Regulation of myocardial amino acid balance in the conscious dog.
The effects in vivo of physiologic increases in insulin and amino acids on myocardial amino acid balance were evaluated in conscious dogs. Arterial and coronary sinus concentrations of amino acids and coronary blood flow were measured during a 30-min basal and a 100-min experimental period employing three protocols: euglycemic insulin clamp (plasma insulin equaled 70 +/- 11 microU/ml, n = 6); euglycemic insulin clamp during amino acid infusion (plasma insulin equaled 89 +/- 12 microU/ml, n = 6); and suppression of insulin with somatostatin during amino acid infusion (plasma insulin equaled 15 +/- 4 microU/ml, n = 6). Basally, only leucine and isoleucine were removed significantly by myocardium (net branched chain amino acid [BCAA] uptake equaled 0.5 +/- 0.2 mumol/min), while glycine, alanine, and glutamine were released. Glutamine demonstrated the highest net myocardial production (1.6 +/- 0.2 mumol/min). No net exchange was seen for valine, phenylalanine, tyrosine, cysteine, methionine, glutamate, asparagine, serine, threonine, taurine, and aspartate. In group I, hyperinsulinemia caused a decline of all plasma amino acids except alanine; alanine balance switched from release to an uptake of 0.6 +/- 0.4 mumol/min (P less than 0.05), while the myocardial balance of other amino acids was unchanged. In group II, amino acid concentrations rose, and were accompanied by a marked rise in myocardial BCAA uptake (0.4 +/- 0.1-2.6 +/- 0.3 mumol/min, P less than 0.001). Uptake of alanine was again stimulated (0.9 +/- 0.3 mumol/min, P less than 0.01), while glutamine production was unchanged (1.3 +/- 0.4 vs. 1.6 +/- 0.3 mumol/min). In group III, there was a 4-5-fold increase in the plasma concentration of the infused amino acids, accompanied by marked stimulation in uptake of only BCAA (6.8 +/- 0.7 mumol/min). Myocardial glutamine production was unchanged (1.9 +/- 0.4-1.3 +/- 0.7 mumol/min). Within the three experimental groups there were highly significant linear correlations between myocardial uptake and arterial concentration of leucine, isoleucine, valine, and total BCAA (r = 0.98, 0.98, 0.92, and 0.97, respectively); P less than 0.001 for each). In vivo, BCAA are the principal amino acids taken up by the myocardium basally and during amino acid infusion. Plasma BCAA concentration and not insulin determines the rate of myocardial BCAA uptake. Insulin stimulates myocardial alanine uptake. Neither insulin nor amino acid infusion alters myocardial glutamine release.


Systematic review of the concentrations of oligosaccharides in human milk.
Oligosaccharides are the third largest solid component in human milk. These diverse compounds are thought to have numerous beneficial functions in infants, including protection against infectious diseases. The structures of more than 100 oligosaccharides in human milk have been elucidated so far. The aim of this review was to identify the main factors that affect the concentrations of oligosaccharides in human milk and to determine whether it is possible to calculate representative and reliable mean concentrations. A comprehensive literature search on oligosaccharide concentrations in human milk was performed in 6 electronic databases: BIOSIS, Current Contents Search, Embase, Lancet Titles, MEDLINE and PubMed. The initial search resulted in 1363 hits. After the elimination of duplicates, the literature was screened. The application of strict inclusion criteria resulted in 21 articles selected. Oligosaccharide concentrations, both mean values and single values, reported in the literature were sorted by gestational age, secretor status of mothers, and defined lactation periods. Mean concentrations, including confidence limits, of 33 neutral and acidic oligosaccharides reported could be calculated. Concentrations of oligosaccharides in human milk show variations that are dependent on both the secretor type of the mother and the lactation period as examined by analyses of variance. In addition, large interlaboratory variations in the data were observed. Worldwide interlaboratory quantitative analyses of identical milk samples would be required to identify the most reliable methods of determining concentrations of oligosaccharides in human milk. The data presented here contribute to the current knowledge about the composition and quantities of oligosaccharides in human milk and may foster greater understanding of the biological functions of these compounds.


ABC-F translation factors: from antibiotic resistance to immune response.
Energy-dependent translational throttle A (EttA) from Escherichia coli is a paradigmatic ABC-F protein that controls the first step in polypeptide elongation on the ribosome according to the cellular energy status. Biochemical and structural studies have established that ABC-F proteins generally function as translation factors that modulate the conformation of the peptidyl transferase center upon binding to the ribosomal tRNA exit site. These factors, present in both prokaryotes and eukaryotes but not in archaea, use related molecular mechanisms to modulate protein synthesis for heterogenous purposes, ranging from antibiotic resistance and rescue of stalled ribosomes to modulation of the mammalian immune response. Here, we review the canonical studies characterizing the phylogeny, regulation, ribosome interactions, and mechanisms of action of the bacterial ABC-F proteins, and discuss the implications of these studies for the molecular function of eukaryotic ABC-F proteins, including the three human family members.


Long-term follow-up of adolescent depression. A population-based study.
Adolescent depression is common. Earlier studies indicate that relapses and recurrences are common. But many questions are still unanswered. The aim of the present study has been to follow subjects with adolescent depressions, identified in a population-based study, over a 15-year period. Subjects with adolescent depression (n = 362) and a comparison group (n = 250) were followed in the National Swedish registers. The formerly depressed females had significantly more out-patient visits, and a significantly higher proportion (78.4% versus 69.6%) had at least one out-patient visit. Among the males, no significant differences were found as concerns out-patient visits. The formerly depressed females had significantly more in-patient stays (3.6 versus 2.4) and a significantly higher total number of in-patient days (27.4 versus 10.1). A significantly higher proportion had in-patient days due to mental disorders (9.5% versus 4.6%), in particular anxiety disorders (4.9% versus 1.0%). As concerns the males, a significantly higher proportion had in-patient days due to mental disorders (16.5% versus 1.8%), in particular alcohol and drug abuse (7.6% versus 0%). Among the formerly depressed females there were no significant differences against the comparison group as concerns the proportion of being a mother, number of children per woman, or age at first child. However, a significantly higher proportion of the formerly depressed females had had different, usually mild, disorders related to pregnancy (8.6% versus 0.6%). The children of the women with adolescent depressions were not affected.


Synergistic and antagonistic interactions of binary mixtures of polycyclic aromatic hydrocarbons in the upregulation of CYP1 activity and mRNA levels in precision-cut rat liver slices.
The current studies investigate whether synergistic or antagonistic interactions in the upregulation of CYP1 activity occur in binary mixtures of polycyclic aromatic hydrocarbons (PAHs) involving benzo[a]pyrene and five other structurally diverse PAHs of varying carcinogenic activity. Precision-cut rat liver slices were incubated with benzo[a]pyrene alone or in combination with a range of concentrations of a second PAH, and ethoxyresorufin O-deethylase, CYP1A1 and CYP1B1 mRNA levels determined. Concurrent incubation of benzo[a]pyrene with either dibenzo[a,h]anthracene or fluoranthene in liver slices led to a synergistic interaction, at least at low concentrations, in that ethoxyresorufin O-deethylase activity was statistically higher than the added effects when the slices were incubated with the individual compounds. In contrast, benzo[b]fluoranthene and, at high doses only, dibenzo[a,l]pyrene gave rise to antagonism, whereas 1-methylphenanthrene had no effect at all concentrations studied. When CYP1A1 mRNA levels were monitored, benzo[b]fluoranthene gave rise to an antagonistic response when incubated with benzo[a]pyrene, whereas all other compounds displayed synergism, with 1-methylphenathrene being the least effective. A similar picture emerged when CYP1B1 mRNA levels were determined, though the effects were less pronounced. In conclusion, it has been demonstrated that the benzo[a]pyrene-mediated upregulation of CYP1, at the mRNA and activity levels, is synergistically and antagonistically modulated by other PAHs. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 764-775, 2017.


Potentiometric mass titrations: a quick scan for determining the point of zero charge.
A novel technique for determining the point of zero charge (pzc), called 'potentiometric mass titrations technique', has been developed and used for determining the pzc of several industrially used catalytic supports (SiO2, TiO2, gamma-Al2O3 and MgO).


Physical association of beta 2 integrin with GPI-80, a novel glycosylphosphatidylinositol-anchored protein with potential for regulating adhesion and migration.
We recently found a novel GPI-anchored protein, GPI-80, on human phagocytes that may regulate leukocyte adherence, locomotion, and extravasation. To clarify the mechanisms by which GPI-80 functions on leukocytes, we explored the possibility of its physical association with beta 2 integrin which is important for leukocyte adherence, locomotion, and extravasation. beta 2 integrin, detected by anti-CD18 mAb, was coprecipitated with GPI-80 from human neutrophil lysates by a mAb to GPI-80. In addition, GPI-80 was immunoprecipitated from human neutrophil lysates by anti-human CD18 mAb. These results clearly show that GPI-80 is physically associated with beta 2 integrin in human neutrophils.


Main Applications and Recent Research Progresses of Additive Manufacturing in Dentistry.
In recent ten years, with the fast development of digital and engineering manufacturing technology, additive manufacturing has already been more and more widely used in the field of dentistry, from the first personalized surgical guides to the latest personalized restoration crowns and root implants. In particular, the bioprinting of teeth and tissue is of great potential to realize organ regeneration and finally improve the life quality. In this review paper, we firstly presented the workflow of additive manufacturing technology. Then, we summarized the main applications and recent research progresses of additive manufacturing in dentistry. Lastly, we sketched out some challenges and future directions of additive manufacturing technology in dentistry.


