixed firmly to a custom mount that allowed 60 degrees forearm rotation. An external fixator was attached to the distal ulna, leaving a 10-mm space to allow progressive shortening. Pressure sensors were inserted in the DRUJ, and pressure distribution in the joint was recorded after every 1-mm shortening that was performed up to a maximum of 6 mm with or without the application of muscle load. These data were then compared with those obtained with the original length of the ulna in 3 joint positions: neutral, 60 degrees pronation, and 60 degrees supination. The tests were repeated after sectioning either the dorsal or the palmar portion of the radioulnar ligament (RUL) and finally after complete sectioning of the RUL. The peak pressure at the DRUJ increased notably in the intact specimens during progressive ulnar shortening. Compared with the intact specimens, those with partial RUL sectioning exhibited a smaller increase in the peak pressure with ulnar shortening. Complete sectioning of the RUL at its attachment to the ulnar fovea resulted in even smaller increases. The greater the amount of ulnar shortening, the higher is the peak pressure at the DRUJ. The amount of ulnar shortening should be carefully planned to avoid excessive pressure at the DRUJ.


Challenges to and Strategies for Formal Service Utilization among Caregivers in an Underserved Community.
Family caregivers face enormous challenges when attempting to oversee the medical, legal, financial, and daily affairs of loved ones with chronic or life-limiting illness. While formal services and agencies exist to assist caregivers with some of these tasks, caregivers in underserved communities do not utilize these services, or utilize them with unsatisfactory results. This study used focus groups (N = 5 groups) with underserved, minority caregivers (N = 22) to explore their experiences related to care provision, including barriers to support service use and challenges navigating systems related to the broad spectrum of caregiving demands. Thematic content analysis revealed three main themes: (1) prior difficulties with formal service use, (2) difficulties navigating financial, legal, and medical systems, and (3) caregivers' personal strategies to address challenges associated with formal service use and systems navigation. Findings from this study identify underserved caregivers' challenges in utilizing formal services, as well as caregiver-identified strategies for supporting their caregiving activities.


A feasibility study of laparoscopic total gastrectomy for clinical stage I gastric cancer: a prospective multi-center phase II clinical trial, KLASS 03.
With improved short-term surgical outcomes, laparoscopic distal gastrectomy has rapidly gained popularity. However, the safety and feasibility of laparoscopic total gastrectomy (LTG) has not yet been proven due to the difficulty of the technique. This single-arm prospective multi-center study was conducted to evaluate the use of LTG for clinical stage I gastric cancer. Between October 2012 and January 2014, 170 patients with pathologically proven, clinical stage I gastric adenocarcinoma located at the proximal stomach were enrolled. Twenty-two experienced surgeons from 19 institutions participated in this clinical trial. The primary end point was the incidence of postoperative morbidity and mortality at postoperative 30 days. The severity of postoperative complications was categorized according to Clavien-Dindo classification, and the incidence of postoperative morbidity and mortality was compared with that in a historical control. Of the enrolled patients, 160 met criteria for inclusion in the full analysis set. Postoperative morbidity and mortality rates reached 20.6% (33/160) and 0.6% (1/160), respectively. Fifteen patients (9.4%) had grade III or higher complications, and three reoperations (1.9%) were performed. The incidence of morbidity after LTG in this trial did not significantly differ from that reported in a previous study for open total gastrectomy (18%). LTG performed by experienced surgeons showed acceptable postoperative morbidity and mortality for patients with clinical stage I gastric cancer.


Ultrastructural variations following use of several weakly protic alcohols as dehydration agents.
Evaluation has been made of ultrastructural variations which obtain following dehydration and infiltration of glutaraldehyde plus osmium fixed CHO cells with the weakly protic alcohols (methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, propylene glycol and glycerine), acetone alone, and with use of acetone and propylene oxide as transition solvents subsequent to dehydration with ethanol, methanol and ethylene glycol. It appears that the weakly protic alcohols, applied without transition solvent, in addition to some extraction by themselves, variously condition the components of membranes, etc, for possible further extraction by the embedment resin. Extraction by embedment consists mainy of removal of aggregate or 'corpuscular' units from regions assumed to have originally consisted of endomembrane. Relatively discrete extraction pits in membranes are noted in the cases of methanol and ethylene glycol dehydration without transition solvent; whereas use of the other alcohols such as 1-propanol and 2-propanol accentuate the visualization and staining of mitochondrial ribosomes. Cytoplasmic ribosomes stain more strongly when acetone or ethylene glycol are employed as dehydration agents, but some size (length) differences obtain. Apparently, acetone or propylene oxide transition following dehydration with ethanol or methanol (but not the glycols) assists in, or fixes, alterations of endomembrane components into the familiar 'unit membrane' orientation upon which the embedding substances have little discernible effect. Glycol dehydration and infiltration regimens (especially ethylene glycol alone and as a dehydration agent in the application of Bernhard's (1969) staining technique) result in lesser electron density of heterochromatin while accentuating RNP particles. The increased electron density of heterochromatin while accentuating RNP particles. The increased electron density of the RNP particles and the decrease in density of the heterochromatin result in improved visualization of the relationships among nucleolar RNP particles and the nuclear pore complexes.


