Gender differences in pain.
A review of the literature on gender and clinical pain reveals a disproportionate representation of women receiving treatment for many pain conditions and suggests that women report more severe pain, more frequent pain, and pain of longer duration than do men. Gender differences in pain perception have also been extensively studied in the laboratory, and ratings of experimentally induced pain also show some sex disparity, with females generally reporting lower pain thresholds and tolerance than males. However, there is little consensus on whether these apparent differences reflect the way men and women respond to pain, differing social rules for the expression of pain, or biologic differences in the way noxious stimuli are processed. In this paper, our working hypothesis is that the higher prevalence of chronic orofacial pain in women is a result of sex differences in generic pain mechanisms and of as-yet unidentified factors unique to the craniofacial system. We will review the evidence concerning gender differences in the prevalence of pain conditions, with a focus on orofacial pain conditions. Evidence and hypotheses concerning biologic and psychosocial factors that could influence prevalence rates will also be discussed.


[One-dimensional impact dynamic response of cancellous bone].
In this paper a one-dimensional dynamic response of cancellous bone to impact loading is investigated. It is demonstrated, based on the studies with scanning electron microscope, cancellous bone could be viewed as a cellular solid consisting of an interconnected skeleton filled with medulla. A two-phase poroelastic model is introduced to describe the cancellous bone, in which the tissue(material) densities of the skeleton and medulla are assumed to be unchangeable while the corresponding apparent densities are changeable due to the change of volume fraction, the governing equations are derived for the case of a linear poroelastic solid skeleton saturated with an inviscid medulla. Under the impact loading, responses of the skeleton displacement and stress as well as the medullary pressure are obtained with the use of Laplace transform technique. The computational result shows that the cancellous bone is provided with certain features similar to those appearing in viscoelastic solids, which means that the responses do not only depend on time, but furthermore depend on previous loading history. It is worth paying attention to the result that the medullary pressure can be negative. This point is due to the recovery of the skeleton after unloading whereas the medulla is not squeezed out but absorbed into the pores by suction.


[Evaluation of ultrasonography effectiveness in prostate cancer detection].
The database of examining 624 patients aged 49-85 were analyzed to define the diagnostic effectiveness of gray-scale, color and power Doppler transrectal ultrasonography (TRUS). Among them there are 473 (75.8%) cancer patients and 151 (24.2%) benign prostate diseases patients. All the patients underwent a transrectal ultrasound examination with multifocal biopsy. The gray-scale, color and power Doppler transrectal ultrasound examination has the diagnostic accuracy of 75,3%. At this the effectiveness of the method increases with the Gleason sum growing.


Changing Trends in the Global Burden of Cataract Over the Past 30 Years: Retrospective Data Analysis of the Global Burden of Disease Study 2019.
Cataracts now account for the largest proportion of the global burden of blindness and vision loss. Understanding the changing trends in the global burden of cataracts over the past 30 years and the next 15 years is of clear significance for the prevention and control of cataracts in key populations. As far as we know, research on the future burden of cataracts is lacking. This study aims to assess the global burden of cataracts over the past 30 years by using age-period-cohort modeling and to estimate trends in the next 15 years. Data were obtained from the Global Burden of Disease Study 2019, the United Nations Development Programme, and the WHO (World Health Organization) Global Health Observatory data repository. The assessment of trends and disparities in the number and rate of disability-adjusted life years (DALYs) for cataracts from 1990 to 2019 was conducted. The association between the age-standardized DALY rate (ASDR) and the socio-demographic index (SDI), human development index (HDI), national levels of particulate matter <2.5 μm in diameter (PM2.5), and ambient ultraviolet radiation (UVR) was determined using linear regression analysis. Additionally, we used the Nordpred (Harald Fekjær and Bjørn Møller) age-period-cohort model to predict the cataract burden from 2020 to 2034. Globally, the number of DALYs due to cataract increased from 3,492,604 (95% uncertainty interval [UI] 2,481,846-4,719,629) in 1990 to 6,676,281 (95% UI 4,761,210-9,006,193) in 2019. The ASDRs due to cataract decreased from 93.17 (95% UI 66.14-125.32) in 1990 to 82.94 (95% UI 59.06-111.75) in 2019, with an average annual percentage change of -0.37 (95% CI -0.44 to -0.3; P<.001). Age, female sex, air pollution, smoking, high fasting plasma glucose levels, and a high body mass index were risk factors for the burden of cataracts. SDI and HDI were negatively correlated with ASDRs of cataracts, while PM2.5 and UVR were positively associated with them. Higher DALY rates were also associated with lower SDI (R2=0.1939; P<.001), lower HDI (R2=0.2828; P<.001), national PM2.5 concentration (R2=0.1874; P<.001), and ambient UVR levels (R2=0.2354; P<.001). The prediction model suggested that the number of DALYs due to cataract will continue to rise globally, while the cataract DALY rate will continue to decrease. While the ASDR of cataracts has decreased, there has been a notable increase in the number of DALYs over the past 30 years. Projections suggest that the global burden of cataracts will continue to rise over the next 15 years. To address this challenge, appropriate prevention and treatment policies must be implemented.


A mutation in TTF1/NKX2.1 is associated with familial neuroendocrine cell hyperplasia of infancy.
Neuroendocrine cell hyperplasia of infancy (NEHI) is a childhood diffuse lung disease of unknown etiology. We investigated the mechanism for lung disease in a subject whose clinical, imaging, and lung biopsy specimen findings were consistent with NEHI; the subject's extended family and eight other unrelated patients with NEHI were also investigated. The proband's lung biopsy specimen (at age 7 months) and serial CT scans were diagnostic of NEHI. Her mother, an aunt, an uncle, and two first cousins had failure to thrive in infancy and chronic respiratory symptoms that improved with age. Genes associated with autosomal-dominant forms of childhood interstitial lung disease were sequenced. A heterozygous NKX2.1 mutation was identified in the proband and the four other adult family members with histories of childhood lung disease. The mutation results in a nonconservative amino acid substitution in the homeodomain in a codon extensively conserved through evolution. None of these individuals have thyroid disease or movement disorders. NKX2.1 mutations were not identified by sequence analysis in eight other unrelated subjects with NEHI. The nature of the mutation and its segregation with disease support that it is disease-causing. Previously reported NKX2.1 mutations have been associated with "brain-thyroid-lung" syndrome and a spectrum of more severe pulmonary phenotypes. We conclude that genetic mechanisms may cause NEHI and that NKX2.1 mutations may result in, but are not the predominant cause of, this phenotype. We speculate that altered expression of NKX2.1 target genes other than those in the surfactant system may be responsible for the pulmonary pathophysiology of NEHI.


Coronary vasodilatory, spasmolytic and cAMP-phosphodiesterase inhibitory properties of dihydropyranocoumarins and dihydrofuranocoumarins.
Twenty-three dihydropyrano- and dihydrofuranocoumarins, most of plant origin, were examined for their effects on the coronary flow of isolated perfused guinea-pig heart, on the Ba2+-induced spasms in isolated guinea-pig ileum, on the cAMP level in guinea-pig heart homogenate and on the cAMP metabolising activity of purified beef heart cAMP-phosphodiesterase. For certain esters of dihydropyranocoumarin- and dihydrofuranocoumarin alcohols coronary vasodilatory and spasmolytic activities comparable to those of papaverine were observed. A very close correlation between the coronary vasodilatory and the spasmolytic activity was found. The most potent structures maximally increased the cAMP level from 19 pmol/mg protein to about 60 pmol/mg protein and inhibited the cAMP-phosphodiesterase activity with about 90%. The potencies were comparable to those of papaverine. A significant correlation was obtained between the coronary vasodilatory and the cAMP-phosphodiesterase inhibitory activity. The results indicate involvement of cAMP-phosphodiesterase inhibition in coronary vasodilatory effects of acyloxydihydropyrano- and acyloxydihydrofurano-coumarins.


Antarctica: measuring glacier velocity from satellite images.
Many Landsat images of Antarctica show distinctive flow and crevasse features in the floating part of ice streams and outlet glaciers immediately below their grounding zones. Some of the features, which move with the glacier or ice stream, remain visible over many years and thus allow time-lapse measurements of ice velocities. Measurements taken from Landsat images of features on Byrd Glacier agree well with detailed ground and aerial observations. The satellite-image technique thus offers a rapid and cost-effective method of obtaining average velocities, to a first order of accuracy, of many ice streams and outlet glaciers near their termini.


Sensing signatures mediated by chemical structure of molecular solids in laser-induced plasmas.
Laser ablation of organic compounds has been investigated for almost 30 years now, either in the framework of pulse laser deposition for the assembling of new materials or in the context of chemical sensing. Various monitoring techniques such as atomic and molecular fluorescence, time-of-flight mass spectrometry, and optical emission spectroscopy have been used for plasma diagnostics in an attempt to understand the spectral signature and potential origin of gas-phase ions and fragments from organic plasmas. Photochemical and photophysical processes occurring within these systems are generally much more complex than those suggested by observation of optical emission features. Together with laser ablation parameters, the structural and chemical-physical properties of molecules seem to be closely tied to the observed phenomena. The present manuscript, for the first time, discusses the role of molecular structure in the optical emission of organic plasmas. Factors altering the electronic distribution within the organic molecule have been found to have a direct impact on its ensuing optical emissions. The electron structure of an organic molecule, resulting from the presence, nature, and position of its atoms, governs the breakage of the molecule and, as a result, determines the extent of atomization and fragmentation that has proved to directly impact the emissions of CN radicals and C2 dimers. Particular properties of the molecule respond more positively depending on the laser irradiation wavelength, thereby redirecting the ablation process through photochemical or photothermal decomposition pathways. It is of paramount significance for chemical identification purposes how, despite the large energy stored and dissipated by the plasma and the considerable number of transient species formed, the emissions observed never lose sight of the original molecule.