Beam hardening artefacts in computed tomography with photon counting, charge integrating and energy weighting detectors: a simulation study.
Photon counting x-ray imaging provides efficient rejection of the electronics noise, no pulse height (Swank) noise, less noise due to optimal photon energy weighting and the possibility of energy resolved image acquisition. These advantages apply also to CT when projection data are acquired using a photon counting detector. However, photon counting detectors assign a weighting factor of 1 to all detected photons whereas the weighting factor of a charge integrating detector is proportional to the energy of the detected photon. Therefore, data collected by photon counting and charge integrating detectors represent the 'hardening' of the photon beam passed through the object differently. This affects the beam hardening artefacts in the reconstructed CT images. This work represents the first comparative evaluation of the effect of photon counting, charge integrating and energy weighting photon detectors on beam hardening artefacts in CT. Beam hardening artefacts in CT images were evaluated for 20 cm and 14 cm diameter water cylinders with bone and low contrast inserts, at 120 kVp and 90 kVp x-ray tube voltages, respectively. It was shown that charge integrating results in 1.8% less beam hardening artefacts from bone inserts (i.e., CT numbers in the 'shadow' of the bone are less by 1.8% as compared to CT numbers over the periphery of the image), as compared to photon counting. However, optimal photon energy weighting, which provides highest SNR, results in 7.7% higher beam hardening artefacts from bone inserts as compared to photon counting. The magnitude of the 'cupping' artefacts was lower by 1% for charge integrating and higher by 6.1% for energy weighting acquisitions as compared to photon counting. Only the photon counting systems provide an accurate representation of the beam hardening effect due to its flat energy weighting. Because of their energy dependent weighting factors, the charge integrating and energy weighting systems do not provide accurate representation of the beam hardening effect.


Unequal access to opioid agonist treatment and sterile injecting equipment among hospitalized patients with injection drug use-associated infective endocarditis.
Addiction treatment and harm reduction services reduce risks of death and re-infection among patients with injection drug use-associated infective endocarditis (IDU-IE), but these are not offered at many hospitals. Among hospitalized patients with IDU-IE at the two tertiary-care hospitals in the Canadian Maritimes, we aimed to identify (1) the availability of opioid agonist treatment (OAT) and sterile drug injecting equipment, and (2) indicators of potential unmet addiction care needs. Retrospective review of IDU-IE hospitalizations at Queen Elizabeth II Health Sciences Centre (Halifax, Nova Scotia) and the Saint John Regional Hospital (Saint John, New Brunswick), October 2015 -March 2017. In Halifax, there are no addiction medicine providers on staff; in Saint John, infectious diseases physicians also practice addiction medicine. Inclusion criteria were: (1) probable or definite IE as defined by the modified Duke criteria; and (2) injection drug use within the prior 3 months. We identified 38 hospitalizations (21 in Halifax and 17 in Saint John), for 30 unique patients. Among patients with IDU-IE and untreated opioid use disorder, OAT was offered to 36% (5/14) of patients in Halifax and 100% (6/6) of patients in Saint John. Once it was offered, most patients at both sites initiated OAT and planned to continue it after discharge. In Halifax, no patients were offered sterile injecting equipment, and during five hospitalizations staff confiscated patients' own equipment. In Saint John, four patients were offered (and one was provided) injecting equipment in hospital, and during two hospitalizations staff confiscated patients' own equipment. Concerns regarding undertreated pain or opioid withdrawal were documented during 66% (25/38) of hospitalizations, and in-hospital illicit or non-medical drug use during 32% (12/38). Two patients at each site (11%; 4/38) had self-directed discharges against medical advice. Patients with IDU-IE in the Canadian Maritimes have unequal access to evidence-based addiction care depending on where they are hospitalized, which differs from the community-based standard of care. Indicators of potential unmet addiction care needs in hospital were common.


Selection for postgraduate training for general practice: the role of knowledge tests.
Postgraduate training for general practice is a legal requirement in most countries of the European Community, and includes posts in general practice as well as in hospitals. The effectiveness of the training has not been fully evaluated, and it is largely unknown whether the results are satisfactory or what the impact of the separate training components is--nor is it known which characteristics or prior achievements of the trainee influence the end-of-training performance. To determine the value of knowledge tests in the context of entry selection for postgraduate training in general practice. Three (equated) knowledge tests were administered during the two years' postgraduate training of 85 Dutch trainees. The first test was taken at entrance, the second eight months later, and the third shortly before the end of the entire training period. Complete data for 57 trainees were available for analysis. A multiple regression analysis was performed to estimate the predictive values of test 1 and test 2 scores, separately and in combination, for test 3 scores. Since the knowledge test may be used for selection purposes, the analysis was repeated using logistic regression with two pass/fail criteria: a 'minimum criterion' and an 'excellence criterion'. Neither of the two analyses yielded a predictive value of test 1 that was high enough to warrant the use of knowledge tests in the context of entry selection. A 'below minimum' score on test 2 correlated 100% with a 'below minimum' score on test 3. However, the positive predictive value of an above minimum score on test 2 was only 86%. The knowledge tests used in this study are not suitable in the context of entry selection. However, trainees that score 'below minimum' after eight months of training may be regarded as 'at risk' in that they will probably score 'below minimum' at the end of training.


Respiratory presentation of diffuse idiopathic skeletal hyperostosis (DISH): Management and review of the literature.
Background: Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by the ossification of entheses. When localized in the cervical paravertebral region, typical signs and symptoms include stiffness, pain, loss of range of motion, and difficulty swallowing.Clinical Presentation: The authors present two less typical respiratory manifestations of DISH due to cervical osteophytes protrusion and obstruction of the upper airway. The first patient was treated conservatively (application of CPAP during nighttime), while the second required emergency intubation and a combined ENT-neurosurgical operation for the removal of osteophytes.Clinical Relevance: Even though dysphagic symptoms are more frequent, DISH may be a cause of airway obstruction and should be included in the differential diagnosis of respiratory distress and OSA.


Radiotherapy with or without Decompressive Surgery for Metastatic Spinal Cord Compression: A Retrospective Matched-Pair Study Including Data from Prospectively Evaluated Patients.
In 2005, a randomized trial showed that addition of surgery to radiotherapy improved outcomes in patients with metastatic spinal cord compression (MSCC). Since then, only a few studies compared radiotherapy plus surgery to radiotherapy alone. We performed a retrospective matched-pair study including data from prospective cohorts treated after 2005. Seventy-nine patients receiving radiotherapy alone were matched to 79 patients assigned to surgery plus radiotherapy (propensity score method) for age, gender, performance score, tumor type, affected vertebrae, other bone or visceral metastases, interval tumor diagnosis to MSCC, time developing motor deficits, and ambulatory status. Improvement of motor function by ≥1 Frankel grade occurred more often after surgery plus radiotherapy (39.2% vs. 21.5%, p = 0.015). No significant differences were found for post-treatment ambulatory rates (59.5% vs. 67.1%, p = 0.32), local progression-free survival (p = 0.47), overall survival (p = 0.51), and freedom from in-field recurrence of MSCC (90.1% vs. 76.2% at 12 months, p = 0.58). Ten patients (12.7%) died within 30 days following radiotherapy alone and 12 patients (15.2%) died within 30 days following surgery (p = 0.65); 36.7% of surgically treated patients did not complete radiotherapy as planned. Surgery led to significant early improvement of motor function and non-significantly better long-term control. Patients scheduled for surgery must be carefully selected considering potential benefits and risk of perioperative complications.


High-Performance Humidity Sensing in π-Conjugated Molecular Assemblies through the Engineering of Electron/Proton Transport and Device Interfaces.
The development of systems capable of responding to environmental changes, such as humidity, requires the design and assembly of highly sensitive and efficiently transducing elements. Such a challenge can be mastered only by disentangling the role played by each component of the responsive system, thus ultimately achieving high performance by optimizing the synergistic contribution of all functional elements. Here, we designed and synthesized a novel [1]benzothieno[3,2-b][1]benzothiophene derivative equipped with hydrophilic oligoethylene glycol lateral chains (OEG-BTBT) that can electrically transduce subtle changes in ambient humidity with high current ratios (>104) at low voltages (2 V), reaching state-of-the-art performance. Multiscale structural, spectroscopical, and electrical characterizations were employed to elucidate the role of each device constituent, viz., the active material's BTBT core and OEG side chains, and the device interfaces. While the BTBT molecular core promotes the self-assembly of (semi)conducting crystalline films, its OEG side chains are prone to adsorb ambient moisture. These chains act as hotspots for hydrogen bonding with atmospheric water molecules that locally dissociate when a bias voltage is applied, resulting in a mixed electronic/protonic long-range conduction throughout the film. Due to the OEG-BTBT molecules' orientation with respect to the surface and structural defects within the film, water molecules can access the humidity-sensitive sites of the SiO2 substrate surface, whose hydrophilicity can be tuned for an improved device response. The synergistic chemical engineering of materials and interfaces is thus key for designing highly sensitive humidity-responsive electrical devices whose mechanism relies on the interplay of electron and proton transport.


Iodinated glycidyl methacrylate copolymer as a radiopaque material for biomedical applications.
Polymeric biomaterial was synthesized by copolymerizing 50:50 mol% of monomers, glycidyl methacrylate and methyl methacrylate. Iodine atoms were then grafted to the epoxide groups of glycidyl methacrylate units, rendering the copolymer radiopaque. The percentage weight of iodine in the present copolymer was found to be as high as 23%. The iodinated copolymer showed higher glass transition temperature and thermal stability in comparison with unmodified polymer. Radiographic analysis showed that the copolymer possessed excellent radiopacity. The iodinated copolymer was cytocompatible to L929 mouse fibroblast cells. The in vivo toxicological evaluation by intracutaneous reactivity test of the copolymer extracts has revealed that the material was nontoxic. Subcutaneous implantation of iodinated copolymer in rats has shown that the material was well tolerated. Upon explantation and histological examination, no hemorrhage, infection or necrosis was observed. The samples were found to be surrounded by a vascularized capsule consisting of connective tissue cells. The results indicate that the iodinated copolymer is biocompatible and may have suitable applications as implantable materials.


[Errors and complications in the treatment of hemorrhoids].
Long-term results of 724 hemorrhoidectomies were followed up from 6 months till 7 years. Various complications after operation were revealed in 172 (23.3%) patients. In 46 (26.7%) patients the failures were associated with unrecognized proctological diseases before operation, in 51 (30%)--with removal of hemorrhoids and in 63 (36.6%) patients the concomitant diseases of other organs and systems were the causes of complications.


Genome variation of human papillomavirus types: phylogenetic and medical implications.
Human papillomaviruses (HPVs) are described as "types" based on their genome sequences and identified by a number. For example, HPV-6 is associated with genital warts, and HPV-16 with anogenital cancers. The genomes of many HPV types have been reisolated, sequenced and compared to reference "prototypes" countless times by laboratories throughout the world. It was found that each HPV type occurs in the form of "variants", identified by about 2% nucleotide differences in most genes and 5% in less conserved regions. Less than 100 variants of any HPV type have been detected, a scenario that is very different from the quasi-species formed by many RNA viruses. The variants of each HPV type form phylogenetic trees, and variants from specific branches are often unique to specific ethnic groups. Immigrant populations contain, depending on their respective ethnic origins, mixtures of variants. The absence of HPV genomes intermediate to specific types show that all HPV types existed already when humans became a species. Consequently, humans had always suffered from lesions like anogenital cancer, genital warts and common warts. A growing number of epidemiological, etiological and molecular data suggest that variants of the same HPV type are biologically distinct and may confer differential pathogenic risks. Since the distribution of some variants of HPV-16 and 18 correlates with the distribution of human populations that have an increased risk to develop anogenital cancer, the study of HPV type variation may point to one of the reasons for the higher incidence rates of these lesions in specific cohorts.