Aging impairs induction of redox factor-1 after heat stress: a potential mechanism for heat-induced liver injury.
Aging is associated with reduced tolerance to physiological stressors such as hyperthermia. In animal models, heat stress is associated with increased oxidative damage in the livers of old rats. In this study, we evaluated the expression of redox factor-1 (Ref-1), a DNA repair enzyme, and thioredoxin-1 (Trx-1), an antioxidant protein. We hypothesized that these proteins would be induced by heat stress in young animals, and that aging would attenuate this response. Young (6 mo) and old (24 mo) male Fischer 344 rats were exposed to a two-heat stress protocol, and livers were harvested at several time points after the second heat stress. Ref-1 and Trx-1 were evaluated by immunoblot and immunohistochemistry. In young rats, Ref-1 was induced by ~50% immediately (0 h) after heat stress, and returned to control levels at 2 h. We observed no change in Ref-1 after hyperthermia in old rats; however, aging was associated with a 2-fold increase in Ref-1 expression. At 2 h after heat stress, Trx-1 was increased in old rats, but there was no change in young rats. In tissue sections, we observed frequent ductular reactions in the old rats that were positive for both Ref-1 and Trx-1. The impairment in the induction of Ref-1 suggests a mechanism for the increased oxidative injury observed in old rats after heat stress. Furthermore, the observation of ductular reactions positive for both Ref-1 and Trx-1 demonstrates a proliferative cellular niche that develops with aging.


[Necessity to evaluate the genetic safety of xenobiotics in mammalian experiments].
The need to obligatorily evaluate the genetic safety of factors in in vivo experiments is substantiated by the body's protective systems, toxicokinetic features, organ specificity, and the pattern of time and dose dependencies. To substantiate the need for in vivo studies, the author gives the results of long-term studies by the laboratory of genetic monitoring and considers the features of mutagen testing in mammalian versus in vitro experiments. She presents the system developed at the Institute to evaluate the mutagenic properties of environmental factors, by taking into account the organ specificity, the basis of which is a multiorgan karyological analysis. Being a good tool to study the regularities of the toxic action of xenobiotics, this approach is of important scientific and practical value.


Amyloid beta-induced glycogen synthase kinase 3β phosphorylated VDAC1 in Alzheimer's disease: implications for synaptic dysfunction and neuronal damage.
Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinase that is involved in the multiple signaling processes of a cell. Increasing evidence suggests that GSK3β plays a key role in multiple cellular processes in the progression of diabetes, obesity, Alzheimer's disease (AD), Parkinson's disease (PD), inflammatory diseases, schizophrenia, bipolar and several mood disorders, and mitochondrial diseases. Recent research has found that increased GSK3β activity is linked to the pathogenesis of AD through amyloid beta (Aβ), phosphorylated tau and mitochondrial dysfunction. Recent research has also revealed that GSK3β is elevated in AD-affected tissues and is critically involved in dissociating the voltage-dependent anion channel 1 (VDAC1) protein from hexokinases, and causing disrupted glucose metabolism, mitochondrial dysfunction and activating apoptotic cell death. The purpose of this article is to review recent research that is elucidating the role of GSK3β in AD pathogenesis. We discuss the involvement of GSK3β in the phosphorylation of VDAC1 and dissociation of VADC1 with hexokinases in AD neurons.