Next-Generation Sequencing reveals relationship between the larval microbiome and food substrate in the polyphagous Queensland fruit fly.
Insects typically host substantial microbial communities (the 'microbiome') that can serve as a vital source of nutrients and also acts as a modulator of immune function. While recent studies have shown that diet is an important influence on the gut microbiome, very little is known about the dynamics underpinning microbial acquisition from natural food sources. Here, we addressed this gap by comparing the microbiome of larvae of the polyphagous fruit fly Bactrocera tryoni ('Queensland fruit fly') that were collected from five different fruit types (sapodilla [from two different localities], hog plum, pomegranate, green apple, and quince) from North-east to South-east Australia. Using Next-Generation Sequencing on the Illumina MiSeq platform, we addressed two questions: (1) what bacterial communities are available to B. tryoni larvae from different host fruit; and (2) how does the microbiome vary between B. tryoni larvae and its host fruit? The abundant bacterial taxa were similar for B. tryoni larvae from different fruit despite significant differences in the overall microbial community compositions. Our study suggests that the bacterial community structure of B. tryoni larvae is related less to the host fruit (diet) microbiome and more to vertical transfer of the microbiome during egg laying. Our findings also suggest that geographic location may play a quite limited role in structuring of larval microbiomes. This is the first study to use Next-Generation Sequencing to analyze the microbiome of B. tryoni larvae together with the host fruit, an approach that has enabled greatly increased resolution of relationships between the insect's microbiome and that of the surrounding host tissues.


Molecular Engineering of Adeno-Associated Virus Capsid Improves Its Therapeutic Gene Transfer in Murine Models of Hemophilia and Retinal Degeneration.
Recombinant adeno-associated virus (AAV)-based gene therapy has been promising, but several host-related transduction or immune challenges remain. For this mode of therapy to be widely applicable, it is crucial to develop high transduction and permeating vectors that infect the target at significantly low doses. Because glycosylation of capsid proteins is known to be rate limiting in the life cycle of many viruses, we reasoned that perturbation of glycosylation sites in AAV2 capsid will enhance gene delivery. In our first set experiments, pharmacological modulation of the glycosylation status in host cells, modestly decreased (1-fold) AAV2 packaging efficacy while it improved their gene expression (∼74%) in vitro. We then generated 24 mutant AAV2 vectors modified to potentially create or disrupt a glycosylation site in its capsid. Three of them demonstrated a 1.3-2.5-fold increase in transgene expression in multiple cell lines (HeLa, Huh7, and ARPE-19). Hepatic gene transfer of these vectors in hemophilia B mice, resulted in a 2-fold increase in human coagulation factor (F)IX levels, while its T/B-cell immunogenic response was unaltered. Subsequently, intravitreal gene transfer of glycosylation site-modified vectors in C57BL6/J mice demonstrated an increase in green fluorescence protein expression (∼2- to 4-fold) and enhanced permeation across retina. Subretinal administration of these modified vectors containing RPE65 gene further rescued the photoreceptor response in a murine model of Leber congenital amarousis. Our studies highlight the translational potential of glycosylation site-modified AAV2 vectors for hepatic and ocular gene therapy applications.


Oxidative Degradation of Polysorbate Surfactants Studied by Liquid Chromatography-Mass Spectrometry.
Polysorbates (PSs), as acquired from manufacturing processes and chemical nature of fatty acids (FAs) used in production of biotherapeutic formulations, are heterogeneous mixtures of structurally related compounds, covering a wide range of physicochemical properties. Such complexity presents a certain challenge for analysis of these important surfactants and demands the use of methods offering sufficient resolution to monitor individual classes of species and detect changes upon stress. A liquid chromatography mass spectrometry method, benefiting from the use of low m/z marker ions, simplifies profiling of PSs by providing detailed information on FA composition even of chromatographically overlapping peaks. The ability of the method to monitor individual components and follow their changes because of oxidative stress was explored. A water-soluble azo compound was used as a model oxidizer. Major degradation products of PS 80, because of reactions involving double bond, were identified as oxo-C9:0, keto-C18:1, hydroxyl-C18:1, epoxy-C18:0, and hydroperoxy-C18:1. Stability of PS 20 components was found to depend on the carbon number of polyethoxylated (POE) sorbitan FA ester and its order. Rates of oxidative degradation increased with the length of the FA ester and, moreover, POE sorbitan diesters degraded significantly faster in comparison to the corresponding monoesters upon the oxidative stress. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.


New psychoactive substances, safety and mental health in prison officers.
The use of new psychoactive substances (NPS) in UK prisons is believed to have increased substantially. As well as posing a significant threat to prisoners' health, NPS use can trigger violent, unpredictable and aggressive behaviour. Dealing with the direct and indirect effects of NPS therefore has the potential to compromise the physical and psychological safety of prison staff. This study investigates prison officers' perceptions of NPS use in their workplace and their risk of exposure. Relationships between NPS exposure, the workplace safety climate and mental health were also examined. We assessed prison officers' perceptions of the prevalence of NPS use among prisoners in their workplace, their personal exposure and the safety climate in their institution through an online survey. The General Health Questionnaire-12 measured mental health. Descriptive statistics were used to assess officers' perceptions of NPS use in their workplace and their personal exposure and correlations examined relationships between variables. The sample comprised 1956 prison officers (86% male). Most respondents (85%) highlighted NPS as a serious cause for concern in their institution. Two-thirds (66%) reported being personally exposed to NPS at least sometimes, with 22% being exposed once a day or more. Significant relationships were found between officers' perceived NPS exposure, assessments of safety climate and self-reported mental health. Our findings highlight the need for urgent action to reduce the use of NPS among prisoners. This is likely to improve the safety climate of UK prisons and the mental health of staff.


Conjunctival eosinophils in allergic ocular disease.
Tarsal conjunctival scrapings of 317 patients with allergic ocular disease demonstrated that eosinophils were found infrequently in scrapings of patients with mild allergic conditions and were found in only 63% (17/27) of the patients with vernal conjunctivitis. In similar studies of a 12-year-old boy with vernal keratoconjunctivitis, no eosinophils were recovered in his scraping, even though 12 eosinophils were found in five high-power fields of his biopsy specimen. We conclude that eosinophils present in the deep and superficial conjunctival tissues may not be recovered in scrapings; their absence from scrapings should not preclude the diagnosis of allergic ocular disease.


Flat liquid jet as a highly efficient source of terahertz radiation.
Polar liquids are strong absorbers of electromagnetic waves in the terahertz range, therefore, historically such liquids have not been considered as good candidates for terahertz sources. However, flowing liquid medium has explicit advantages, such as a higher damage threshold compared to solid-state sources and more efficient ionization process compared to gases. Here we report systematic study of efficient generation of terahertz radiation in flat liquid jets under sub-picosecond single-color optical excitation. We demonstrate how medium parameters such as molecular density, ionization energy and linear absorption contribute to the terahertz emission from the flat liquid jets. Our simulation and experimental measurements reveal that the terahertz energy has quasi-quadratic dependence on the optical excitation pulse energy. Moreover, the optimal pump pulse duration, which depends on the thickness of the jet is theoretically predicted and experimentally confirmed. The obtained optical-to-terahertz energy conversion efficiency is more than 0.05%. It is comparable to the commonly used optical rectification in most of electro-optical crystals and two-color air filamentation. These results, significantly advancing prior research, can be successfully applied to create a new alternative source of terahertz radiation.


The presence of humic substances and DNA in RNA extracts affects hybridization results.
RNA extracts obtained from environmental samples are frequently contaminated with coextracted humic substances and DNA. It was demonstrated that the response in rRNA-targeted oligonucleotide probe hybridizations decreased as the concentrations of humic substances and DNA in RNA extracts increased. The decrease in hybridization signal in the presence of humic substances appeared to be due to saturation of the hybridization membrane with humic substances, resulting in a lower amount of target rRNA bound to the membrane. The decrease in hybridization response in the presence of low amounts of DNA may be the result of reduced rRNA target accessibility. The presence of high amounts of DNA in RNA extracts resulted in membrane saturation. Consistent with the observations for DNA contamination, the addition of poly(A) to RNA extracts, a common practice used to prepare RNA dilutions for membrane blotting, also reduced hybridization signals, likely because of reduced target accessibility and membrane saturation effects.


Covalent modification and active site-directed inactivation of a low molecular weight phosphotyrosyl protein phosphatase.
Covalent modification experiments were conducted in order to identify active site residues of the 18-kDa cytoplasmic phosphotyrosyl protein phosphatases. The enzyme was inactivated by diethyl pyrocarbonate, phenylglyoxal, cyclohexanedione, iodoacetate, iodoacetamide, phenylarsine oxide, and certain epoxides in a manner consistent with the modification of active site residues. Phenylglyoxal and cyclohexanedione both bind to the active site in a rapid preequilibrium process and thus act as active site-directed inhibitors. The pH dependencies of the inactivation by iodoacetate and by iodoacetamide were examined in detail and compared with rate data for the alkylation of glutathione as a model compound. The enzyme inactivation data permitted the determination of pKa values of two reactive cysteines at or near the active site. Although phosphomycin is simply a competitive inhibitor of the enzyme, it was found that 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) and (R)- and (S)-benzylglycidol act as irreversible covalent inactivators, consistent with the importance of a hydrophobic moiety on the substrate in controlling substrate specificity. EPNP exhibits characteristics of an active site-directed inactivator, with a preequilibrium binding constant somewhat smaller than that of phosphate ion. The pH dependencies of inactivation of EPNP and (S)-benzylglycidol are identical to that observed for iodoacetamide and similar to that for iodoacetate, suggesting that they modify similar groups. Sequencing of the tryptic digests of the EPNP-labeled enzyme indicates that Cys-62 and Cys-145 are labeled. Phenylarsine oxide acts as a very slow, tight-binding inhibitor of the enzyme. The results are interpreted in terms of an active site model that incorporates a histidine-cysteine ion pair, similar to that present in papain.


[Radiation burden of patients in conventional diagnostic radiology: analysis of radiologic practice in Serbia].
X-rays are by far most significant contributor to total population dose from man-made sources of radiation. Diagnostic reference levels provide frameworks to reduce variability. The aim of this study is to establish, for the first time, a baseline for national diagnostic reference levels in Serbia for the most common X-ray examination types. Dose estimates are based on measurements of kerma-area product and Entrance surface air kerma for at least ten patients for each examination type, in each of 16 randomly selected hospitals in Serbia. Mean, median and third quartile values of patient doses are reported. Results have shown wide variation of mean hospital doses. Entrance surface doses were compared with previously published diagnostic reference levels. Doses for all studied examination types except chest radiography were within European DRL. The reasons for dose variation are discussed. The findings emphasize the importance of regular patient dose measurement to ensure that patient doses are kept as low as reasonable achievable.