Ultrasound imaging tracking of mesenchymal stem cells intracellularly labeled with biosynthetic gas vesicles for treatment of rheumatoid arthritis.
Rationale: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and damage to articular tissues that can lead to irreversible joint damage and progressive disability. The multipotent mesenchymal stem cells (MSCs) play an important role in immune disorders and tissue regeneration. However, their immunosuppressive effects and the underlying mechanisms are largely unclear due to the lack of tools for real-time imaging of MSCs in vivo. Gas vesicles (GVs) are biosynthetic nanobubbles that are ejected from aquatic microbes, such as bacteria and archaea, and have an excellent ultrasound imaging capacity. Methods: We harvested MSCs from the bone marrow of Sprague Dawley (SD) rats. Then, GVs were synthesized and incubated with MSCs to obtain intracellularly labeled MSCs. We firstly tested the ultrasound imaging of GV@MSCs in vitro and in vivo and then explored the therapeutic effect of GV@MSCs combined with methotrexate (MTX) in RA rats. Results: These GV@MSCs showed significant contrast-enhanced ultrasound signals without a loss of viability and differentiation capacity. In addition, the GV@MSCs could be imaged in real-time for 5 days using ultrasound both in vitro and in vivo, making it possible to visually track their migration and homing to the joint cavity from the subcutaneous layer of lateral malleolus joints in the injected RA rats. Furthermore, GV@MSCs significantly enhanced the curative effect of methotrexate (MTX) against RA, resulting in decreased paw thickness, lower arthritis index score, reduced bone erosion and cartilage destruction, compared to the PBS, free MTX, and GV@MSCs groups. Conclusion: We developed a novel therapeutic strategy against RA using GVs-loaded MSCs that can be tracked in vivo in real-time.


Clinical features and clinical course of thyroid-associated ophthalmopathy: a case series of 3620 Chinese cases.
To determine the clinical features and course of thyroid-associated ophthalmopathy (TAO) in a large sample of Chinese patients. We retrospectively identified a cohort of consecutive patients diagnosed with TAO at the West China Hospital from October 1, 2009 to October 1, 2019. We analysed clinical data from 3620 patients, including demographic data, clinical manifestations, ophthalmology examinations, and prognosis. TAO most frequently occurred with hyperthyroidism, with most patients developing TAO after thyroid disease (TD). The TAO phenotype was asymmetric in 375 (50.7%) euthyroid patients, 25 (27.8%) hypothyroid patients, and 314 (12.1%) hyperthyroid patients (p < 0.0001). The most frequent symptom was lid lag and the most commonly involved extraocular muscle was the inferior rectus. Severity assessment (NOSPECS score) and clinical activity assessment (Clinical Activity Scores, CAS) differed significantly between male and female patients (P < 0.000). The majority (88.8%) of patients had clinically inactive TAO, and only 3.2% of cases were sight-threatening. Regarding the clinical process, 75.5% of patients had an active phase time less than 12 months and 2.1% showed complete remission. TAO most commonly develops in females and is closely related to hyperthyroidism. Euthyroid TAO often has an asymmetric clinical phenotype. CAS combined with magnetic resonance imaging can improve the detection of TAO. NOSPECS scores should be slightly refined regarding the criteria for corneal involvement. Clinical management of TAO should be individualized according to CAS or NOSPECS assessments and a multidisciplinary approach is paramount. A minority of patients showed complete remission.


Carbonylchromium derivatives of bismuth: new syntheses and relevance to cbond;o activation.
We have discovered a series of novel pentacarbonylchromium derivatives of bismuth from the reactions of NaBiO(3) with [Cr(CO)(6)] in KOH/MeOH solutions. When the reaction was carried out at room temperature, the highly charged [Bi[Cr(CO)(5)](4)](3-) (1) was obtained, whose structure was shown by X-ray analysis to possess a central bismuth atom tetrahedrally coordinated to four [Cr(CO)(5)] groups. As the reaction was heated at 80 degrees C, the methyl-substituted complex [MeBi[Cr(CO)(5)](3)](2-)(2) was obtained, presumably via the CbondO activation of MeOH. Further reactions of 1 with CH(2)Cl(2) or CHtbondCCH(2)Br form the halo-substituted complexes [XBi[Cr(CO)(5)](3)](2-)(X=Cl, 3; Br, 4), respectively. On the other hand, the reactions of 1 with RI (R=Me, Et) led to the formation of the alkyl-substituted complexes [RBi[Cr(CO)(5)](3)](2-)(R=Me, 2; Et). The formation of complexes 1-4 is discussed, presumably via the intermediate bismuthinidene [Bi[Cr(CO)(5)](3)](-) or the trianion [Bi[Cr(CO)(5)](3)](3-).


Effect of transforming growth factor beta (TGF-beta) on ATP citrate lyase in isolated hepatocytes.
Transforming growth factor beta (TGF-beta) activates ATP citrate lyase in freshly isolated rat liver hepatocytes in a time dependent manner. Maximal stimulation of the enzyme occurred with less than thirty minutes of incubation of the cells with TGF-beta. The half-maximal effect on the enzyme determined in hepatocytes incubated with TGF-beta for 10 min at 37 degrees C was elicited by TGF-beta concentrations in the 10-11 - 10-12 M range. The potential role of TGF-beta stimulation of ATP citrate lyase activity in new membrane synthesis is discussed.


Silicon nanopillar substrates for enhancing signal intensity in DNA microarrays.
The use of ordered, high-aspect ratio nanopillar arrays on the surface of silicon-based chips to enhance signal intensity in DNA microarrays is reported. These nanopillars consisting either of a single silicon dioxide substrate or a dual silicon/silicon dioxide substrate are fabricated using deep-UV lithography followed by reactive ion etching. These pillar type arrays provide a three-dimensional high surface-density platform that increases the immobilization capacity of captured probes, enhances target accessibility and reduces background noise interference in DNA microarrays, leading to improved signal-to-noise ratios, sensitivity and specificity. Consequently, it was found that the use of such nanopillars enhanced the hybridization signals by up to seven times as compared to silicon dioxide thin film substrates. In addition, hybridization of synthetic targets to capture probes that contained a single-base variation showed that the perfect matched duplex signals on dual-substrate nanopillars can be up to 23 times higher than the mismatched duplex signals, allowing the targets to be unambiguously identified. These results suggest that the nanopillars, particularly the dual-substrate pillars, are able to enhance the hybridization signals and discrimination power in nucleic acids-based detection, providing an alternative platform for improving the performance of DNA microarrays.


The effects of inbreeding on testicular sperm concentration in Peromyscus polionotus.
Inbreeding effects on fitness have most often been quantified via juvenile mortality. However, inbred adults may suffer from inbreeding depression if their fertility or fecundity is compromised as a consequence of inbreeding. Here, the effects of inbreeding on male fertility in oldfield mice, Peromyscus polionotus, were examined. Testicular sperm concentration was assessed in 93 males, 68 of which were paired for breeding. Forty of the 68 paired males failed to produce offspring. Total testicular sperm count, sperm count (g testis)(-1), and testis mass all declined significantly with increasing inbreeding coefficient. Sperm concentration did not significantly impact reproductive success. Although sperm concentration in males of most species can decline to low levels before reproductive impairment is detectable, the declines in testicular sperm concentration found here suggest that inbreeding can affect fertility in adult males. Furthermore, monitoring testicular sperm concentration could provide a mechanism to monitor potential declines in reproductive performance before population-level reproductive success is irreparably impaired. The implications for the management of small, captive and wild populations may be substantial.


Anti-Müllerian hormone and antral follicle count reveal a late impairment of ovarian reserve in patients undergoing low-gonadotoxic regimens for hematological malignancies.
The impact of cancer therapy on the reproductive potential of patients is increasingly recognized because survival rates of patients have clearly improved in recent years. Different fertility preservation methods, either generally accepted or still experimental, are currently available, and counseling of patients requires a delicate balance between the efficacy and side effects of the proposed method and the characteristics of both the tumor and the therapy. Deeper knowledge of the effects of cancer therapy on the reproductive potential of patients over time is required to identify the most appropriate fertility preservation method. In this paper, we report a case-control study in which female patients who were diagnosed with hematological malignancies and treated with chemotherapy and/or radiotherapy were compared with age-matched controls in terms of ovarian reserve, as measured by ultrasound examination and hormonal status. By stratifying patients for gonadotoxicity of the therapy received and time elapsed from the end of the therapy, we report that patients treated with low gonadotoxic therapies, while being similar to age-matched controls in their ovarian reserve when evaluated within a few years from the end of the therapy, show a clear impairment over longer times. We also report that anti-Müllerian hormone is the most sensitive hormonal parameter in detecting changes in ovarian reserve when compared with follicle-stimulating hormone or inhibin-B. This study stresses the importance of accurate counseling at the time of diagnosis of cancer and emphasizes the risks of infertility with low gonadotoxic therapies that may reduce the reproductive window of survivors.


Evidence for a common pattern of peptidergic innervation of cnidocytes.
Tentacles from representatives of all four classes of the phylum Cnidaria were examined using antibodies against the neuropeptides FMRFamide and RFamide to reveal the organization of neurons and nerve nets associated with cnidocytes. The tentacles of all species examined contained FMRFamide- or RFamide-immunoreactive neurons, in varying densities. In representatives from the Scyphozoa, Hydrozoa, and Cubozoa, the FMRFamide-immunoreactive neurons formed plexuses at the base of the cnidocyte assemblages; in anthozoans, the absence of discrete assemblies of cnidocytes precluded visual co-localization of cnidocytes and immunoreactive neurons. In all four classes, immunoreactive sensory cells connected these peptidergic nerve nets to the surface of the tentacle. These findings suggest that members of all four cnidarian classes share a common organizational pattern, and it is proposed that this peptidergic innervation may be involved in the chemosensory regulation of cnidocyte discharge.