Activation of NF-kappaB by antineoplastic agents. Role of protein kinase C.
Paclitaxel can induce tumor necrosis factor (TNF) and interleukin-1 gene expression, similar to lipopolysaccharides. Since lipopolysaccharide-induced expression of TNF is related to activation of NF-kappaB, we determined whether NF-kappaB could be activated by paclitaxel. In the human lung adenocarcinoma cell line A549, paclitaxel activated NF-kappaB in a dose-dependent manner with maximal activation after 2-4 h. Since paclitaxel could up-regulate TNF and interleukin-1 secretion and subsequent NF-kappaB activation could be caused by these cytokines, the effect of two other groups of anticancer drugs including vinca alkaloids (vinblastine and vincristine) and anthracyclines (daunomycin and doxorubicin), neither of which induce TNF or interleukin-1 gene expression, were examined. Like paclitaxel, vinblastine, vincristine, daunomycin, and doxorubicin each caused activation of NF-kappaB. Therefore, it is unlikely that activation of NF-kappaB caused by these agents or by paclitaxel is mediated via cytokine up-regulation. Furthermore, actinomycin D and cycloheximide, inhibitors of transcription and translation, respectively, did not inhibit paclitaxel-induced NF-kappaB activation. Several other transcription factors such as AP-1, AP-2, CREB, SP-1, or TFIID were not activated by antineoplastic agents demonstrating specificity of NF-kappaB activation. The involvement of both subunits in the NF-kappaB DNA binding complex was demonstrated by its abrogation by anti-p65 and by supershift by anti-p50 antibodies. Since protein phosphorylation is implicated in the activation of NF-kappaB, the effect of anticancer drugs on protein kinase C activity was measured. Vincristine, daunomycin, and paclitaxel significantly increased protein kinase C activity, and vinblastine and doxorubicin caused similar trends. Following treatment with antineoplastics (1-4 h), cytoplasmic IkappaBalpha degradation occurred concomitantly with translocation of p65 to the nucleus. Specific protein kinase C inhibitors (bisindolylmaleimide (GF109203X) and calphostin C) blocked the activation of NF-kappaB by each compound. Hence, protein kinase C activation may contribute to NF-kappaB activation by antineoplastic agents.


Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Rofecoxib Phase III Protocol 035 Study Group.
To compare the clinical efficacy of rofecoxib, a specific inhibitor of cyclooxygenase 2 (COX-2), with that of diclofenac in patients with osteoarthritis (OA) and to evaluate the safety and tolerability of rofecoxib. We performed a randomized, double-blind, active comparator-controlled trial in 784 adults with OA of the knee or hip. Patients were randomized to 1 of 3 treatment groups: 12.5 mg of rofecoxib once daily, 25 mg of rofecoxib once daily, and 50 mg of diclofenac 3 times daily. Clinical efficacy and safety were evaluated over a 1-year continuous treatment period. Rofecoxib at dosages of 12.5 and 25 mg demonstrated efficacy that was clinically comparable to that of diclofenac, as assessed by all 3 primary end points according to predefined comparability criteria. Results from secondary end points were consistent with those of the primary end points. There were small statistical differences favoring diclofenac for 2 of the end points. All treatments were well tolerated. Rofecoxib was well tolerated and provided efficacy that was clinically comparable, according to predefined statistical criteria, to that of 150 mg of diclofenac per day in this 1-year study. Specific inhibition of COX-2 provided therapeutic efficacy in OA.


Metabolite and transcript profiling of berry skin during fruit development elucidates differential regulation between Cabernet Sauvignon and Shiraz cultivars at branching points in the polyphenol pathway.
Grapevine berries undergo complex biochemical changes during fruit maturation, many of which are dependent upon the variety and its environment. In order to elucidate the varietal dependent developmental regulation of primary and specialized metabolism, berry skins of Cabernet Sauvignon and Shiraz were subjected to gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) based metabolite profiling from pre-veraison to harvest. The generated dataset was augmented with transcript profiling using RNAseq. The analysis of the metabolite data revealed similar developmental patterns of change in primary metabolites between the two cultivars. Nevertheless, towards maturity the extent of change in the major organic acid and sugars (i.e. sucrose, trehalose, malate) and precursors of aromatic and phenolic compounds such as quinate and shikimate was greater in Shiraz compared to Cabernet Sauvignon. In contrast, distinct directional projections on the PCA plot of the two cultivars samples towards maturation when using the specialized metabolite profiles were apparent, suggesting a cultivar-dependent regulation of the specialized metabolism. Generally, Shiraz displayed greater upregulation of the entire polyphenol pathway and specifically higher accumulation of piceid and coumaroyl anthocyanin forms than Cabernet Sauvignon from veraison onwards. Transcript profiling revealed coordinated increased transcript abundance for genes encoding enzymes of committing steps in the phenylpropanoid pathway. The anthocyanin metabolite profile showed F3'5'H-mediated delphinidin-type anthocyanin enrichment in both varieties towards maturation, consistent with the transcript data, indicating that the F3'5'H-governed branching step dominates the anthocyanin profile at late berry development. Correlation analysis confirmed the tightly coordinated metabolic changes during development, and suggested a source-sink relation between the central and specialized metabolism, stronger in Shiraz than Cabernet Sauvignon. RNAseq analysis also revealed that the two cultivars exhibited distinct pattern of changes in genes related to abscisic acid (ABA) biosynthesis enzymes. Compared with CS, Shiraz showed higher number of significant correlations between metabolites, which together with the relatively higher expression of flavonoid genes supports the evidence of increased accumulation of coumaroyl anthocyanins in that cultivar. Enhanced stress related metabolism, e.g. trehalose, stilbene and ABA in Shiraz berry-skin are consistent with its relatively higher susceptibility to environmental cues.