Use of a Personalized Multimedia Education Platform Improves Preoperative Teaching for Lung Cancer Patients.
We sought to develop and evaluate a personalized multimedia education (ME) tool for preoperative patient education to improve patient health knowledge, quality of life and satisfaction with care in thoracic surgery. The ME tool was developed and deployed in outpatient clinic during preoperative teaching for patients undergoing surgical resection for lung cancer for quality improvement. Patients were given an electronic survey prior to preoperative teaching and at initial postoperative visit to assess teaching effectiveness and care satisfaction. Sequential patients received either standard preoperative teaching or teaching using the ME tool. Pre- and postoperative survey responses were compared using independent sample paired t test and multivariable linear regression modeling for adjustment. The final ME tool was an iPad application that incorporated real-time annotations of 3-dimensional, interactive anatomic diagrams. The tool featured video tours of operations, and radiology image import for annotation by the surgeon. Forty-eight patients were included in this pilot study (standard education n = 26; ME, n = 22). ME patients had significantly higher satisfaction scores compared to SE patients with respect to length of education materials, clarity of content, supportiveness of content and willingness to recommend materials to others. There was no difference in length of clinic visit between groups. Both patient and provider input can be used to create an innovative electronic preoperative educational tool that prepares and empowers patients in shared decision-making before surgery. Improvements in health literacy and self-efficacy may be more difficult to achieve but remain important as multimedia teaching tools are further developed.


Possible Contributions of Nongenomic Actions of Thyroid Hormones to the Vasculopathic Complex of COVID-19 Infection.
Integrin αvβ3 is a cell membrane structural protein whose extracellular domain contains a receptor for L-thyroxine (T4). The integrin is expressed in rapidly dividing cells and its internalization is prompted by T4. The protein binds viruses and we have raised the possibility elsewhere that action of free T4 (FT4)-when he latter is increased in the nonthyroidal illness syndrome (NTIS) known to complicate COVID-19 infecction-may enhance cellular uptke of SARS-CoV-2 and its receptor. Because T4 also acts nongenomically via the integrin to promote platelet aggregation and angiogenesis, we suggest here that T4 may contribute to the coagulopathy and endothelial abnormalities that can develop in COVID-19 infections, particularly when the lung is primary affected. Elevated FT4 has been described in the NTIS of COVID-19 patients and may be associated with increased illness severity, but the finding of FT4 elevation is inconsistent in the NTIS literature. Circulating 3,5',3'-triiodo-L-thyronine (reverse T3, rT3) are frequently elevated in NTIS. Thought to be biologically inactive, rT3in fact stimulates cancer cell proliferation via avb3 and also may increase actin polymerization. We propose here that rT3 in the NTIS complicating systemic COVIF-19 infection may support coagulation and disordered blood vessel formation via actin polymerization.


Evaluation of the effect of phenylpropanoids on the binding of heparin to human serum albumin and glycosylated human serum albumin concerning anticoagulant activity: A comparison study.
The nonenzymatic advanced glycation end products (AGEs) and the accumulation of AGEs are the two main factors associated with the long-term pathogenesis of diabetes. Human serum albumin (HSA) as the most abundant serum protein has a higher fortuity to be modified by nonenzymatic glycation. In this study, the interaction of three phenylpropanoids (caffeic acid (Caf), p-coumaric acid (Cou), and cinnamic acid (Cin)) toward HSA and glycosylated HSA (gHSA) was analyzed by multiple spectroscopic techniques combined with molecular docking. The formation of fibrils in HSA and gHSA was confirmed by the Thioflavin T (ThT) assay. The phenylpropanoids have shown anti-fibrillation properties in vitro. The obtained thermodynamic parameters indicated that hydrogen bonding and van der Waals forces are the main forces in the binding interaction, and the quenching mechanism of the protein fluorescence is static. Molecular docking results, as well as the in vitro results, showed that Caf, Cou, and Cin exhibit more stable interactions with HSA, respectively. In addition, molecular docking analysis showed that Caf and Cou interact well with K199. Given the critical role of K199 in HSA glycosylation in diabetic patients, this process inhibits the interaction of stabilizer compounds and thus accelerates gHSA aggregation.


[Thoracic imaging in the elderly].
In our hospital, 30% of plain chest radiographs are performed in patients over 70. Somewhat surprisingly, few papers specifically dealing with the aging lung are available in the radiological literature. It is obvious however that the differential diagnosis of a chest lesion is not the same if the patient is 40 or 70. A false positive diagnosis is a frequent potential mistake in aging subjects, for example: chondral calcification versus pulmonary nodule, hyperinflation versus emphysema, "normal aging" bronchial and tracheal calcification versus hypercalcemia, diaphragmatic defect versus tumor, diaphragmatic pseudotumor versus lymph node, false diagnosis of aortic knob dissection, false diagnosis of syphilitic aortitis, inaccurate CT-detection of valvular and coronary calcifications, confusion between valvular and annular mitral calcification. Much work is still needed to exploit CT in its clinical applications for the aging lung.


[Possible mechanisms of polyuria in progressive chronic renal failure].
Elucidation of the role of saluresis and osmotic diuresis in renal function of patients with chronic renal failure. The trial included 68 subjects, among them 25 patients with chronic renal failure (CRF) of the third and fourth degree aged 16 to 72 years. Enzyme immunoassay was used to measure osmolality, sodium, potassium, magnesium, calcium and creatinine concentrations in the serum and urine as well as urine prostaglandin E2. Renal function was studied in CRF patients with a 75-90% fall of glomerular filtration rate. Creatinine clearance was 19.9 +/- 0.96, it varied in different patients from 10.6 to 29.7 ml/min. It is shown that diuresis does not correlate with the total ion excretion (Na+ plus K+)(r = 0.946, p < 0.0001). A correlation was found between excretion of these ions and Mg2+ ions this indicating location of reabsorption reduction in the thick ascending limb of Henle loop. In CRF patients (Na+ plus K+) excretion correlated with PGE2 excretion (r = 0.65, p < 0.0001). It is suggested that at this stage of chronic renal failure the mechanism of a diuresis increase is not due to osmotic diuresis but rather to secretion of prostaglandin E2 which inhibits cation reabsorption and stimulates diuresis. Differences are considered between osmotic diuresis and different types of saluresis; their possible mechanisms are discussed.


Is menstrual Psychosis a Forgotten Entity?
The connection between menstruation and psychosis has been recognized since the 18th Century. However, there are few case reports available in modern times describing about 30 patients with this condition. The psychosis may occur in the premenstrual phase in some patients and in others it begins with the onset of menses. Polymorphic psychosis is the commonly described clinical picture in these patients with an admixture of mood symptoms and psychotic symptoms. We describe a 42-year old lady who developed psychotic symptoms with the onset of her menses. The patient had irritability and aggression, persecutory ideas, hallucinatory behavior, increased religiosity, formal thought disorder, disorganized behavior and poor self-care lasting for about 20 days after which she will spontaneously remit for about 10 days till the onset of her next menses. These symptoms began about 13 years after her last childbirth and were present in this cyclical manner for the last seven years. She was admitted in view of gross disorganization and was treated with 4 mg per day of risperidone. She did not develop symptoms with onset of her next menstrual period and was discharged. She maintained well on the prophylaxis for a period of three months. After that, she discontinued medications and had a relapse of symptoms lasting the first two weeks of her menstrual cycle and remained well for about two weeks thereafter. Hormonal assays did not reveal abnormal levels of gonadal hormones. We discuss the association between menstrual cycles and the potential association of psychosis with estrogen levels. Various conditions that lead to fluctuation in estrogen levels, such as menopause, postpartum period as well as post-oopherectomy period have been described to lead to a risk for psychotic symptoms. Similarly, the cyclical changes in estrogen levels during the course of a menstrual cycle leads to psychosis in some women.


Localization of aggregating proteins in bacteria depends on the rate of addition.
Many proteins are observed to localize to specific subcellular regions within bacteria. Recent experiments have shown that proteins that have self-interactions that lead them to aggregate tend to localize to the poles. Theoretical modeling of the localization of aggregating protein within bacterial cell geometries shows that aggregates can spontaneously localize to the pole due to nucleoid occlusion. The resulting polar localization, whether it be to a single pole or to both was shown to depend on the rate of protein addition. Motivated by these predictions we selected a set of genes from Escherichia coli, whose protein products have been reported to localize when tagged with green fluorescent protein (GFP), and explored the dynamics of their localization. We induced protein expression from each gene at different rates and found that in all cases unipolar patterning is favored at low rates of expression whereas bipolar is favored at higher rates of expression. Our findings are consistent with the predictions of the model, suggesting that localization may be due to aggregation plus nucleoid occlusion. When we expressed GFP by itself under the same conditions, no localization was observed. These experiments highlight the potential importance of protein aggregation, nucleoid occlusion and rate of protein expression in driving polar localization of functional proteins in bacteria.


The molecular basis of dapsone activation of CYP2C9-catalyzed nonsteroidal anti-inflammatory drug oxidation.
Positive heterotropic cooperativity, or "activation," results in an instantaneous increase in enzyme activity in the absence of an increase in protein expression. Thus, cytochrome P450 (CYP) enzyme activation presents as a potential drug-drug interaction mechanism. It has been demonstrated previously that dapsone activates the CYP2C9-catalyzed oxidation of a number of nonsteroidal anti-inflammatory drugs in vitro. Here, we conducted molecular dynamics simulations (MDS) together with enzyme kinetic investigations and site-directed mutagenesis to elucidate the molecular basis of the activation of CYP2C9-catalyzed S-flurbiprofen 4'-hydroxylation and S-naproxen O-demethylation by dapsone. Supplementation of incubations of recombinant CYP2C9 with dapsone increased the catalytic efficiency of flurbiprofen and naproxen oxidation by 2.3- and 16.5-fold, respectively. MDS demonstrated that activation arises predominantly from aromatic interactions between the substrate, dapsone, and the phenyl rings of Phe114 and Phe476 within a common binding domain of the CYP2C9 active site, rather than involvement of a distinct effector site. Mutagenesis of Phe114 and Phe476 abrogated flurbiprofen and naproxen oxidation, and MDS and kinetic studies with the CYP2C9 mutants further identified a pivotal role of Phe476 in dapsone activation. MDS additionally showed that aromatic stacking interactions between two molecules of naproxen are necessary for binding in a catalytically favorable orientation. In contrast to flurbiprofen and naproxen, dapsone did not activate the 4'-hydroxylation of diclofenac, suggesting that the CYP2C9 active site favors cooperative binding of nonsteroidal anti-inflammatory drugs with a planar or near-planar geometry. More generally, the work confirms the utility of MDS for investigating ligand binding in CYP enzymes.