Differentiation of acute myeloid leukemia (AML) cells with ATRA reduces 18F-FDG uptake and increases sensitivity towards ABT-737-induced apoptosis.
Acute myeloid leukemia (AML) is a malignant disease of the bone marrow, comprising various subtypes. We have investigated seven different AML cell lines that showed different sensitivities toward the inducer of apoptosis ABT-737, with IC50 concentrations ranging from 9.9 nM to 1.8 µM. Besides, the AML cell lines revealed distinct differences in 18F-FDG uptake ranging from 4.1 to 11.0%. Moreover, the Pearson coefficient (0.363) suggests a moderate correlation between 18F-FDG uptake and the IC50 values of ABT-737. Differentiation of the AML cell lines NB-4 and AML-193 with all-trans-retinoic-acid (ATRA) induced a significant increase in sensitivity towards ABT-737 along with a reduced uptake of 18F-FDG. Therefore, 18F-FDG uptake could be predictive on sensitivity to treatment with ABT-737. Furthermore, because differentiation treatment of AML cells using ATRA reduced 18F-FDG uptake and increased sensitivity towards ABT-737, a combined treatment regimen with ATRA and ABT-737 might be a promising therapeutic option in the future.


Spinal neurogenesis and axon projection: a correlative study in the rat.
The purpose of the present study was to determine the relationship between the duration of a spinal neuron's neurogenic period and the length of its axon or level of projection. Spinal segment L1 was chosen for examination and neurons were divided into four projection groups: 1) supraspinal projection (SSp), 2) long ascending propriospinal (LAPr), 3) short ascending propriospinal (SAPr), and 4) descending propriospinal (DPr). To determine the duration of the neurogenic period for each group, 3H-thymidine was administered to fetal rats during the proliferative period for spinal neuroblasts on one of embryonic (E) days E13 through E16. Between 50 and 100 days after birth neurons in each group were labeled with the retrograde fluorescent tracer Fluoro-Gold. To demonstrate nerve cells with SSp projections, spinal cords were hemisected at spinal segment C3 in one group of animals and Fluoro-Gold was applied to the sectioned surface of the cord. Three additional sets of animals were used to label nerve cells with LAPr, SAPr, and DPr projections by injecting Fluoro-Gold into the gray matter at spinal segments C6, T12, and L5, respectively. Neurons labeled with both Fluoro-Gold and 3H-thymidine and neurons labeled with Fluoro-Gold alone in each animal in each group were counted and the data statistically analyzed. Results showed that within each spinal lamina neurons with different projections were generated, i.e., completed cell division, at significantly different rates. Neurons with the longest axons, those with SSP projections, were generated first. These were followed by those with LAPr projections, and finally those with SAPr and DPr projections. In most laminate there was no significant difference between the neurogenic periods of rostrally projecting short propriospinal (SAPr) neurons versus caudally projecting short propriospinal (DPr) neurons. It was concluded that the duration of the neurogenic period for a given group of neurons within each spinal lamina is inversely related to the distance between the nerve cell and its projection site regardless of the direction of its projection.


[Glucocorticoid therapy in rheumatoid arthritis - pro].
Glucocorticoids are invaluable in the therapy of chronic-inflammatory diseases, like rheumatoid arthritis (RA). They act fast and efficient to suppress inflammation and serve to bridge the gap until disease modifying drugs (DMARD) show effect. However, the value of glucocorticoids with regard to their cost / benefit ratio in long term RA therapy is still controvers. In this short review, the main aspects favoring glucocorticoids as DMARD in long term RA therapy will be discussed. It becomes apparent, that at low dosage (prednisolone ≤ 5 mg / d), careful selection and monitoring of patients, and osteoporosis prophylaxis according to guidelines, long term therapy with glucocorticoids is an option and, with a favorable cost / benefit ratio, contributes to inflammation control and prevention of structural damage.


Reversible Assembly of Terpyridine Incorporated Norbornene-Based Polymer via a Ring-Opening Metathesis Polymerization and Its Self-Healing Property.
We induced a terpyridine moiety into a norbornene-based polymer to demonstrate its self-healing property, without an external stimulus, such as light, heat, or healing agent, using metal⁻ligand interactions. We synthesized terpyridine incorporated norbornene-based polymers using a ring-opening metathesis polymerization. The sol state of diluted polymer solutions was converted into supramolecular assembled gels, through the addition of transition metal ions (Ni2+, Co2+, Fe2+, and Zn2+). In particular, a supramolecular complex gel with Zn2+, which is a metal with a lower binding affinity, demonstrated fast self-healing properties, without any additional external stimuli, and its mechanical properties were completely recovered.


Towards objective and reproducible study of patient-doctor interaction: Automatic text analysis based VR-CoDES annotation of consultation transcripts.
While increasingly appreciated for its importance, the interaction between health care professionals (HCP) and patients is notoriously difficult to study, with both methodological and practical challenges. The former has been addressed by the so-called Verona coding definitions of emotional sequences (VR-CoDES) - a system for identifying and coding patient emotions and the corresponding HCP responses - shown to be reliable and informative in a number of independent studies in different health care delivery contexts. In the preset work we focus on the practical challenge of the scalability of this coding system, namely on making it easily usable more widely and on applying it on larger patient cohorts. In particular, VR-CoDES is inherently complex and training is required to ensure consistent annotation of audio recordings or textual transcripts of consultations. Following up on our previous pilot investigation, in the the present paper we describe the first automatic, computer based algorithm capable of providing coarse level coding of textual transcripts. We investigate different representations of patient utterances and classification methodologies, and label each utterance as either containing an explicit expression of emotional distress (a `concern'), an implicit one (a `cue'), or neither. Using a data corpus comprising 200 consultations between radiotherapists and adult female breast cancer patients we demonstrate excellent labelling performance.


MRI shows increased sciatic nerve cross sectional area in inherited and inflammatory neuropathies.
Measurements of the cross sectional area of the sciatic nerve are described in a group of 10 patients with genetically confirmed Charcot-Marie-Tooth disease type 1A (CMT1A), nine patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 10 healthy controls using MRI. One mid-thigh of each individual was imaged using a short tau inversion recovery sequence and the nerve appearance evaluated radiologically with respect to the signal intensity and visibility of the internal neural structure. The cross sectional area of the sciatic nerve of each individual was measured by defining irregular enclosing regions of interest on the MRI images. The sciatic nerve area was enlarged in both CMT1A (p<0.001) and CIDP (p=0.008) compared with controls and in CMT1A compared with CIDP (p<0.001). Median (interquartile range) areas were 67.6 (16.2) mm(2) for the CIDP group, 135.9 (46.5) mm(2) for the CMT1A group and 43.3 (19.9) mm(2) for the control group. The critical upper value for discriminating pathologically enlarged nerves from normal controls with p<0.05 was 64.4 mm(2). Quantification of sciatic nerve hypertrophy on MRI may be of assistance in cases where the diagnosis is still in doubt, providing an objective pathological marker complimenting other clinical investigations.


A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells.
A farnesylated and methylated form of prelamin A called progerin causes Hutchinson-Gilford progeria syndrome (HGPS). Inhibiting progerin methylation by inactivating the isoprenylcysteine carboxylmethyltransferase (ICMT) gene stimulates proliferation of HGPS cells and improves survival of Zmpste24-deficient mice. However, we don't know whether Icmt inactivation improves phenotypes in an authentic HGPS mouse model. Moreover, it is unknown whether pharmacologic targeting of ICMT would be tolerated by cells and produce similar cellular effects as genetic inactivation. Here, we show that knockout of Icmt improves survival of HGPS mice and restores vascular smooth muscle cell numbers in the aorta. We also synthesized a potent ICMT inhibitor called C75 and found that it delays senescence and stimulates proliferation of late-passage HGPS cells and Zmpste24-deficient mouse fibroblasts. Importantly, C75 did not influence proliferation of wild-type human cells or Zmpste24-deficient mouse cells lacking Icmt, indicating drug specificity. These results raise hopes that ICMT inhibitors could be useful for treating children with HGPS.


Failure to achieve therapeutic levels with high-dose posaconazole tablets potentially due to enhanced clearance.
Aim To describe a case of persistent sub-therapeutic posaconazole levels in setting of salvage chemotherapy for relapsed acute myeloid leukemia. Case details A 57-year-old male was admitted for the management of relapsed acute myeloid leukemia and ongoing pulmonary aspergillosis. While continuing on posaconazole tablet 300 mg daily, he received a course of salvage chemotherapy. The initial steady state posaconazole trough level was therapeutic at 0.84 mg/L (target >0.70 mg/L). However, after five days, the level had dropped to 0.40 mg/L, coinciding with hyperbilirubinemia and hypoalbuminemia. Bilirubin level peaked at 36 µm/L (normal high <20 µm/L), albumin levels were consistently low, averaging at 25 g/L (range 33-46 g/L). The patient had been compliant and there were no underlying gastrointestinal conditions identified which might have potentially affected posaconazole absorption. Outcome An increase in posaconazole dose failed to achieve target levels and treatment was changed to voriconazole. However, levels were surprisingly supra-therapeutic, resulting in side effects and substantial dose reduction was required. Conclusion Failure to achieve target posaconazole levels despite increased dosing may be attributed to factors other than impaired oral absorption. Enhanced metabolism and clearance could be associated with hypoalbuminemia and hyperbilirubinemia. Further case studies, including PK modelling, are required to confirm this effect.


Multiple calcium channel transcripts in rat osteosarcoma cells: selective activation of alpha 1D isoform by parathyroid hormone.
Osteoblasts express calcium channels that are thought to be involved in the transduction of extracellular signals regulating bone metabolism. The molecular identity of the pore-forming subunit (alpha 1) of L-type calcium channel(s) was determined in rat osteosarcoma UMR-106 cells, which express an osteoblast phenotype. A homology-based reverse transcriptase-polymerase chain reaction cloning strategy was employed that used primers spanning the fourth domain. Three types of cDNAs were isolated, corresponding to the alpha 1S (skeletal), alpha 1C (cardiac), and alpha 1D (neuroendocrine) isoforms. In the transmembrane segment IVS3 and the extracellular loop formed by the IVS3-S4 linker, a single pattern of mRNA splicing was found that occurs in all three types of calcium channel transcripts. Northern blot analysis revealed an 8.6-kb mRNA that hybridized to the alpha 1C probe and 4.8- and 11.7-kb mRNAs that hybridized to the alpha 1S and alpha 1D probes. Antisense oligonucleotides directed to the calcium channel alpha 1D transcript, but not those directed to alpha 1S or alpha 1C transcripts, inhibited the rise of intracellular calcium induced by parathyroid hormone. However, alpha 1D antisense oligonucleotides had no effect on the accumulation of cAMP induced by parathyroid hormone. When L-type calcium channels were activated with Bay K 8644, antisense oligonucleotides to each of the three isoforms partially inhibited the rise of intracellular calcium. The present results provide evidence for the expression of three distinct calcium channel alpha 1-subunit isoforms in an osteoblast-like cell line. We conclude that the alpha 1D isoform is selectively activated by parathyroid hormone.