The effect of montelukast in a model of gouty arthritis induced by sodium monourate crystals.
Non-steroidal anti-inflammatory drugs (NSAIDS) are the first line of therapy in acute gouty arthritis. NSAIDs inhibit the cyclooxygenase pathway, but not the lipooxygenase activity and can have many adverse effects and thus have a limited effect on the control of inflammation in this disease. In this work we studied the effect of montelukast on the cellular inflammatory infiltrate in a model of murine arthritis induced by sodium monourate crystals (SMU), using a subcutaneous air cavity (air pouch) in BALB/c mice. Seven groups of BALB/c mice (n = 4) were distributed into five experimental groups and two inflammatory control groups, a positive and a negative one. Previous to SMU exposure, the experimental groups received montelukast (1 and 0.01 mg/Kg/w) and/or indomethacine (2.5 mg/Kg/w), followed by administration of SMU in the air pouch. The total and differential counts of inflammatory cells were analyzed after 2, 6, 12 and 24 hours. Montelukast, significantly reduced the total number of cells (p < 0.05), with a predominant impact on polymorphonuclear over mononuclear cells, especially after 12 hours of the medication. The montelukast/indometacine combination showed an additive effect. Our data show that montelukast has an anti-inflammatory effect in the model of gouty arthritis. Consequently, anti-leukotrienes could represent a new and effective therapy, either isolated or combined with conventional therapy of gouty arthritis.


Ocean acidification causes fundamental changes in the cellular metabolism of the Arctic copepod Calanus glacialis as detected by metabolomic analysis.
Using a targeted metabolomic approach we investigated the effects of low seawater pH on energy metabolism in two late copepodite stages (CIV and CV) of the keystone Arctic copepod species Calanus glacialis. Exposure to decreasing seawater pH (from 8.0 to 7.0) caused increased ATP, ADP and NAD+ and decreased AMP concentrations in stage CIV, and increased ATP and phospho-L-arginine and decreased AMP concentrations in stage CV. Metabolic pathway enrichment analysis showed enrichment of the TCA cycle and a range of amino acid metabolic pathways in both stages. Concentrations of lactate, malate, fumarate and alpha-ketoglutarate (all involved in the TCA cycle) increased in stage CIV, whereas only alpha-ketoglutarate increased in stage CV. Based on the pattern of concentration changes in glucose, pyruvate, TCA cycle metabolites, and free amino acids, we hypothesise that ocean acidification will lead to a shift in energy production from carbohydrate metabolism in the glycolysis toward amino acid metabolism in the TCA cycle and oxidative phosphorylation in stage CIV. In stage CV, concentrations of most of the analysed free fatty acids increased, suggesting in particular that ocean acidification increases the metabolism of stored wax esters in this stage. Moreover, aminoacyl-tRNA biosynthesis was enriched in both stages indicating increased enzyme production to handle low pH stress.


Studies on DNA topoisomerases I and II in herpes simplex virus type 2-infected cells.
It has been suggested that herpes simplex virus (HSV) type 1 may induce a virus-specific DNA topoisomerase activity which copurifies with virus-induced DNA polymerase. We have examined DNA topoisomerase (TOPO) I and II activities in HSV-2-infected HeLa S3 cells. Both activities were partially purified using DEAE-cellulose, phosphocellulose and double-stranded DNA cellulose column chromatography. It was found that both activities could be separated from HSV-2-specific DNA polymerase. Throughout the purification TOPO I could be immunologically detected with a monoclonal antibody developed against human TOPO I. Regardless of the source, mock- or HSV-2-infected human cells, both types of topoisomerase were equally tolerant of 200 mM-KCl. There appeared to be no apparent heterogeneity of TOPO I in HeLa S3 cells through the course of the HSV-2 infection. We conclude that host cell topoisomerases are quite stable in HSV-2-infected HeLa S3 cells and that there is no evidence that HSV-2 is capable of inducing HSV-2-specific TOPO I and TOPO II activities.