Isoelectric focusing studies on the beta-fructofuranosidases and alpha-glucosidases of Streptococcus mitis.
Extracts of Streptococcus mitis ATCC 903 were analysed for beta-fructofuranosidase and alpha-glucosidase activities by isoelectric focusing in thin-layer polyacrylamide gels combined with zymogram procedures. Three bands of activity were visualized in the gels after incubation with sucrose (pI 4.05, 4.25 and 4.85) and three other bands after incubation with p-nitrophenyl alpha-D-glucopyranoside (pI 3.90, 4.45 and 4.65). The enzymes responsible for the reaction with sucrose were identified as beta-fructofuranosidases (EC 18.104.22.168) for the following reasons: identical enzyme bands were visualized in the gels after incubation with raffinose; no enzyme bands appeared in the gel after incubation with the alpha-glucosides maltose, turanose, trehalose and melezitose; and the soluble fraction hydrolysed sucrose to equimolar amounts of glucose and fructose.


Incidental Finding of Malpositioned Pacing Lead in the Left Ventricle in a Patient With Subacute Subdural Hematoma.
Malposition of the right ventricular lead into the left ventricle is an unusual complication of challenging management. We report a case of an elderly woman with a dual chamber permanent pacemaker implanted 2 months before admission because of high grade AV block, who presented to our institution with sub acute subdural hematoma along the left fronto-parietal area. Incidental ventricular pacemaker lead in the left ventricle was found on chest CT scan. The patient was not candidate for anticoagulation due to her recent subdural hematoma, hence a discussion about the risks of explantation of the pacemaker lead led to patient's lead extraction without any complication.


Vasopressin in liver disease--should we turn on or off?
Arginine vasopressin is a naturally occurring peptide with established physiological functions acting as a vasoconstrictor through V1 receptors or an aquagenic agent allowing free water retention through V2 receptors in the kidney. Portal haemodynamic changes of chronic liver disease are responsible for the lethal consequences of cirrhosis--bleeding oesophageal varices and hepatorenal syndrome. Increasing hepatic vascular resistance to blood flow coupled with central hypovolaemia and a hyperdynamic circulation driven by changes in nitric oxide responsiveness disturbs the normal circulatory physiology raising portal pressure. Vasopressin and its analogues are potent vasoconstrictors and can be utilised in the management of the complications of cirrhosis. Hyponatraemia is common in end stage liver disease due in part to sodium retention and a decreased free water clearance. Diuretic therapy often leads to a worsening of the sodium status and have little true effect on improving free water clearance. Recently a new class of drugs, V2 receptor antagonists, have been evaluated in chronic liver disease whereby increasing free water clearance they may reduce ascitic fluid development. This review addresses the pharmacology of both vasopressin agonists and antagonists, their clinical application and future potential roles in managing patients with acute on chronic liver failure.


Vitamin D Intake and the Risk of Incident Kidney Stones.
Kidney stones are a common and painful condition. Longitudinal prospective studies on the association between the intake of vitamin D and the risk of incident kidney stones are lacking. We performed a prospective analysis of 193,551 participants in the Health Professionals Follow-up Study and Nurses' Health Study I and II. Participants were divided into categories of total (less than 100, 100 to 199, 200 to 399, 400 to 599, 600 to 999, 1,000 IU per day or greater) and supplemental (none, less than 400, 400 to 599, 600 to 999, 1,000 IU per day or greater) vitamin D intake. During a followup of 3,316,846 person-years there were 6,576 incident kidney stone events. Cox proportional hazards regression models were adjusted for age, body mass index, comorbidities, use of medications and intake of other nutrients. After multivariate adjustment there was no statistically significant association between vitamin D intake and risk of stones in the HPFS (HR for 1,000 or greater vs less than 100 IU per day 1.08, 95% CI 0.80, 1.47, p for trend = 0.92) and the NHS I (HR 0.99, 95% CI 0.73, 1.35, p for trend = 0.70), whereas there was a suggestion of a higher risk in the NHS II (HR 1.18, 95% CI 0.94, 1.48, p for trend = 0.02). Similar results were found for supplemental vitamin D intake. Vitamin D intake in typical amounts was not statistically associated with risk of kidney stone formation, although higher risk with higher doses than those studied here cannot be excluded.


Reproducibility of nerve fiber layer thickness measurements using optical coherence tomography in silicone oil-filled eyes.
To evaluate the reproducibility of nerve fiber layer (NFL) thickness measurements by optical coherence tomography (OCT) in individuals with silicone oil-filled eyes. Eighteen patients who had undergone pars plana vitrectomy and silicone oil tamponade for retinal detachment were enrolled in a prospective, case-controlled clinical study. Each patient underwent OCT measurement of NFL thickness. Five repetitions of a series of scans on five separate occasions within a 0.5-month period were performed. Each eye was scanned at two different nerve head programs [radius (R) = 1.5 and R = 1.73]. The contralateral healthy eye was used as control. For each option (R = 1.5 and R = 1.73) and region (superior, inferior, temporal, nasal and overall mean), variance components and intraclass correlation coefficients (ICCs) were determined using repeated-measures regression. In these models, NFL thickness, as measured by OCT, was considered to have three variance components: intersubject, intervisit (within subject, between dates), and intravisit (within subject, within date). The ICC (intersubject variance/total variance) was used as a measure of reliability. The contralateral healthy eye provided a higher degree of reproducibility than the silicone oil-filled eye (p = 0.0001). Reproducibility was higher in a given eye on a given visit than from visit to visit. Reproducibility as measured by ICCs was as follows: R = 1.5, 0.54/0.30 (control eyes/silicone oil-filled eyes); R = 1.73, 0.51/0.30. Reproducibility results for OCT measurement of NFL thickness are different in healthy eyes and silicone oil-filled eyes. NFL thickness measurement is not reliable in silicone oil-filled eyes.


Testicular failure in boys with Prader-Willi syndrome: longitudinal studies of reproductive hormones.
The pathophysiology of hypogonadism in boys with Prader-Willi Syndrome (PWS) remains uncertain. Several reports described hypogonadotropic hypogonadism, some reported primary gonadal failure, and others a combination of both. The aim of the study was to evaluate gonadal function over time in boys with PWS and the effect of GH treatment. We made a longitudinal assessment of inhibin B, FSH, testosterone, and LH levels in prepubertal boys and male adolescents with PWS. We studied 68 boys participating in the Dutch PWS Cohort study. Serum inhibin B, FSH, LH, and testosterone levels were compared with reference values. Boys with PWS had normal inhibin B levels between 6 months and 10 yr of age, but after onset of puberty, inhibin B levels declined to less than the 5th percentile, and FSH levels increased to more than the 95th percentile. Two years after the onset of puberty and in young adults, inhibin B levels were significantly lower (P=0.008 and P<0.0001), and FSH levels were significantly higher (P=0.034 and P<0.0001) than at onset of puberty. Testosterone levels increased but remained below the 5th percentile, and LH levels increased but not above the 95th percentile. Age showed a significant correlation with inhibin B levels (r=-0.31; P=0.001) after 9 yr of age. GH treatment had no significant effect on inhibin B levels. Our study indicates that the majority of male patients with PWS have primary testicular failure, which becomes apparent after onset of puberty. Hypogonadotropic hypogonadism did not appear to be the main reason of hypogonadism in most boys.


BME 2.0: Engineering the Future of Medicine.
If the 20th century was the age of mapping and controlling the external world, the 21st century is the biomedical age of mapping and controlling the biological internal world. The biomedical age is bringing new technological breakthroughs for sensing and controlling human biomolecules, cells, tissues, and organs, which underpin new frontiers in the biomedical discovery, data, biomanufacturing, and translational sciences. This article reviews what we believe will be the next wave of biomedical engineering (BME) education in support of the biomedical age, what we have termed BME 2.0. BME 2.0 was announced on October 12 2017 at BMES 49 (https://www.bme.jhu.edu/news-events/news/miller-opens-2017-bmes-annual-meeting-with-vision-for-new-bme-era/). We present several principles upon which we believe the BME 2.0 curriculum should be constructed, and from these principles, we describe what view as the foundations that form the next generations of curricula in support of the BME enterprise. The core principles of BME 2.0 education are (a) educate students bilingually, from day 1, in the languages of modern molecular biology and the analytical modeling of complex biological systems; (b) prepare every student to be a biomedical data scientist; (c) build a unique BME community for discovery and innovation via a vertically integrated and convergent learning environment spanning the university and hospital systems; (d) champion an educational culture of inclusive excellence; and (e) codify in the curriculum ongoing discoveries at the frontiers of the discipline, thus ensuring BME 2.0 as a launchpad for training the future leaders of the biotechnology marketplaces. We envision that the BME 2.0 education is the path for providing every student with the training to lead in this new era of engineering the future of medicine in the 21st century.


The day Norway cried: Proximity and distress in Norwegian citizens following the 22nd July 2011 terrorist attacks in Oslo and on Utøya Island.
Terrorism may create fear and stress reactions not only in the direct victims, but also in the general population. This study investigated emotional responses in the Norwegian population following the 22nd July 2011 terrorist attacks. We hypothesized that Oslo residents would report a higher level of fear responses compared with people living outside Oslo and that proximity would be associated with early distress and later post-traumatic stress reactions. Representative samples were drawn from the Norwegian Population Registry. Telephone interviews were conducted 4-5 months after the attacks. The response rate for the Oslo sample (N=465) was 24% of the total sample, and 43% of those who were actually reached by phone and asked to participate. Corresponding figures for the sample living outside Oslo (N=716) were 19% and 30%. Our results show strong immediate emotional responses, particularly sadness and a feeling of unreality, in both samples. Jumpiness and other fear responses were significantly higher among Oslo residents. Current level of risk perception was low 4-5 months after the attacks; however, a significant minority reported to feel less safe than before. Geographical and psychological proximity were associated with early emotional responses. Psychological proximity was significantly associated with post-traumatic stress reactions, while measures of geographical proximity were not. Immediate emotional responses, first-week reactions, and first-week jumpiness were uniquely and significantly associated with post-traumatic stress reactions. Post-traumatic stress reactions were elevated in ethnic minorities. The terrorist attacks seem to have had a significant effect on the Norwegian population, creating sadness and insecurity, at least in the short term. Proximity to the terrorist attacks was strongly associated with distress in the population, and early distress was strongly related to later post-traumatic stress reactions. Our results indicate that psychological proximity is more strongly associated with post-traumatic stress reactions than geographical proximity, and underline the importance of differentiated measurements of various aspects of early distress.