Prediction of response to acute neuroleptic treatment in schizophrenia.
Predicting the outcome of treatment with neuroleptics and understanding the factors that contribute to variability in the response to these drugs have preoccupied researchers and clinicians since the class was developed. Clinicians need empirically based prospective criteria in order to choose a treatment strategy that will lead to the best response from the patient while minimizing side effects. Thus the optimal strategy will match patient, illness and drug characteristics. Before a response can be predicted, the researcher needs explicit concepts and definitions on the course of the illness, drug responses, treatment outcome and predictive criteria. Whereas outcome refers to an arbitrary endpoint of an illness, whether spontaneous or modified by treatment, response is a treatment-related concept. Response refers to a change in the course of the illness which is defined either by pre- or post-treatment criteria and is caused by treatment. Apart from treatment, the spontaneous course of the illness is shaped and modified by various factors, which are referred to as potential outcome/response predictors sampled from a wide area of patient, illness and environmental characteristics. A superordinate concept of prediction must show how these potential determinants of (treatment) course and outcome relate to each other in biopsychosocial terms. Valid predictions of response can only be expected if recognizable rules are operative in the illness course and the treatment outcome. With increasing knowledge about the pathophysiology of the illness, its course and potential determinants, the development of valid predictive algorithms will be promoted. The application of vigorous research strategies in future pharmacological treatment studies will also be required to reach this goal.


Phospho-DeltaNp63alpha/NF-Y protein complex transcriptionally regulates DDIT3 expression in squamous cell carcinoma cells upon cisplatin exposure.
Cisplatin remains the most important chemotherapeutic agent for patients with human head and neck cancer. However, tumor cells often develop resistance to cisplatin-induced apoptosis. We previously found that head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin display a marked ATM-induced phosphorylation of DeltaNp63alpha. However, the mutated Np63-S385G failed to undergo phosphorylation by ATM kinase. We used HNSCC cell lines expressing the wild type DeltaNp63alpha or mutated DeltaNp63alpha-S385G to determine the effect of S385G mutation on the DeltaNp63alpha transcriptional activity and protein-protein interactions. The S385G mutation in DeltaNp63alpha dramatically abolished the upregulation/downregulation of downstream gene targets and the binding of DeltaNp63alpha-S385G to certain promoters. In contrast to the non-phosphorylated DeltaNp63alpha-S385G, the phospho-DeltaNp63alpha forms protein-protein complexes with NF-YA transcription factor and regulates the transcription of DDIT3 gene implicated in the programmed cell death of HNSCC cells upon cisplatin exposure. We suggest that the transcriptional activation of DeltaNp63alpha through its phosphorylation by ATM kinase in HNSCC cells exposed to cisplatin is a critical step in the subsequent sensitivity of certain human head and neck cancers to platinum therapy.


Lead wire fracture associated with normal therapeutic impedance measurements in a patient with a kinetra neurostimulator.
Objectives. We present a case report of a patient with complete lead wire fracture with approximately 3-mm separation of the wire fragments that had three electrode impedance measurements and therapy impedance measurement that would be consistent with an intact wire. Materials and Methods. Retrospective chart review. Results. The patient experienced abrupt worsening of gait freezing while tremor control remained stable. Despite normal therapeutic impedance measurement, clinical suspicion for a hardware problem remained due to her description of brief dystonic hand posturing witnessed during impedance measurements in the clinic. This led to further diagnostic evaluation and eventual surgical replacement of the lead wire. Conclusions. Impedance measurements are not absolutely reliable for the detection of hardware malfunction in a patient with a Kinetra neurostimulator.


Role of autonomic nervous system on heart rate in experimental hypertension.
Heart rate and the role of the autonomic nervous system in hypertensive conscious rats by subtotal nephrectomy were studied. Heart rate is significantly higher in the hypertensive rats. Sympathetic blockade with an intravenous injection of propranolol produces a higher decrease in heart rate of hypertensive rats than in control rats. Intravenous injection of atropine produces an increase in heart rate in both groups of animals. It is significantly higher in the control rats than in hypertensive animals. When the autonomic nervous system is blocked with atropine and propranolol, intrinsic heart rate is similar in both groups of animals. Similar results are obtained after blocking ganglionic transmission with hexamethonium. No significative differences are observed in heart rate after intracerebroventricular injection of hemicholinium-3 between both groups of rats. Results show an increased cardiac sympathetic tone, reduced parasympathetic activities, no alterations in the pacemaker activity and implications of central acetylcholine. These alterations in the autonomic nervous system have an important role in the maintenance of elevated heart rate in this experimental model of arterial hypertension.


Barriers to a classroom-based universal prevention program for depressive symptoms in Chinese adolescents: A qualitative study.
Universal prevention is a practical approach to preventing depressive symptoms in adolescents, but barriers might reduce its effectiveness. This study explored possible barriers to universal prevention of depressive symptoms in Chinese adolescents. We interviewed thirteen adolescents who participated in the program. Thematic analysis was used to analyse the data. The results revealed three categories of barriers. The first category was participants' maladaptive coping strategies and beliefs about negative emotions. They tended to use avoidance coping, did not believe that negative emotions can be regulated, and had an unrealistic wish for a quick fix. The second category originated from the prevention contents. The complexity of the psychological techniques and the lack of proficiency among the participants were important barriers. The third category was the setting of the psychological course. Participants were reluctant to invest cognitive effort in the psychological course. The large-size class also made it challenging to have an in-depth exploration into emotions and thoughts. Our study added to the existing literature by providing more knowledge of barriers to universal prevention. Future research and practice need to adequately address these barriers so that universal prevention can be conducted more effectively.


CYCLOPHOSPHAMIDE TREATMENT ALTERS THE CONTRACTILITY OF ISOLATED RAT VAS DEFERENS.
Influence of cyclophosphamide treatment (40. mg/kg, ip on alternate days for 5 times) was assessed on 1 m mol BaCl2-induced in vitro rhythmic contractions in isolated rat vas deferens. The mean frequency (contractions per min) and amplitude (g tension) of rhythmic contractions were significantly decreased in the tissues isolated from cyclophosphamide-treated rats as compared to the control tissues. These findings indicate a decrease in the contractility and, therefore, functioning of rat vas deferens under cyclophosphamide therapy.


Surface-enhanced Raman spectroscopy (SERS): a powerful technique to study the SEI layer in batteries.
The solid electrolyte interphase (SEI) layer on a silicon anode is investigated by SERS. Gold electrodeposition on a silicon electrode is confirmed by SEM, and Raman enhancement is proved, allowing determination of the partial composition of its SEI. For the first time, organophosphate-derivatives seem to be detected by Raman.


Recognition of intestinal epithelial HIF-1alpha activation by Pseudomonas aeruginosa.
Human intestinal epithelial cell monolayers (Caco-2) subjected to hypoxia and reoxygenation release soluble factors into the apical medium that activate the virulence of the opportunistic pathogen Pseudomonas aeruginosa to express the potent barrier-dysregulating protein PA-I lectin/adhesin. In this study, we defined the role of hypoxia-inducible factor (HIF)-1alpha in this response. We tested the ability of medium from Caco-2 cells with forced expression of HIF-1alpha to increase PA-I expression in P. aeruginosa and found that medium from Caco-2 cells overexpressing HIF-1alpha increased PA-I expression compared with medium from control cells (P < 0.001, ANOVA). To identify the components responsible for this response, medium was fractionated by molecular weight and subjected to mass spectroscopy, which identified adenosine as the possible mediator. Both adenosine and its immediate downstream metabolite inosine induced PA-I expression in P. aeruginosa in a dose-dependent fashion. Because inosine was not detectable in the medium of Caco-2 cells exposed to hypoxia or overexpressing HIF-1alpha, we hypothesized that P. aeruginosa itself might metabolize adenosine to inosine. Using mutant and parental strains of P. aeruginosa, we demonstrated that P. aeruginosa metabolized adenosine to inosine via adenosine deaminase and that the conditioned medium enhanced the extracellular accumulation of inosine. Together, these results provide evidence that P. aeruginosa can recognize and respond to extracellular end products of intestinal hypoxia that are released after activation of HIF-1alpha. The ability of P. aeruginosa to metabolize adenosine to inosine may represent a subversive microbial virulence strategy that deprives the epithelium of the cytoprotective actions of adenosine.


Milk composition in women from five different regions of China: the great diversity of milk fatty acids.
Human milk samples were obtained from 146 lactating women living in five distinct geographic regions of the People's Republic of China. The regions were characterized as follows: pastoral, rural, urban 1, urban 2, and marine. Dietary information obtained on a subsample of women providing milk suggested distinct differences in the food availability in the five regions and the habitual diets of the lactating women studied. The milk concentration of docosahexaenoic acid (DHA) varied greatly (g/100 g total fatty acids): 0.44 +/- 0.29 (pastoral), 0.68 +/- 0.29 (rural), 0.88 +/- 0.34 (urban 1), 0.82 +/- 0.35 (urban 2), and 2.78 +/- 1.20 (marine region). Docosahexaenoic acid is critical for brain and retina development in the infant. Milk arachidonic acid (AA) ranged from 0.80 +/- 0.14 (rural) to 1.17 +/- 0.33 and 1.22 +/- 0.32 g/100 g fatty acids from the marine and pastoral regions. Arachidonic acid is associated with infant growth. The AA to DHA ratio (g/g) was highly variable also: 2.77 (pastoral), 1.18 (rural), 1.01 (urban 1), 1.23 (urban 2), and 0.42 (marine). The DHA concentration found in the milk of women from the marine region was twice as high as any reported previously, but was in a range similar to the amounts found in the milk of women fed fish oil. Seafood consumption by the women residing in the marine region is a likely contributor to the DHA concentration in their milk. These data illustrate the heterogeneity of the fatty acid composition of human milk and suggest a great influence of geography and the maternal diet on concentrations of DHA and AA in human milk.