Chemical name to structure: OPSIN, an open source solution.
We have produced an open source, freely available, algorithm (Open Parser for Systematic IUPAC Nomenclature, OPSIN) that interprets the majority of organic chemical nomenclature in a fast and precise manner. This has been achieved using an approach based on a regular grammar. This grammar is used to guide tokenization, a potentially difficult problem in chemical names. From the parsed chemical name, an XML parse tree is constructed that is operated on in a stepwise manner until the structure has been reconstructed from the name. Results from OPSIN on various computer generated name/structure pair sets are presented. These show exceptionally high precision (99.8%+) and, when using general organic chemical nomenclature, high recall (98.7-99.2%). This software can serve as the basis for future open source developments of chemical name interpretation.


Long-term outcomes after bariatric surgery: fifteen-year follow-up of adjustable gastric banding and a systematic review of the bariatric surgical literature.
To describe the long-term outcomes after laparoscopic adjustable gastric banding (LAGB) and compare these with the published literature on bariatric surgery. Because obesity is a chronic disease, any proposed obesity treatment should be expected to demonstrate long-term durability to be considered effective. Yet for bariatric surgery, few long-term weight loss data are available. We report our 15-year follow-up data after LAGB and provide a systematic review of the peer-reviewed literature for weight loss at 10 years or more after bariatric surgical procedures. We performed a prospective longitudinal cohort study of LAGB patients using an electronic database system (LapBase) to track progress, measure weight changes, and document revisional procedures. The evolution of the LAGB procedure was recognized, and revisional rates for 3 separate periods between September 1994 and December 2011 were described. In addition, we performed a systematic review of the peer-reviewed published literature collecting all reports that included weight loss data at or beyond 10 years. A total of 3227 patients, with a mean age of 47 years and a mean body mass index of 43.8 kg/m, were treated by laparoscopic adjustable gastric band placement between September 1994 and December 2011. Seven hundred fourteen patients had completed at least 10 years of follow-up. Follow-up was intact in 81% of patients overall and 78% of those beyond 10 years. There was no perioperative mortality for the primary placement or for any revisional procedures. There was 47.1% of excess weight loss (% EWL) at 15 years [n = 54; 95% confidence interval (CI) = 8.3] and 62% EWL at 16 years (n = 14; 95% CI = 13.6). There was a mean of 47.0% EWL (n = 714; 95% CI = 1.3) for all patients who were at or beyond 10 years follow-up. Revisional procedures were performed for proximal enlargement (26%), erosion (3.4%), and port and tubing problems (21%). The band was explanted in 5.6%. The need for revision decreased as the technique evolved, with 40% revision rate for proximal gastric enlargements in the first 10 years, reducing to 6.4% in the past 5 years. The revision group showed a similar weight loss to the overall group beyond 10 years. The systematic review of all bariatric procedures with 10 or more years of follow-up showed greater than 50% EWL for all current procedures. The weighted mean at maximum follow-up for LAGB was 54.2% EWL and for Roux-en-Y gastric bypass was 54.0% EWL. The LAGB study from 1 center demonstrates a durable weight loss with 47% EWL maintained to 15 years. This weight loss occurred regardless of whether any revisional procedures were needed. A systematic review shows substantial and similar long-term weight losses for LAGB and other bariatric procedures.


The evaluation of teeth loosening of the upper jaw in adaptive period of orthodontic treatment by braces.
Introduction: Tooth loosening is divided into physiological and pathological one, but there is tooth loosening that occurs during orthodontic treatment (OT) and depends on the tissues of parodontium and strength of orthodontic apparatus. The aim of the research is to evaluate teeth loosening of the upper jaw during adaptive period in patients with permanent bite who were treated by braces. Materials and methods: Periostometry (device «Periotest») of teeth to 30 patients who are from 14 to 27 years old with the pathology of the first type based Angle's classification. The evaluation of teeth loosening was done before OT, in 1 month, in 3 months and in 6 months. Results: The average index of teeth loosening before OT in patients included 3,08±1,29, so it corresponded to norm indices. In 1 month after braces fixation indices of tooth loosening were increased. Middle index of teeth loosening on the third month of OT was 5,84±0,77 relative units, that in 1,9 times more than periostometric indices before OT. Conclusions: Changes of teeth loosening during OT by braces during the first month after fixation. It should be noted that during the first month of OT data of periostometry determine the enlargement of teeth loosening of all teeth in 1,38, in 3 months there is decrease of teeth loosening for all types of teeth. On the 6th month of OT indices of teeth loosening continue decreasing but with lesser intensity and not achieve such level which was to the beginning of OT.