The characterization of pretreated lignocellulosic substrates prior to enzymatic hydrolysis, part 1: a modified Simons' staining technique.
To date, there is limited knowledge available regarding the key features of pretreated lignocellulosic substrates that promote the effective enzymatic hydrolysis of the cellulose component to glucose during bioconversion processes to produce ethanol. Fundamentally, cellulase enzymes require access to the cellulose to carry out effective hydrolysis. Porosity and the overall surface area of substrates have major structural features influencing the hydrolysis of pretreated substrates by cellulases. Simons' Stain (SS) is a potentially useful semiquantitative method for estimating the available surface area of lignocellulosic substrates. In this study, a modified, rapid SS method was developed, where the processing time was decreased from >50 to 6 h and the maximum dye adsorbed on the substrate was calculated using the adsorption isotherm for the orange and blue components of the dye mixture. The modified SS test readily measures the decrease in accessibility and hydrolyzability of a steam pretreated substrate that had been dried under three different drying regimes. For each of the lignocellulosic substrates, the total dye adsorption correlated well with the hydrolysis yields resulting in a correlation coefficient of r(2) = 0.95. The modified SS procedure is an effective tool for assessing how lignocellulosic substrates might be potentially hydrolyzed by cellulases.


AMP-activated protein kinase in the heart: role during health and disease.
AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is expressed in most mammalian tissues including cardiac muscle. Among the multiple biological processes influenced by AMPK, regulation of fuel supply and energy-generating pathways in response to the metabolic needs of the organism is fundamental and likely accounts for the remarkable evolutionary conservation of this enzyme complex. By regulating the activity of acetyl-coenzyme A carboxylase, AMPK affects levels of malonyl-coenzyme A, a key energy regulator in the cell. AMPK is generally quiescent under normal conditions but is activated in response to hormonal signals and stresses sufficient to produce an increase in AMP/ATP ratio, such as hypoglycemia, strenuous exercise, anoxia, and ischemia. Once active, muscle AMPK enhances uptake and oxidative metabolism of fatty acids as well as increases glucose transport and glycolysis. Data from AMPK deficiency models suggest that AMPK activity might influence the pathophysiology and therapy of diabetes and increase heart tolerance to ischemia. Effects that are not as well understood include AMPK regulation of transcription. Different AMPK isoforms are found in distinct locations within the cell and have distinct functions in different tissues. A principal mode of AMPK activation is phosphorylation by upstream kinases (eg, LKB1). These kinases have a fundamental role in cell-cycle regulation and protein synthesis, suggesting involvement in a number of human disorders including cardiac hypertrophy, apoptosis, cancer, and atherosclerosis. The physiological role played by AMPK during health and disease is far from being clearly defined. Naturally occurring mutations affecting the nucleotide-sensing modules in the regulatory gamma subunit of AMPK lead to enzyme dysregulation and inappropriate activation under resting conditions. Glycogen accumulation ensues, leading to human disease manifesting as cardiac hypertrophy, accessory atrioventricular connections, and degeneration of the physiological conduction system. Whether AMPK is a key participant or bystander in other disease states and whether its selective manipulation may significantly benefit these conditions remain important questions.


Poor Kids? Economic Resources and Adverse Peer Relations in a Nationally Representative Sample of Swedish Adolescents.
There is limited knowledge on the impact of economic resources on adverse peer relations during adolescence. This study used a nationally representative sample (n = 4725, 51% girls) of Swedish eighth-grade students (approximately age fourteen) to examine associations between economic resources and adverse peer relations in the form of peer rejection and bullying victimization. Adolescents from households in the lowest within-school household income quintile were found to be rejected by school class peers to a greater extent than more advantaged students, but an association was not found between relative household income and bullying victimization. In contrast, adolescents unable to participate in activities with peers for economic reasons experienced more rejection and were at higher risk of victimization. The results underline the multidimensionality of adverse peer relations and advance our knowledge on how economic resources relate to peer relations in youth.


Autologous bone marrow cell transplantation combined with off-pump coronary artery bypass grafting in patients with ischemic cardiomyopathy.
Clinical studies have demonstrated that intracoronary or intramyocardial transplantation of bone marrow mononuclear cells (BMMNCs) into ischemic myocardium improves cardiac function. The objective of the present study was to evaluate the safety and feasibility of intramyocardial BMMNC transplantation into nongraftable areas in combination with off-pump coronary artery bypass grafting in patients with ischemic cardiomyopathy. Five male patients with myocardial infarction lasting for more than 1 month and with nongraftable myocardium received autologous mononuclear cell transplantation during off-pump coronary artery bypass grafting. Autologous bone marrow was aspirated from the iliac crest. BMMNCs (mean 1.6, standard error [SE] 0.3 x 10(9)) including CD34-positive cells (mean 6.8, SE 1.1 x 10(6)) and AC133-positive cells (mean 3.1, SE 1.7 x 10(6)) were injected into the nongraftable ischemic myocardium. Heart function was evaluated with the use of echocardiography, and myocardial perfusion was examined with single photon emission computed tomography technetium-99mTc sestamibi scans. Two months after cell transplantation, the mean ejection fraction had increased by 7.4%, SE 1.9% (p = 0.016) compared with that before cell transplantation and off-pump coronary artery bypass grafting. The increase in ejection fraction was not correlated with the number of transplanted total mononuclear cells, CD34-positive cells and AC133-positive cells. Myocardial perfusion at the cell-transplanted area increased after cell transplantation and off-pump coronary artery bypass grafting. No arrhythmia was observed. The present clinical study suggests that intramyocardial transplantation of autologous BMMNCs into the ischemic area during off-pump coronary artery bypass grafting is both feasible and safe and has beneficial effects on cardiac function.


Chrysiogenes arsenatis gen. nov., sp. nov., a new arsenate-respiring bacterium isolated from gold mine wastewater.
A new strictly anaerobic bacterium (strain BAL-1T) has been isolated from a reed bed at Ballarat Goldfields in Australia. The organism grew by reducing arsenate [As(V)] to arsenite [As(III)], using acetate as the electron donor and carbon source; acetate alone did not support growth. When BAL-1T was grown with arsenate as the terminal electron acceptor, acetate could be replaced by pyruvate, L- and D-lactate, succinate, malate, and fumarate but not by H2, formate, citrate, glutamate, other amino acids, sugars, or benzoate. When acetate was the electron donor, arsenate could be replaced by nitrate or nitrite but not by sulfate, thiosulfate, or iron oxide. Nitrate was reduced to ammonia via nitrite. The doubling time for growth on acetate (5 mM) plus arsenate (5 mM) or nitrate (5 mM) was 4 h. The G+C content of the DNA is 49 mol%. The 16S rRNA sequence data for the organism support the hypothesis that this organism is phylogenetically unique and at present is the first representative of a new deeply branching lineage of the Bacteria. This organism is described as Chrysiogenes arsenatis gen. nov., sp. nov.


Autologous chondrocyte implantation for the treatment of cartilage lesions of the knee: a systematic review of randomized studies.
Autologous chondrocyte implantation (ACI) techniques are becoming more popular for the treatment of full thickness cartilage lesions of the knee joint. However, there is no systematic information for the efficacy of the new generation ACI techniques compared to other treatment options. A systematic review of the existing evidence from randomized clinical trials of ACI treatment would contribute to understanding the advantages and limitations of this method and would inform the planning of future studies. Using pre-defined criteria, we searched a number of electronic databases to identify all the existing randomized control trials of any type of ACI treatment. Risk of bias was assessed and an analysis of the reported outcomes was performed. Information on the clinical efficacy and safety of ACI compared to other interventions was collected and presented. Nine trials were identified with 626 patients. Patients ranged from 15 to 52 years, and the size of treated lesions was between 1 and 22 cm(2). ACI was associated with improvement in clinical outcomes compared to baseline. However, the body of evidence did not suggest any superiority of ACI over other treatments. Complication rates were comparable between interventions except from an increased rate of graft hypertrophies after ACI with periosteum. ACI is an effective treatment for full thickness chondral defects of the knee, providing an improvement of clinical outcomes. However, there is insufficient data to say whether ACI is superior to other treatment strategies. More high quality studies and harmonization in the reported outcomes are needed before specific suggestions for practice can be made.


[Practice of pharmaceutical care--therapeutic drug monitoring and pharmacoeconomics of glaucoma--].
Clinical pharmacists now have many jobs in a hospital, including dispensing services, drug information, drug counseling for patients, therapeutic drug monitoring (TDM), and clinical research coordinating. These are important and essential jobs for a hospital pharmacist in his drug profession. During the performance of pharmaceutical services for patients and physicians, clinical pharmacists have an opportunity to change the medicine of a prescription. In this review, we outline the new developments in TDM and pharmacoeconomics achieved by pharmaceutical care at Hiroshima University Hospital. Pharmaceutical care is the professional practice in which the pharmacist takes charge of the needs of a patient related to his/her drugs. One of the aims was to investigate drug induced interaction in pharmacotherapy, and another was evaluation of the clinical efficacy of Bayesian analysis in detoxication treatments of overdoses using TDM. Pharmacoeconomics is an important aspect of the practice of pharmaceutical care. This review investigated the daily cost of ophthalmic solutions used in treating glaucoma and allergic conjunctivitis in Japan. It also summarizes the recent practice of pharmaceutical care in pharmacotherapy and pharmacoeconomics.