The prevalence of depression in geriatric medical outpatients.
One hundred and fifty-nine patients attending a geriatric medical outpatient clinic were screened for depression using the geriatric depression scale (GDS) and brief assessment schedule depression cards (BASDEC). Twenty-two (13.8%) patients screened positive with one or other test, 13 (8.2%) being positive with both screening tests. There was a highly significant correlation between the two screening tests but the BASDEC instrument was quicker and easier to administer. Eighteen of 22 patients who screened as positive proved to have clinical depression. On subsequent re-testing of 17 of these patients 4-6 weeks later, eight were still positive, but nine patients were now negative and subjectively felt better. These findings suggest the possibility of a transient mood disturbance occurring in elderly patients akin to recurrent brief depression seen in younger subjects, and have implications for starting therapy in apparently depressed elderly people.


Differential Senescence of Maize Hybrids following Ear Removal : II. Selected Leaf.
In conjunction with a study of the effects of ear removal on the senescence of whole maize (Zea mays L.) plants, visual symptoms and associated changes in constituent contents and activities of a selected leaf (first leaf above the ear) were determined. Leaves were sampled from field-grown eared and earless Pioneer brand 3382, B73 x Mo17, and Farm Services brand 854 maize hybrids at nine times during the grainfilling period.VISUAL SYMPTOMS INDICATED THE FOLLOWING SEQUENCE AND RATE OF SENESCENCE: earless B73 x Mo17 > earless P3382 >> eared B73 x Mo17 >> eared P3382 </= earless FS854 > eared FS854. All earless hybrids showed increases in leaf dry weight and sugar content; however, the increases were transitory for P3382 and B73 x Mo17, but continuous throughout the grain-filling period for FS854, indicative of continued photosynthetic activity of the latter. All earless hybrids exhibited similar and transitory starch accumulation patterns. Thus, FS854 was an exception to the concept that carbohydrate accumulation accelerates leaf senescence. Ear removal resulted in accelerated losses of reduced N, phosphoenolpyruvate and ribulose bisphosphate carboxylases, phosphorus, chlorophyll, nitrate reductase activity, and moisture for P3382 and B73 x Mo17 plants. In contrast, the loss of all components (except phosphorus) was similar for the selected leaf of earless and eared FS854.Although the loss of nitrate reductase activity, reduced N, and carboxylating enzymes accurately reflected the development of senescence of the selected leaf, the rate of net loss of reduced N and carboxylating enzymes appeared to be regulated. We deduced that the rate of flux of N into the leaf was a factor in regulating the differing rates of senescence observed for the six treatments; however, we cannot rule out the possibility of concurrent influence of growth regulators or other metabolites.


Bronchial challenge with hypertonic KCl solution in the diagnosis of bronchial asthma. A comparison with the challenge performed by inhalation of distilled water.
97 symptom-free asthmatics, 56 patients with chronic bronchitis and 32 healthy persons were challenged by inhalation of ultrasonically nebulised hypertonic KCl solution. 24 patients out of the group of asthmatics were challenged also by the inhalation of distilled water to compare its bronchial effect and diagnostic value in bronchial asthma with those of hypertonic (10%) KCl solution. KCl solution caused positive bronchial reaction in each patient with asthma after less than 100 inhalations. The increase of airway resistance (Raw) showed a dose dependence in contrary to bronchitics and healthy persons who failed to show any positive bronchial reaction in any of the cases. Distilled water induced a much lower increase in Raw than 10% KCl solution in the same doses inhaled in each patient with asthma, i.e. more inhalations (longer time) were needed to reach a positive bronchial reaction. The bronchial sensitivity against KCl solution and distilled water did not show clear-out parallelism. The results suggest that the positivity of challenge test performed by the inhalation of hypertonic KCl solution - similarly to that of distilled water (published by others) - seems to be specific for asthma. Challenge test performed with 10% solution has advantages relative to that performed by distilled water, primarily because of the non negligible proportion of false negativity of the latter in the group of asthmatics.


Randomised placebo controlled trial of beta agonist dose reduction in asthma.
Many patients continue to take regular beta agonists, often at high doses, contrary to national and international guidelines. Some studies have suggested that this can worsen asthma control, but whether such patients can reduce their dose of beta agonist and whether they would benefit from this has not been determined. Reduction of beta agonist dose was studied in a placebo controlled parallel group study. Following a run in period, 33 subjects with asthma taking regular beta agonists were converted to an equivalent dose of terbutaline via a Turbohaler. Two weeks later terbutaline was continued at the same dose or changed to placebo in two stages a week apart. The change over period was covered by an increased dose of inhaled steroid to attenuate any immediate effects of the change in dose. Subjects then attended weekly for six weeks for measurement of forced expiratory volume in one second (FEV1) and the dose of methacholine that produced a 20% fall in FEV1 (PD20). Peak expiratory flow (PEF) and symptom scores were recorded twice daily throughout the study. Exacerbations, lung function, bronchial responsiveness, bronchodilator response, beta agonist use, and symptoms were compared before and six weeks after reduction in the dose of beta agonist. Twenty five of the 33 subjects completed the study; three patients in each group withdrew due to an asthma exacerbation. The median terbutaline dose fell from 2500 to 500 micrograms/day in the beta agonist reduction group and from 3000 to 2250 micrograms/day in the control group. There were small non-significant changes in FEV1, PEF, symptom scores and PD20 methacholine over the course of the study. The FEV1 response to a beta agonist was greater in those who reduced their beta agonist dose than in the control group although the final FEV1 achieved was the same. Patients with asthma taking high doses of beta agonists can reduce the amount of beta agonist they use without a significant change in their asthma control. There was no evidence of improved asthma control with beta agonist dose reduction.


Chemical thermodynamics of ultrasound speed in solutions and liquid mixtures.
A comprehensive formalism is developed to treat thermodynamically speed of ultrasound data for solutions and liquid mixtures. For solutions, the apparent speed of ultrasound of a solute is introduced and proposed to take the place of empirically defined quantities. The partial speed of ultrasound of a solute is defined and related to the partial molar volume and partial molar isentropic compression. For liquid mixtures, the concept of speed of sound before mixing pure liquids is presented and used to define the change in speed of ultrasound upon ideal mixing, which is predicted to be generally a negative quantity. A new thermodynamic equation is derived linking the values for excess speed of ultrasound, excess molar volume and excess molar isentropic compression of a mixture, and its applications are discussed. Ideal and excess apparent speeds of ultrasound, as well as ideal and excess partial speeds of ultrasound, are defined for substances making up a liquid mixture. Accurate speeds of ultrasound in 31 mixtures of water with the amphiphile 2-(ethylamino)ethanol at 293.15 K are reported. These data are used to demonstrate the ability of the apparent speed of ultrasound to describe the impact of solutes on sonic properties of solutions and the advantages of analysing thermodynamic properties of binary liquid mixtures in terms of the dependence on composition of Balankina's ratios between excess and ideal values. It is concluded that the new thermodynamic functions defined for speeds of ultrasound in solutions and liquid mixtures give, at the least, equivalent information on molecular aspects to the usual functions related to the isentropic compressibility, without needing density data for this purpose.


ILT4 inhibition prevents TAM- and dysfunctional T cell-mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in NSCLC with EGFR activation.
Rationale: Immune checkpoint inhibitors (ICIs) against the PD-1/PD-L1 pathway showed limited success in non-small cell lung cancer (NSCLC) patients, especially in those with activating epidermal growth factor receptor (EGFR) mutations. Elucidation of the mechanisms underlying EGFR-mediated tumor immune escape and the development of effective immune therapeutics are urgently needed. Immunoglobulin-like transcript (ILT) 4, a crucial immunosuppressive molecule initially identified in myeloid cells, is enriched in solid tumor cells and promotes the malignant behavior of NSCLC. However, the upstream regulation of ILT4 overexpression and its function in tumor immunity of NSCLC with EGFR activation remains unclear. Methods: ILT4 expression and EGFR phosphorylation in human NSCLC tissues and cell lines were analyzed using immunohistochemistry (IHC), real-time PCR, Western blotting, immunofluorescence, and flow cytometry. The molecular signaling for EGFR-regulated ILT4 expression was investigated using mRNA microarray and The Cancer Genome Atlas (TCGA) database analyses and then confirmed by Western blotting. The regulation of tumor cell proliferation and apoptosis by ILT4 was examined by CCK8 proliferation and apoptosis assays. The impact of ILT4 and PD-L1 on tumor-associated macrophage (TAM) recruitment and polarization was evaluated using Transwell migration assay, flow cytometry, enzyme linked immunosorbent assay (ELISA) and real-time PCR, while their impact on T cell survival and cytotoxicity was analyzed by CFSE proliferation assay, apoptotic assay, flow cytometry, ELISA and cytolytic assay. Tumor immunotherapy models targeting at paired Ig-like receptor B (PIR-B, an ortholog of ILT4 in mouse)/ILT4 and/or PD-L1 were established in C57BL/6 mice inoculated with stable EGFR- overexpressing Lewis lung carcinoma (LLC) cells and in humanized NSG mice inoculated with EGFR mutant, gefitinib-resistant PC9 (PC9-GR) or EGFR-overexpressing wild type H1299 cells. PIR-B and ILT4 inhibition was implemented by infection of specific knockdown lentivirus and PD-L1 was blocked using human/mouse neutralizing antibodies. The tumor growth model was established in NSG mice injected with PIR-B-downregulated LLC cells to evaluate the effect of PIR-B on tumor proliferation. The frequencies and phenotypes of macrophages and T cells in mouse spleens and blood were detected by flow cytometry while those in tumor tissues were determined by IHC and immunofluorescence. Results: We found that ILT4 expression in tumor cells was positively correlated with EGFR phosphorylation in human NSCLC tissues. Using NSCLC cell lines, we demonstrated that ILT4 was upregulated by both tyrosine kinase mutation-induced and epidermal growth factor (EGF)-dependent EGFR activation and subsequent AKT/ERK1/2 phosphorylation. Overexpressed ILT4 in EGFR-activated tumor cells induced TAM recruitment and M2-like polarization, which impaired T cell function. ILT4 also directly inhibited T cell proliferation, cytotoxicity, and IFN-γ expression and secretion. In EGFR-activated cell lines in vitro and in wild-type EGFR-activated C57BL/6 and humanized NSG immunotherapy models in vivo, either ILT4 (PIR-B) or PD-L1 inhibition enhanced anti-tumor immunity and suppressed tumor progression by counteracting TAM- and dysfunctional T cell- induced immuno-suppressive TME; the combined inhibition of both molecules showed the most dramatic tumor retraction. Surprisingly, in EGFR mutant, TKI resistant humanized NSG immunotherapy model, ILT4 inhibition alone rather than in combination with a PD-L1 inhibitor suppressed tumor growth and immune evasion. Conclusions: ILT4 was induced by activation of EGFR-AKT and ERK1/2 signaling in NSCLC cells. Overexpressed ILT4 suppressed tumor immunity by recruiting M2-like TAMs and impairing T cell response, while ILT4 inhibition prevented immunosuppression and tumor promotion. Furthermore, ILT4 inhibition enhanced the efficacy of PD-L1 inhibitor in EGFR wild-type but not in EGFR mutant NSCLC. Our study identified novel mechanisms for EGFR-mediated tumor immune escape, and provided promising immunotherapeutic strategies for patients with EGFR-activated NSCLC.