Activations of mitogen-activated protein kinases and regulation of their downstream molecules after rat lung transplantation from donors after cardiac death.
Accepting organs donated after cardiac death (DCD) is an effective approach to the donor shortage. However, lung transplantations from DCD donors show severe rapid pulmonary graft dysfunction (PGD) followed by warm ischemia-reperfusion injury (IRI). This study sought to clarify the molecular mediators in warm IRI, including activation of mitogen-activated protein kinase (MAPK) and the downstream cascades. We performed single left lung transplantation using organs from male Sprague-Dawley rats after 0 (CIT group), 30 (30WIT group), or 180 (180WIT group) minutes of warm ischemia time. Pulmonary graft functions were estimated by blood gas analysis. At 1 hour after reperfusion, the phosphorylation status of MAPKs (ERK, p38, and JNK) and the gene expression levels of transcription factors (Egr-1 and ATF-3) and immune mediators (MCP-1, MIP-2, PAI-1, ICAM-1, TNF-α, IL-1β, IL-6, and COX-2) in the grafts were examined using Western blotting and real-time polymerase chain reaction assays. Severe PGD was observed in the 180WIT group compared with transplanted lungs in the other groups, which exhibited good pulmonary graft function. ERK and JNK activations, as well as mRNA levels of transcription factors (Egr-1 and ATF3) significantly increased with greater warm ischemic times. The pattern of JNK activation correlated with the severity of PGD. MCP-1, ICAM-1, IL-1β, IL-6, and COX-2 were also up-regulated among the 180WIT group, although MIP-2 and PAI-1 showed no significant differences among the groups. We suggest that the ERK and JNK pathways may play important roles to induce the injury caused by prolonged warm ischemia followed by reperfusion in the setting of lung transplantation from DCD donors.


Ca2+ dependency of N-cadherin function probed by laser tweezer and atomic force microscopy.
This study was undertaken to provide a biophysical basis for the hypothesis that activity-dependent modulation of cadherin-mediated adhesion by transient changes of extracellular calcium ([Ca2+]e) is causally involved in coordination of synaptic plasticity. Characterization of homophilic N-cadherin binding by atomic force microscopy and laser tweezer trapping of N-cadherin-coated microbeads attached to the cell surface of cultured neuronal cells showed that adhesive activity of N-cadherin is effectively regulated between 0.3 and 0.8 mm [Ca2+]e. Furthermore, we show that an increase of [Ca2+]i, which is known to be essential for induction of synaptic plasticity, causes significant reduction of cadherin-mediated bead adhesion that could be completely suppressed by inhibition of actin depolymerization. The results of this study show that N-cadherin has ideal biophysical properties to serve as a Ca2+-dependent sensor for synaptic activity and, at the same time, is strategically located to control synaptic adhesion. A drop of [Ca2+]e and a concomitant increase of [Ca2+]i may act in concert to modulate N-cadherin-based adhesive contacts at synaptic sites.


Color vision deficiencies and camouflage: a comparative study between normal and CVD observers.
There is a belief that observers with color vision deficiencies (CVD) perform better in detecting camouflaged objects than normal observers. Some studies have concluded contradictory findings when studying the performance of normal and CVD observers in the camouflage detection tasks in different conditions. This work presents a literature review on this topic, dividing it into three different and contradictory types of results: better performance for CVD, for normal observers, or same performance. Besides, two psychophysical experiments have been designed and carried out in a calibrated computer monitor on both normal and CVD human observers to measure the searching times of the different types of observers needed to find camouflaged stimuli in two different types of stimuli. Results show the trend that, in our experimental conditions, normal observers need shorter searching times than CVD observers in finding camouflaged stimuli both in images of natural scenes and in images with synthetic stimuli.


Bosniak classification for complex renal cysts: history and critical analysis.
The Bosniak classification for renal cysts was developed in the late 1980s in an attempt to standardize the description and management of complex cystic renal lesions. Alterations were made to such a classification in the 1990s and, the last one, in 2005. Currently, five categories of cystic renal lesions are defined - namely, I, II, II-F, III and IV -, according to their degree of complexity and likelihood of malignancy. Despite being initially described for computed tomography, this classification has been also utilized with some advantages also for magnetic resonance imaging. The present article reviews the different phases of this classification, its diagnostic efficacy and the most controversial features of its use.


[Clinical--anatomic ground of caudal approach in newborns with surgical pathology].
Anatomic research have been done on 20 dead bodies of newborns for updating of caudal block level. For definition of caudal block level it was proved, that injection of coloring agent in volume of 0.5 ml/kg, 1 ml/kg and 1.2 ml/kg promotes reaching middle thoracic, high thoracic and highest level of epidural block. Analysis of hemodynamic and serum cortisol level in 25 newborns with surgical pathology showed the best analgesic effect in 15 newborns, who have got caudal-epidural anesthesia comparably with 10 newborns, who have got traditional multicomponent general anesthesia.


Early risk assessment for viral haemorrhagic fever: experience at the Hospital for Tropical Diseases, London, UK.
To implement a policy of systematic screening for viral haemorrhagic fever (VHF) among travellers returning from African countries with fever, commencing at initial clinical contact. A protocol based on UK Advisory Committee on Dangerous Pathogens guidance was developed collaboratively by medical, nursing and laboratory staff. Audit was carried out to quantify resource demands and effects on time to diagnose malaria, the main differential diagnosis. A protocol is now implemented for all patients presenting to HTD with fever, with clear guidelines for interaction with clinical and laboratory staff at each stage. The protocol required moderate amounts of clinical and laboratory staff time and resulted in some additional hospital admissions. The time to a diagnosis of malaria increased from a median of 90 (range 50-125) min in patients without VHF risk to a median of 140 (range 101-225) min (p=0.0025) in those assessed as at risk. Although all acute medical services need to have robust procedures for early detection of patients with serious transmissible conditions, few implement such a policy. Our protocol requires increased human and other resources but has no important impact on the rapidity of diagnosis of malaria, and is now embedded in local practice.


Case 309: Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy.
A 64-year-old man presented with a 6-month history of lightheadedness and intermittent balance and coordination difficulties. Two months before admission, symptoms became more substantial and persistent, with a worsening sense of disequilibrium and unsteady gait. He reported difficulties pronouncing words and mild word-finding difficulties. His wife noted a change in his cognition and memory over the same time. His medical history included well-controlled chronic obstructive pulmonary disease (COPD) secondary to a long history of smoking with associated unintentional 30-lb (13.6-kg) weight loss over the previous 3 years, for which chest CT scanning was performed, revealing no abnormality. On clinical examination, the patient was alert and oriented but had slurred speech. A positive Romberg sign was noted, finger-to-nose and hand rapid alternating movement tests revealed impairment on the right side, and his gait was ataxic. The motor examination revealed normal muscle tone, bulk, and power in the upper and lower extremities. Sensory testing results were normal. Initial MRI of the brain at admission revealed abnormal findings in the left supratentorial brain. Of note, this patient's presentation predated the COVID-19 pandemic. Cerebrospinal fluid (CSF) analysis revealed predominant pleocytosis (23 × 106/L; normal range, [0-5] × 106/L) (78% lymphocytes, 22% monocytes), elevated protein level (1.23 g/L; normal range, 0.19-0.64 g/L), oligoclonal bands (faint one or two), and a high immunoglobulin G (IgG) index (0.130 g/L; normal reference, ≤0.059 g/L). Despite extensive initial work-up for inflammatory, infectious, autoimmune, or neoplastic causes, a definitive diagnosis was not reached. Thus, repeat MRI of the brain was performed 2 weeks after admission.


Endogenous salicylic acid protects rice plants from oxidative damage caused by aging as well as biotic and abiotic stress.
Salicylic acid (SA) is a key endogenous signal that mediates defense gene expression and disease resistance in many dicotyledonous species. In contrast to tobacco and Arabidopsis, which contain low basal levels of SA, rice has two orders of magnitude higher levels of SA and appears to be insensitive to exogenous SA treatment. To determine the role of SA in rice plants, we have generated SA-deficient transgenic rice by expressing the bacterial salicylate hydroxylase that degrades SA. Depletion of high levels of endogenous SA in transgenic rice does not measurably affect defense gene expression, but reduces the plant's capacity to detoxify reactive oxygen intermediates (ROI). SA-deficient transgenic rice contains elevated levels of superoxide and H2O2, and exhibits spontaneous lesion formation in an age- and light-dependent manner. Exogenous application of SA analog benzothiadiazole complements SA deficiency and suppresses ROI levels and lesion formation. Although an increase of conjugated catechol was detected in SA-deficient rice, catechol does not appear to significantly affect ROI levels based on the endogenous catechol data and exogenous catechol treatment. When infected with the blast fungus (Magnaporthe grisea), SA-deficient rice exhibits increased susceptibility to oxidative bursts elicited by avirulent isolates. Furthermore, SA-deficient rice is hyperresponsive to oxidative damage caused by paraquat treatment. Taken together, our results strongly suggest that SA plays an important role to modulate redox balance and protect rice plants from oxidative stress.


Long-term efficacy and safety of incobotulinumtoxinA and conventional treatment of poststroke arm spasticity: a prospective, non-interventional, open-label, parallel-group study.
To compare the efficacy and safety of incobotulinumtoxinA with conventional antispastic therapy for poststroke arm spasticity in routine clinical practice over a 1-year period. Prospective, non-interventional, open-label, parallel-group study. 47 centres in Germany. Patients with poststroke arm spasticity; 108 receiving incobotulinumtoxinA, 110 conventional therapy. Conventional antispastic treatment including oral antispastic medications, physiotherapy and occupational therapy or 3-monthly incobotulinumtoxinA injections plus conventional therapy if required. The main outcome measure was changes in muscle tone (Ashworth Scale) over the 1-year treatment period. Changes in functional disability (Disability Assessment Scale) and quality of life (Short-Form-12 Health Survey) were additionally assessed. Ratings for therapy outcome (Goal Attainment Scale), and efficacy and tolerability of treatment (Global Clinical Impression Scale) were also obtained. Muscle tone improved for all spasticity patterns with the Ashworth Scale responder rates between 63% and 86% (incobotulinumtoxinA) and 16-27% (conventional therapy). Median improvement in functional disability was -1.0 (incobotulinumtoxinA) and 0.0 (conventional measures) for all domains. Treatment goals were attained by 93% of incobotulinumtoxinA patients and 30% of patients under conventional therapy. Most physicians (93%) and patients (90%) rated efficacy as good or very good under incobotulinumtoxinA; the proportions were much lower under conventional therapy (36% and 37%). Tolerability under incobotulinumtoxinA was considered good or very good by 99% of physicians and patients (76% and 66%, respectively, under conventional therapy). Quality of life under incobotulinumtoxinA improved by 8.0 (physical score) and 10.8 (mental score) and by 0.8 and 5.7, respectively, under conventional therapy. IncobotulinumtoxinA combined with rehabilitation and oral medication produces a much more robust improvement in all aspects of arm spasticity than conventional antispastic treatment. Effects are stable over a period of 1 year, whereas adverse effects are negligible. IncobotulinumtoxinA should be considered the treatment of choice for poststroke arm spasticity.


Clinical and economic outcomes of hospital acquired pneumonia in intra-abdominal surgery patients.
To measure the clinical and economic impact of postoperative hospital-acquired pneumonia (HAP) and to identify risk factors for the development of HAP. Although postoperative HAP is recognized to be an major risk associated with surgery, little is known about the overall outcomes of patients whose hospital stay is complicated by HAP following surgery. We studied 618,495 patients who underwent an intra-abdominal operation from the National Inpatient Sample database over a 1-year period (January 2000 to December 2000) using CPT codes and discharge diagnoses identified by the Clinical Classification Software. Data collected included demographic characteristics, type of operation, in-hospital mortality, discharge disposition, length of stay, and hospital charges. Of the 13,292 patients with HAP following intra-abdominal surgery, 1421 died prior to discharge (mortality = 10.7%) compared with 7217 deaths in the control group of patients without HAP following intra-abdominal surgery (mortality = 1.2%) (P < 0.001). HAP was independently associated with a 4.13-fold (95% confidence interval = 3.94-4.34) increase in risk to be discharged to a skilled nursing facility. The mean length of hospital stay for intra-abdominal patients who developed HAP was significantly greater compared with intra-abdominal surgery patients who did not develop HAP (17.10 days versus 6.07 days, P < 0.001). After adjusting for patient characteristics, HAP was independently associated with a 75% (28,160.95 dollars; 95% confidence interval, 27,543.76 dollars - 28,778.13 dollars) mean increase in total hospital charges. Given the high incidence and significant impact of HAP on patient outcomes, early preventive strategies and interventions to reduce HAP should be a priority.


Recent Advances in Sulfur Dioxide Releasing Nanoplatforms for Cancer Therapy.
Sulfur dioxide (SO2), long considered to be a harmful atmospheric pollutant, has recently been posited as the fourth gasotransmitter, as it is produced endogenously in mammals and has important pathophysiological effects. The field of tumor therapy has witnessed a paradigm shift with the emergence of SO2-based gas therapy. This has been possible because SO2 is a potent glutathione consumer that can promote the production of reactive oxygen species, eventually leading to oxidative-stress-induced cancer cell death. Nevertheless, this therapeutic gas cannot be directly administrated in gaseous form. Thus, various nano formulations incorporating SO2 donors or prodrugs capable of storing and releasing SO2 have been developed in an attempt to achieve active/passive intratumoral accumulation and SO2 release in the tumor microenvironment. In this review article, the advances over the past decade in nanoplatforms incorporating sulfur SO2 prodrugs to provide controlled release of SO2 for cancer therapy are summarized. We first describe the synthesis of polypeptide SO2 prodrugs to overcome multiple drug resistance that was pioneered by our group, followed by other macromolecular SO2 prodrug structures that self-assemble into nanoparticles for tumor therapy. Second, we describe nanoplatforms composed of various small-molecule SO2 donors with endogenous or exogenous stimuli responsiveness, including thiol activated, acid-sensitive, and ultraviolet or near-infrared light-responsive SO2 donors, which have been used for tumor inhibition. Combinations of SO2 gas therapy with photodynamic therapy, chemotherapy, photothermal therapy, sonodynamic therapy, and nanocatalytic tumor therapy are also presented. Finally, we discuss the current limitations and challenges and the future outlook for SO2-based gas therapy. STATEMENT OF SIGNIFICANCE: : Gas therapy is attracting increasing attention in the scientific community because it is a highly promising strategy against cancer owing to its inherent biosafety and avoidance of drug resistance. Sulfur dioxide (SO2) is recently found to be produced endogenously in mammals with important pathophysiological effects. This review summarizes recent advances in sulfur dioxide (SO2) releasing nanosystems for cancer therapy, including polymeric prodrugs, endogenous or exogenous stimulus-activated SO2 donors delivered by nanoplatform and combination therapy strategies.


What to do now? How women with breast cancer make fertility preservation decisions.
There has been increased attention paid to cancer-related infertility and fertility preservation. However, how cancer patients decide whether or not to pursue fertility preservation has not been fully examined. The data come from 34 interviews with women in the USA diagnosed with breast cancer prior to 40 years of age who contemplated fertility preservation prior to cancer treatment. Fully transcribed interviews were coded through a three-staged inductive process. Three sets of factors that shaped the decision-making process of the respondents regarding fertility preservation treatment options were identified: perceived benefits (e.g. ability to use 'younger' eggs in the future), inhibiting concerns (e.g. success rates) and influential relationships (e.g. physicians, parents and partners). Respondents saw their main fertility preservation decision as choosing whether or not to pursue egg/embryo banking. The decision-making process was complicated and included both health-related and personal considerations, with many respondents reporting a lack of support services for fertility issues. Findings suggest that greater attention needs to be placed on presenting patients with a wider range of options. Those who counsel patients regarding fertility preservation decisions should be aware of the influence of relationship dynamics, broader health care concerns, and fertility histories on these decisions. KEY MESSAGE POINTS: While fertility preservation has garnered greater attention, less is known about how cancer patients make fertility preservation decisions. Despite the range of choices for fertility preservation, respondents identified egg/embryo banking as their primary option. Many factors outside of cancer concerns inhibit and facilitate fertility preservation decisions including fertility history and family relationship dynamics.


From the histophotometer to the confocal microscope: the evolution of analytical microscopy.
With new ideas and with the aid of modern technology, novel microscopical and micro-analytical methods are practically implemented, as a fruit of the co-operative effect of theoretical and experimental advances achieved in distinct fields. The results obtained in the development of new micro-analytical instruments and in their applications, increasingly help to solve many investigative problems in materials science and in biology. Among the oldest forms of analytical microscopy, some encountered histophotometers while, among the latest, some are working with confocal microscopes. Given by one that had the opportunity of attending to both of the developments, an overview encompassing these two instruments can hopefully serve to illustrate the progress of analytical microscopy, a discipline evolving during the second half of this century.


The binding of kappa- and sigma-opiates in rat brain.
Detailed displacements of [3H]dihydromorphine by ketocyclazocine and SKF 10,047, [3H]ethylketocyclazocine by SKF 10,047, and [3H]SKF 10,047 by ketocyclazocine are all multiphasic, suggesting multiple binding sites. After treating brain tissue in vitro with naloxazone, all displacements lose the initial inhibition of 3H-ligand binding by low concentrations of unlabeled drugs. Together with Scatchard analysis of saturation experiments, these studies suggest a common site which binds mu-, kappa, and sigma-opiates and enkephalins equally well and with highest affinity (KD less than 1 nM). The ability of unlabeled drugs to displace the low affinity binding of [3H]dihydromorphine (KD = 3 nM), [3H]ethylketocyclazocine (KD = 4 nM), [3H]SKF 10,047 (KD = 6 nM), and D-Ala2-D-Leu5-[3H]enkephalin (KD = 5 nM) remaining after treating tissue with naloxazone demonstrates unique pharmacological profiles for each. These results suggest the existence of distinct binding sites for kappa- and sigma-opiates which differ from those sites which selectively bind morphine (mu) and enkephalin (delta).


Control of the reproductive axis: Balancing act between stimulatory and inhibitory inputs.
As for most vertebrates, reproduction in poultry is controlled by an integrated axis [the hypothalamo-pituitary-gonadal (HPG) axis]. External and internal cues are integrated at the level of the hypothalamus to initiate gonadal recruitment and control the subsequent reproductive cycle. Until recently, it was believed that the HPG was exclusively under stimulatory control from hypothalamic gonadotropin releasing hormone (GnRH). However in 2000, the discovery of gonadotropin inhibitory hormone (GnIH), an inhibitory peptide, changed this dogma. Since then, evidence accumulated to confirm that in fact the HPG is under a dual control system with a stimulatory and an inhibitory branch. In this paper, we review the organization of this dual control system, the mechanisms controlling the synthesis and release of GnRH and GnIH, and the possible integration and interactions between the two branches to regulate pituitary gonadotropes' function. Furthermore, as light perception and photoperiod are the primary cues utilized by the poultry industry in controlled environments, special consideration was given to potential practical applications.


Modelling the changes induced by chronic desipramine treatment on the factors governing the agonism at prejunctional alpha 2-adrenoceptors.
1. The adaptational changes induced after chronic desipramine treatment on functional responsiveness of alpha 2-adrenoceptor activation were investigated in prostatic portions of the rat vas deferens. 2. For this purpose, clonidine and xylazine were studied for their effects on twitch contractions elicited by electrical field stimulation of prostatic portions removed 48 h after the last injection to the animals of vehicle or desipramine (10 mg kg-1, i.p.; 14 days). Operational model-fitting and the nested hyperbolic method were used to analyse the effects of irreversible receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 300 nM) on the alpha 2-adrenoceptor-mediated effects of clonidine, either in vehicle- or in desipramine-treated animals. 3. Treatment with desipramine decreased the potency (increased the EC50) of clonidine and xylazine by about 12 and 9 fold respectively. However, the treatment did not modify the maximal effect (alpha) elicited by either agonist. The estimates of apparent affinity for clonidine did not depend on the method of calculation as the 'null' method and the 'operational' method gave similar answers. Estimates of tau values for both agonists revealed that chronic desipramine treatment resulted in significant decreases in the efficacy of agonists. However, desipramine treatment was not associated with significant changes in the affinity constant for clonidine while for xylazine, the operational model provided a higher estimate of KA (lower affinity) after desipramine treatment. 4. The results indicate a large receptor reserve at prejunctional alpha 2-adrenoceptors which is modulated by chronic desipramine treatment. 5. The comparison of results obtained after chronic desipramine exposure with those by using EEDQ suggests that chronic desipramine treatment is not a useful experimental intervention for the purpose of estimating agonist affinities and efficacies.