Bud Induction with Cytokinin : A LOCAL RESPONSE TO LOCAL APPLICATION.
A portion of the surface of detached Graptopetalum paraquayense E. Walther leaves can be used to assay small amounts of reagents in lanolin for their ability to induce shoots only at the site of application. The cytokinins benzyladenine, kinetin, and 6-(gamma,gamma-dimethylallylamino)purine (DMAAP) were tested, and DMAAP was most effective in bud induction at concentrations below 1%. The higher the hormone concentration, the sooner the appearance of leaf primordia and the higher the ultimate yield of buds. Leaves treated with DMAAP for 2 days developed buds as rapidly as those with longer treatments.


Work-based antipoverty programs for parents can enhance the school performance and social behavior of children.
We assess the impact of the New Hope Project, an antipoverty program tested in a random assignment experimental design, on family functioning and developmental outcomes for preschool- and school-aged children (N = 913). New Hope offered wage supplements sufficient to raise family income above the poverty threshold and subsidies for child care and health insurance to adults who worked full-time. New Hope had strong positive effects on boys' academic achievement, classroom behavior skills, positive social behavior, and problem behaviors, as reported by teachers, and on boys' own expectations for advanced education and occupational aspirations. There were not corresponding program effects for girls. The child outcomes may have resulted from a combination of the following: Children in New Hope families spent more time in formal child care programs and other structured activities away from home than did children in control families. New Hope parents were employed more, had more material resources, reported more social support, and expressed less stress and more optimism about achieving their goals than did parents in the control sample. The results suggest that an anti-poverty program that provides support for combining work and family responsibilities can have beneficial effects on the development of school-age children.


Spitz nevus is relatively frequent in adults: a clinico-pathologic study of 247 cases related to patient's age.
Spitz nevus is a clinico-pathologic entity that can cause diagnostic concern, particularly in adults. Many studies have been performed to establish reliable histologic criteria, in the attempt to differentiate this lesion from melanoma. A series of 247 Spitz nevi, 6 of which were formerly classified as melanomas, were reviewed for clinical and histopathological parameters. Patients older than 20 comprised 66% of cases, with a predominance of women. The lower extremity was more affected in females of any age, whereas the trunk was more frequently involved in men over 40. Histopathologic examination showed the following differences among Spitz nevi related to age: acanthosis, parakeratosis, pagetoid infiltration, and Kamino bodies were more frequent in young people, whereas multinucleated melanocytes were more frequent in adults. The latter also had lesions that were less pigmented, with less maturation and more desmoplasia. At a mean follow-up of 94 months (range 52-172), recurrence at the site of biopsy or metastases were absent. In our study, a greater proportion of Spitz nevi occurred in adults than in previous series. Moreover, the relative incidence of Spitz nevus compared with melanoma in our population was higher than in other studies. Histopathologic criteria elaborated to diagnose Spitz nevus, applied to our cases, appeared reliable, allowing a correct diagnosis, even in adults.


Improving quality of care in general practices by self-audit, benchmarking and quality circles.
Guideline adherence of general practitioners (GP) regarding treatment of chronic conditions shows room for improvement. Thus, concepts have to be designed to promote quality of care. The aim of the interventional study "Improvement of Quality by Benchmarking" was to assess whether quality can be improved by self-auditing, benchmarking and quality circles in Salzburg (Austria) and South Tyrol (Italy). In this publication we present the Austrian results. Quality indicators were developed in a consensus process for eight chronic diseases based on pre-existing quality management systems. A quality score consisting of 35 indicators was calculated (0-5 points per indicator depending on fulfilment, maximum 175 points). Data were extracted from the electronic health records of participating practices in 2012, 2013 and 2014. A statistical pre-post analysis was performed using Wilcoxon signed-rank tests. A total of 20 GPs participated in the project. The mean quality score increased from 62.0 at baseline to 84.0 at the second follow-up (p = 0.003). Regarding the individual quality indicators, strong improvements were achieved between baseline and first follow-up, especially in process indicators concerning documentation. Between the first and second follow-up, quality remained in most cases at the same level. The validity of results is limited because of structural and technical problems. Due to the uncontrolled pre-post design we cannot exclude external influences on the results. Nevertheless, the intervention was able to improve measured quality of care. Barriers were detected that should be considered in a possible implementation of quality control programs.


[Assisting adolescent women: a report on an experience].
This paper reports the experience with a group of adolescent women in a Basic Health Center, in the municipality of Santa Maria, RS, Brazil, through an extension project developed by the teaching staff and the academicians of the Nursing and Psychology Courses of Universidade Federal do Rio Grande do Sul (UFSM), whose objective is carrying out integrated actions that provide spaces for reflection and discussion with adolescents. For such purpose, a participative methodology was adopted in which the adolescents effectively perform in the educational process. Didactical workshops provided dynamic activities on the themes and important reflections among the people involved, evidencing the relevance of the activities of this nature at the level of basic care.


DHA Suppresses Hepatic Lipid Accumulation via Cyclin D1 in Zebrafish.
With the widespread use of high-fat diets (HFDs) in aquaculture, fatty livers are frequently observed in many fish species. The aim of this study was to investigate if docosahexaenoic acid (DHA) could be used to reduce the fatty liver in zebrafish generated by a 16% soybean oil-HFD over 2 weeks of feeding. The DHA was added to iso-lipidic HFD at 0.5, 1.0, and 2.0% of diet. Supplementation of DHA reduced growth and feed efficiency in a dose dependent manner being lowest in the HFDHA2.0 group. Hepatic triglyceride (TG) in zebrafish fed 0.5% DHA-supplemented HFD (HFDHA0.5) was significantly lower than in the HFD control. Transcriptional analyses of hepatic genes showed that lipid synthesis was reduced, while fatty acid β-oxidation was increased in the HFDHA0.5 group. Furthermore, the expression of Cyclin D1 in liver of zebrafish fed HFDHA0.5 was significantly reduced compared to that in fish fed HFD. In zebrafish liver cells, Cyclin D1 knockdown and blocking of Cyclin D1-CDK4 signal led to inhibited lipid biosynthesis and elevated lipid β-oxidation. Besides, DHA-supplemented diet resulted in a rich of Proteobacteria and Actinobacteriota in gut microbiota, which promoted lipid β-oxidation but did not alter the expression of Cyclin D1 in germ-free zebrafish model. In conclusion, DHA not only inhibits hepatic lipid synthesis and promotes lipid β-oxidation via Cyclin D1 inhibition, but also facilitates lipid β-oxidation via gut microbiota. This study reveals the lipid-lowering effects of DHA and highlights the importance of fatty acid composition when formulating fish HFD.


Bridging the language barrier: the use of interpreters in primary care nursing.
Language barriers present a major obstacle to minority ethnic communities accessing primary healthcare. Whereas it is recognised that interpreting services are generally inadequate and inappropriate reliance is placed on family members to interpret, little is known about how nurses working in primary care utilise interpreters to overcome language barriers. The present paper reports on a study examining the utilisation of interpreting services by a range of primary care nurses from the perspectives of the nurses, interpreters and minority ethnic communities. Focus groups were undertaken with five separate groups of district nurses, health visitors, practice nurses, community midwives and specialist nurses, three groups of interpreters from different interpreting services, and five groups of participants from the main community languages in the locality where the study was undertaken (i.e. Arabic, Bengali, Cantonese, Somali and Urdu). Focus group discussions were tape-recorded and subsequently transcribed. Data analysis drew upon the principles of 'framework' analysis. The use of interpreters by primary care nurses varied considerably. Nurses who had received training in using interpreters and who had most control over the timing of patient visits were more likely to use interpreting services. Inadequate training of both nurses and interpreters adversely affected the quality of interaction where interpreters were used. Primary care nurses acted as gatekeepers to interpreting services. Whereas interpreting services were generally perceived to be inadequate, many nurses were accepting of the status quo and prepared to rely on family members to interpret rather than champion the need to improve services.


Figure-of-eight vs. interrupted sternal wire closure of median sternotomy.
Sternal dehiscence is a rare but devastating complication following median sternotomy for cardiac surgery. The optimal technique for sternal closure is unclear. We conducted this prospective randomized trial to compare the incidence of sternal dehiscence after figure-of-8 and simple interrupted suturing in patients undergoing coronary artery bypass grafting. Between January 2007 and June 2008, 98 patients had figure-of-8 suturing and 97 had interrupted sutures. The mean age of the patients was 60.9 +/- 7.6 years. The overall sternal dehiscence rate was 8%; 7 cases in the in figure-of-8 group and 9 in the interrupted group. Thirteen patients had no wound infection and healed with conservative treatment. Only 3 patients had sternal dehiscence with infection: 2 with simple interrupted closure and 1 with figure-of-8 sternal closure. There was no significant difference in rates of sternal dehiscence between the 2 groups. It was concluded that figure-of-8 sternal suturing is equally effective as simple interrupted suturing in preventing sternal dehiscence.