Transcriptome analysis of Salicornia europaea under saline conditions revealed the adaptive primary metabolic pathways as early events to facilitate salt adaptation.
Halophytes such as Salicornia europaea have evolved to exhibit unique mechanisms controlled by complex networks and regulated by numerous genes and interactions to adapt to habitats with high salinity. However, these mechanisms remain unknown. To investigate the mechanism by which halophytes tolerate salt based on changes in the whole transcriptome, we performed transcriptome sequencing and functional annotation by database search. Using the unigene database, we conducted digital gene expression analysis of S. europaea at various time points after these materials were treated with NaCl. We also quantified ion uptakes. Gene functional enrichment analysis was performed to determine the important pathways involved in this process. A total of 57,151 unigenes with lengths of >300 bp were assembled, in which 57.5% of these unigenes were functionally annotated. Differentially expressed genes indicated that cell wall metabolism and lignin biosynthetic pathways were significantly enriched in S. europaea to promote the development of the xylem under saline conditions. This result is consistent with the increase in sodium uptake as ions pass through the xylem. Given that PSII efficiency remained unaltered, salt treatment activated the expression of electron transfer-related genes encoded by the chloroplast chromosome. Chlorophyll biosynthesis was also inhibited, indicating the energy-efficient state of the electron transfer system of S. europaea. The key function of adjusting important primary metabolic pathways in salt adaption was identified by analyzing the changes in the transcriptome of S. europaea. These pathways could involve unique salt tolerance mechanisms in halophytes. This study also provided information as the basis of future investigations on salt response genes in S. europaea. Ample gene resources were also provided to improve the genes responsible for the salt tolerance ability of crops.


Industry Perceptions of HERDA in Performance Horses.
Hereditary equine regional derma asthenia (HERDA), an autosomal-recessive trait, found in Quarter Horses, causes abnormal collagen structure. Owing to current breeding practices, 3.5% of registered quarter horses and 28.3% of the cow horse population are heterozygote carriers. Research demonstrated homozygote horses develop hyperextensible skin susceptible to injury and other abnormal tissues containing high fibrillar collagen content. No research exists determining the effects of the disease in heterozygote carriers. Currently, 30% of cutting sires are HERDA carriers, potentially increasing the number of heterozygous individuals when bred. The objective of the present study is to gauge knowledge of the disease, perception, and concerns of the diseases' impact on horse performance and perceived value and breeding decisions. A Qualtrics link was distributed to horse owners via extension specialists and was available online on equine-related Facebook pages. Overall group means and standard deviations for constructs were reported. A total of 228 responses were collected. Most participants were involved in reining and cutting and 34.6% reported they were very familiar with the disease. Participants (78.5%) reported that HERDA status affects value of a breeding animal. Owners of HERDA carriers (62.5%) noticed no difference in performance or injury compared with noncarriers. Respondents (95.2%) believed that all breeding animals should have HERDA status available. Respondents are attempting to make informed breeding decisions based on HERDA status by pairing carriers with noncarriers; however, it remains to be seen if that is adequate to control the disease. Education regarding breeding practices and its impact on the genetic pool are warranted.


A Litopenaeus vannamei Hemocyanin-Derived Antimicrobial Peptide (Peptide B11) Attenuates Cancer Cells' Proliferation.
Antimicrobial peptides play important roles in the immune response to pathogens and tumor cells; for this reason, they are being exploited for therapeutic use. In this study, we describe a Litopenaeus vannamei hemocyanin-derived peptide, denoted B11, which shares similar features with other anticancer peptides and attenuates the proliferation of cancer cells. Cell viability assay revealed that B11 significantly inhibited the proliferation of human cervical (HeLa), human hepatocellular carcinoma (HepG2), and human esophageal cancer (EC109) cancer cell lines, but not normal liver cell lines (T-antigen-immortalized human liver epithelial (THLE) cells or THLE-3), by inducing morphological changes, nuclear condensation, and margination, features which are indicative of apoptosis. Besides, peptide B11-induced apoptosis was confirmed by isothiocyanate-labeled Annexin V/propidium iodide (Annexin V-FITC/PI) double staining of HeLa cells. Moreover, cell uptake studies, confocal microscopy, and Western blot analysis revealed that rhodamine-labeled B11 permeated HeLa cells and localized to the mitochondria, causing mitochondria dysfunction through lost mitochondrial membrane potential, which consequently triggered the induction of apoptosis. Increased expression levels of caspase-9, caspase-3, and Bax (Bcl-2-associated X) proteins, coupled with a decrease in Bcl-2 (B-cell lymphoma 2) protein, confirmed that peptide B11 induced apoptosis via the mitochondrial pathway. Thus, the hemocyanin-derived peptide, B11, inhibits the proliferation of cancer cells by causing mitochondrial dysfunction and inducing apoptotic cell death, for which reason it could be explored as an anticancer peptide.


Molecular phylogeny and taxonomy of the genus Pythium.
The phylogeny of 116 species and varieties of Pythium was studied using parsimony and phenetic analysis of the ITS region of the nuclear ribosomal DNA. The D1, D2 and D3 regions of the adjacent large subunit nuclear ribosomal DNA of half the Pythium strains were also sequenced and gave a phylogeny congruent with the ITS data. All the 40 presently available ex-type strains were included in this study, as well as 20 sequences of recently described species from GenBank. Species for which no ex-type strains were available were represented by either authentic strains (6), strains used in the 1981 monograph of the genus by van der Plaats-Niterink (33), or strains selected on morphological criteria (17). Parsimony analysis generated two major clades representing the Pythium species with filamentous or globose sporangia. A small clade of species with contiguous sporangia was found in between the two main clades. A total number of 11 smaller clades was recognized, which often correlated with host-type or substrate and in several cases with a subset of morphological characters. Many characters used in species descriptions, such as antheridium position, did not correlate with phylogeny. A comparison of the ex-type and representative strains with all ITS sequences of Pythium in GenBank revealed limited infraspecific variation with the exception of P. rostratum, P. irregulare, P. heterothallicum, and P. ultimum. The total number of species examined was 116 (including 60 ex-type strains). Twenty-six species had ITS sequences identical or nearly identical to formerly described species, suggesting possible conspecificity. The importance of comparing ITS sequences of putative new species to the now available ITS database in order to avoid unwarranted new species names being introduced.


Anxiety and depression seem less common in patients with autoreactive chronic spontaneous urticaria.
Chronic spontaneous urticaria (CSU) is a common and disabling skin disease which is often associated with psychiatric comorbidities such as anxiety and depression. These conditions are widely thought to cause, drive and/or maintain CSU, and have been reported as making an important contribution to the low quality of life in patients with CSU. Almost half of all patients with CSU have autoreactive CSU which can be readily diagnosed by the autologous serum skin test. The prevalence and effects of psychiatric comorbidities in this important subgroup are largely unknown. We carried out a study on two groups of patients with CSU, and found that the anxiety and depression scores were lower in patients with autoreactive CSU than in those with nonautoreactive CSU, the first such finding, to our knowledge. In addition, we found that patients with autoreactive CSU were less likely to have Hospital Anxiety and Depression Scale scores indicative for anxiety or depression compared with patients with nonautoreactive CSU. Our results support the view that autoreactive CSU represents a distinct CSU subgroup with a different disease pattern and a lower rate of psychiatric comorbidities.


Hormonal control of thermogenesis in perfused muscle of Muscovy ducklings.
Endocrine stimulation of muscle nonshivering thermogenesis (NST) in ducklings was investigated in vitro using a perfused hindlimb preparation maintained at 25 degrees C. Effects of flow rate, norepinephrine (NE), epinephrine, and glucagon on perfused muscle oxygen consumption (MO2) and perfusion pressure were studied. Control ducklings (Cairina moschata, 5 wk old) reared at thermoneutrality (25 degrees C, TN) were compared with two age-matched groups exhibiting muscle NST in vivo: cold-acclimated ducklings (4 degrees C, 4 wk, CA) and glucagon-treated ducklings (103 nmol/kg twice-daily, intraperitoneally, GT). Basal MO2 was higher in CA than in TN or GT ducklings and increased in all groups with elevated flow rates. Catecholamines increased both MO2 and perfusion pressure. The maximal effect on MO2 was higher in CA (+ 36%) and GT ducklings (+ 43%) than in controls (+ 31%), but was associated with reduced vasoconstriction. Flow rate did not consistently potentiate the NE response. At high doses, catecholamines became inhibitory on MO2 while a monotonous increase of pressure was still observed. Glucagon, by contrast, slightly decreased both MO2 and pressure. This vasodilatory effect was greater in CA ducklings than controls in preconstricted preparations. In vivo, low-dose epinephrine induced a modest thermogenic effect (+ 10%) in CA ducklings. These findings showed that duckling muscle thermogenesis is directly stimulated in vitro by catecholamines but not by glucagon. Higher in vitro thermogenic effects of NE in ducklings that were expected to exhibit muscle NST in vivo suggests catecholamine involvement in muscle NST in vivo. Potential vascular control of avian muscle NST is discussed.


Implications of impulsive and affective symptoms for serotonin function in bulimia nervosa.
Bulimic, impulsive and depressive syndromes have all been associated with abnormalities in brain serotonin (5-hydroxytryptamine; 5-HT) mechanisms. We had 26 bulimic women and 22 normal-eater women report impulsive, affective, self-destructive and bulimic symptoms, and then provide serial blood samples for measurement of: [3H]-paroxetine binding in platelets; and, prolactin (PRL) responses following oral meta-chlorophenylpiperazine (m-CPP). Bulimic status was associated with markedly reduced density of paroxetine-binding sites, modest blunting of m-CPP stimulated PRL response, and greater nausea following m-CPP. Biological variables did not co-vary with most psychopathological or eating-symptom indices. However, there were inverse associations (in bulimic women only) between scores indicating impulsivity (largely 'unreflectiveness') and density of platelet 5-HT uptake sites. Our observations link bulimia nervosa to altered 5-HT functioning, and suggest that there may be a relatively symptom-specific association between impulsivity and reduced 5-HT reuptake.