Ultraviolet-driven switchable superliquiphobic/superliquiphilic coating for separation of oil-water mixtures and emulsions and water purification.
Materials with switchable wettability by external stimuli are of interest in on-demand oil-water separation. Among these materials, ultraviolet (UV) light-stimuli TiO2-based materials are considered as predominant candidates due to the photoinduced superliquiphilicity of TiO2. Besides the photoinduced superliquiphilic property, the photocatalysis is another important intrinsic property of TiO2 which has applications in liquid purification. Therefore, TiO2-based material with these two properties can achieve both separation of diverse oil-water mixtures and liquid purification. In this study, a substrate-independent, UV-driven switchable superliquiphobic/superliquiphilic coating was developed by a facile one-pot method. The wettability of the coating can be rapidly switched between superhydrophobicity/superoleophilicity and superhydrophilicity/underwater superoleophobicity by UV irradiation and heating process, which can be used for on-demand separation of both immiscible oil-water mixtures and emulsions. Such a coating can also be used for the degradation of soluble contamination in water during UV irradiation due to the photocatalysis property of TiO2. The coating provides an effective solution for both on-demand oil-water separation and water purification, which is of interest in both industrial and domestic applications.


Visual field expansion after visual restoration therapy.
To determine whether visual field expansion occurs with visual restoration therapy (VRT), using fundus-controlled microperimetry to assess visual fields. This longitudinal cohort analysis assesses patients' visual fields before and after visual restoration therapy using microperimetry and standard high-resolution perimetry. Seven patients with stroke-induced homonymous field cuts were studied. Visual restoration therapy is a computerized, home-based treatment aimed at reducing the size of the visual field defect of stroke patients with hemianopia through repetitive stimulation of the visual borderzone adjacent to the blind field. During twice-daily therapy for three months patients maintain central fixation while responding to eccentrically placed stimuli in the visual borderzone. The programme is adjusted monthly to changes in the patient's visual field. Controversy exists as to whether expansion of visual fields measured at home with high-resolution perimetry is due to inadvertent eye movements and therefore would overrepresent the treatment's effect. Microperimentry uses an infrared camera to track retinal vessels so that any shift or movement between the reference image and the real-time fundus image corrects the stimulus position, thus delivering stimuli to known retinal locations, and allowing accurate assessment of visual fields independent of eye movements. There was an average improvement in stimulus detection rate by microperimetry of 12.5% (range -1.4% to 38.9%, P =0.033). Six of 7 patients had ≥ 3% improvement in stimulus detection by home-based perimetry. Our results demonstrate modest but real expansion in visual fields following visual restoration therapy which is not due to eye movements.


Meta-analysis of epidemiological studies of association of P53 codon 72 polymorphism with bladder cancer.
Although there have been many studies investigating a possible association between p53 codon 72 polymorphism and risk of bladder cancer, the results have been inconsistent. We conducted a meta-analysis of six epidemiological studies, which included 597 bladder cancer cases and 731 controls. Patients with bladder cancer had a significantly lower frequency of Pro/Arg [odds ratio (OR) = 0.80, 95% confidence interval (CI) = 0.64-0.99], when compared to controls. Stratifying for race, we found that among Caucasians, patients with bladder cancer had a significantly higher frequency of Arg/Arg (OR = 1.64, 95%CI = 1.18-2.28) and a lower frequency of Pro/Arg (OR = 0.62, 95%CI = 0.44-0.86), compared to controls. Stratifying various studies by the stage of bladder cancer, we found that invasive bladder cancers had a significantly lower frequency of Arg/Arg (OR = 0.58, 95%CI = 0.36-0.93) and a higher frequency of Pro/Arg (OR = 0.62, 95%CI = 0.44-0.86) than did non-invasive bladder cancers. No significant association was found between this genotype and human papilloma virus. Based on our meta-analysis, we suggest that p53 codon 72 polymorphism is associated with bladder cancer and that genotypic distribution of this polymorphism varies with the stage of bladder cancer.


Application of the Prague C and M criteria for endoscopic description of columnar-lined esophagus in South Korea.
To ascertain whether the Prague circumferential (C) length and maximal (M) length criteria for grading the extent of Barrett's esophagus can be applied prior to its widespread application in South Korea. Two hundred and thirteen consecutive cases with endoscopic columnar-lined esophagus (CLE) were included and classified according to the Prague C and M criteria. Of 213 cases with CLE, the distribution of maximum CLE lengths was: 0.5-0.9 cm in 99 cases (46.5%); 1.0-1.4 cm in 63 cases (29.6%); 1.5-1.9 cm in 15 cases (7.0%); 2.0-2.4 cm in 14 cases (6.6%); 2.5-2.9 cm in 1 case (0.5%); and 7.0 cm in 1 case (0.5%). Twenty cases (9.4%) had columnar islands alone. Two hundred and eight cases (97.7%) lacked the circumferential CLE component (C0Mx). Columnar islands were found in 70 cases (32.9%), of which 20 cases (9.4%) had columnar islands alone. In regions where most CLE patients display short or ultrashort tongue-like appearance, more detailed descriptions of CLE's in < 1.0 cm lengths and columnar islands, as well as avoidance of repeating the prefix "C0" need to be considered in parallel with the widespread application of the Prague system in South Korea.


Human health effects of dichloromethane: key findings and scientific issues.
The U.S. EPA's Integrated Risk Information System (IRIS) completed an updated toxicological review of dichloromethane in November 2011. In this commentary we summarize key results and issues of this review, including exposure sources, identification of potential health effects, and updated physiologically based pharmacokinetic (PBPK) modeling. We performed a comprehensive review of primary research studies and evaluation of PBPK models. Hepatotoxicity was observed in oral and inhalation exposure studies in several studies in animals; neurological effects were also identified as a potential area of concern. Dichloromethane was classified as likely to be carcinogenic in humans based primarily on evidence of carcinogenicity at two sites (liver and lung) in male and female B6C3F1 mice (inhalation exposure) and at one site (liver) in male B6C3F1 mice (drinking-water exposure). Recent epidemiologic studies of dichloromethane (seven studies of hematopoietic cancers published since 2000) provide additional data raising concerns about associations with non-Hodgkin lymphoma and multiple myeloma. Although there are gaps in the database for dichloromethane genotoxicity (i.e., DNA adduct formation and gene mutations in target tissues in vivo), the positive DNA damage assays correlated with tissue and/or species availability of functional glutathione S-transferase (GST) metabolic activity, the key activation pathway for dichloromethane-induced cancer. Innovations in the IRIS assessment include estimation of cancer risk specifically for a presumed sensitive genotype (GST-theta-1+/+), and PBPK modeling accounting for human physiological distributions based on the expected distribution for all individuals 6 months to 80 years of age. The 2011 IRIS assessment of dichloromethane provides insights into the toxicity of a commonly used solvent.


Patterned biochemical functionalization improves aptamer-based detection of unlabeled thrombin in a sandwich assay.
Here we propose a platform for the detection of unlabeled human α-thrombin down to the picomolar range in a fluorescence-based aptamer assay. In this concept, thrombin is captured between two different thrombin binding aptamers, TBA1 (15mer) and TBA2 (29mer), each labeled with a specific fluorescent dye. One aptamer is attached to the surface, the second one is in solution and recognizes surface-captured thrombin. To improve the limit of detection and the comparability of measurements, we employed and compared two approaches to pattern the chip substrate-microcontact printing of organosilanes onto bare glass slides, and controlled printing of the capture aptamer TBA1 in arrays onto functionalized glass substrates using a nanoplotter device. The parallel presence of functionalized and control areas acts as an internal reference. We demonstrate that both techniques enable the detection of thrombin concentrations in a wide range from 0.02 to 200 nM with a detection limit at 20 pM. Finally, the developed method could be transferred to any substrate to probe different targets that have two distinct possible receptors without the need for direct target labeling.


Essential fatty acids and their metabolites in signal transduction.
The above examples argue that the diversity of eicosanoid structures is reflected in distinct actions, that the membrane-permeable nature of these molecules provides a system for interactive cellular signalling that may be particularly important in the nervous system, and that convincing evidence exists for direct actions of eicosanoids on both ion channels and kinases, as well as G-protein-coupled receptors.


A case for modular design: Implications for implementing evidence-based interventions with culturally-diverse youth.
Community-based therapists are frequently faced with the complex task of applying existing research knowledge to clients who may differ markedly from those enrolled in controlled outcome studies. The current paper examines the utility of modular psychotherapy design as one method of facilitating the flexible delivery of evidence-based mental health services to ethnically and culturally diverse children and families. Modularity complements existing approaches to the provision of culturally-sensitive, empirically-informed treatment through its ability to balance the prioritization of research evidence and local practitioner cultural knowledge. Specific applications of modular principles to clinical work with diverse youth are highlighted. Special considerations and limitations relevant to modular psychotherapy and the overall mental health services research literature are discussed, as well as the continued importance of individual clinicians' cultural competence and use of treatment progress monitoring, both of which should be combined with identified treatment modules to support the delivery of high-quality care.


Sex-dependent changes in blood-brain barrier permeability in epileptic rats following acute hyperosmotic exposure.
Osmotic and ionic balance in the central nervous system is especially regulated by solutes and water transport across the blood-brain barrier. The aim of this study was to investigate the effect of systemic hyperosmolarity on the blood-brain barrier permeability in both sexes after experimentally induced seizures. Eight groups of rats were studied: Group I: female control; Group II: male control; Group III: hyperosmotic female; Group IV: hyperosmotic male; Group V: non-hyperosmotic female + seizure; Group VI: non-hyperosmotic male + seizure; Group VII: hyperosmotic female + seizure; Group VIII: hyperosmotic male + seizure. In female rats with pentylenetetrazol-induced seizures, the extravasation of Evans-blue was greater in the brains of hyperosmotic animals than that in normal rats (P < 0.02). However, in male rats, the extravasation of Evans-blue was similar in the brains of hyperosmotic male rats and normal rats after seizure. Our results concluded that hyperosmotic female rats were shown to have a large increase in blood-brain barrier permeability in comparison to hyperosmotic male rats after pentylenetetrazol-induced seizures.


Determination of the free energy landscape of alpha-synuclein using spin label nuclear magnetic resonance measurements.
Natively unfolded proteins present a challenge for structure determination because they populate highly heterogeneous ensembles of conformations. A useful source of structural information about these states is provided by paramagnetic relaxation enhancement measurements by nuclear magnetic resonance spectroscopy, from which long-range interatomic distances can be estimated. Here we describe a method for using such distances as restraints in molecular dynamics simulations to obtain a mapping of the free energy landscapes of natively unfolded proteins. We demonstrate the method in the case of alpha-synuclein and validate the results by a comparison with electron transfer measurements. Our findings indicate that our procedure provides an accurate estimate of the relative statistical weights of the different conformations populated by alpha-synuclein in its natively unfolded state.