Photodynamic therapy combined with surgical management of extensive anogenital condylomatosis in a patient with systemic lupus erythematosus.
Infections with human papillomavirus in the anogenital area result in warty, papillary, and condylomatous lesions. The giant anogenital wart is relatively uncommon. Treatment of giant wart is challenging, especially in the immunosuppressive population. Here, a patient with systemic lupus erythematosis had extensive, fast-growing, recurrent anogenital condylomatosis shaped as giant cauliflowers. We reported this case and the successful treatment of photodynamic therapy combined with surgical management. It provided the feasibility for surgical ablation combined with ALA-PDT performed for these kinds of challenging cases.


Cloning, expression, and characterization of recombinant nitric oxide synthase-like protein from Bacillus anthracis.
Nitric oxide synthase (NOS) is amongst a family of evolutionarily conserved enzymes, involved in a multi-turnover process that results in NO as a product. The significant role of NO in various pathological and physiological processes has created an interest in this enzyme from several perspectives. This study describes for the first time, cloning and expression of a NOS-like protein, baNOS, from Bacillus anthracis, a pathogenic bacterium responsible for causing anthrax. baNOS was expressed in Escherichia coli as a soluble and catalytically active enzyme. Homology models generated for baNOS indicated that the key structural features that are involved in the substrate and active site interaction have been highly conserved. Further, the behavior of baNOS in terms of heme-substrate interactions and heme-transitions was studied in detail. The optical perturbation spectra of the heme domain demonstrated that the ligands perturb the heme site in a ligand specific manner. baNOS forms a five-coordinate, high-spin complex with l-arginine analogs and a six-coordinate low-spin complex with inhibitor imidazole. Studies indicated that the binding of l-arginine, N(omega)-hydroxy-l-arginine, and imidazole produces various spectroscopic species that closely correspond to the equivalent complexes of mammalian NOS. The values of spectral binding constants further corroborated these results. The overall conservation of the key structural features and the correlation of heme-substrate interactions in baNOS and mammalian NOS, thus, point towards an interesting phenomenon of convergent evolution. Importantly, the NO generated by NOS of mammalian macrophages plays a potent role in antimicrobicidal activity. Because of the existence of high structural and behavioral similarity between mammalian NOS and baNOS, we propose that NO produced by B. anthracis may also have a pivotal pathophysiological role in anthrax infection. Therefore, this first report of characterization of a NOS-like protein from a pathogenic bacterium opens up avenues for further studies in understanding the importance of this protein in pathogenicity.


The Slicing Method: Determining Insensitivity Regions of Probability Weighting Functions.
A popular rule of thumb, usually called "heuristic technique" in Behavioral Economics, for determining the likelihood insensitivity regions of probability weighting functions (pwf's) is based on searching for points at which the pwf's are twice their values at half the points. Although this technique works remarkably well for many commonly used pwf's, it sometimes fails to provide the correct answer. In order to cover the class of pwf's for which the heuristic technique does not work, in this paper we propose, discuss, and illustrate an extension of the technique into what we call the "slicing method," which is capable of finding the subadditivity and insensitivity regions of any continuous pwf.


Somatosensory evoked potentials associated with tactile stimulation at detection threshold in man.
Somatosensory evoked potentials elicited by sub- and supraliminal tactile pulses were studied during continuous threshold measurement. Two threshold methods were used: a modified tracking method and a detection method. With both methods threshold estimates of the same order of magnitude were obtained. Stimuli just above the threshold elicited a distinct somatosensory evoked potential with components P50, P100, N190 and P400. No such SEP was associated with the subliminal stimuli. However, in some cases some potential oscillations were obtained, time-locked to the subliminal stimuli; these are suggested to be due to errors in responding. In control experiments detected stimuli elicited a distinct SEP, but no SEP was associated with undetected stimuli of identical amplitude. The results indicate that in the psychophysical threshold determination the neural processing reflected in the SEP is associated only with supraliminal tactile stimulation. The lack of evoked brain activity associated with subliminal tactile stimuli supports the hypothesis derived from human microneurographic studies, stating that the tactile detection threshold may be based on an extremely small peripheral input, perhaps only on a single impulse in a single peripheral fiber.


Hiding children to avoid ARV treatment.
In the last issue, we reported on the case of a Montréal woman with HIV who lost custody of her two HIV-positive children after refusing to consent to their treatment with antiretroviral therapy.


Human muscle protein synthesis is modulated by extracellular, not intramuscular amino acid availability: a dose-response study.
To test the hypothesis that muscle protein synthesis (MPS) is regulated by the concentration of extracellular amino acids, we investigated the dose-response relationship between the rate of human MPS and the concentrations of blood and intramuscular amino acids. We increased blood mixed amino acid concentrations by up to 240 % above basal levels by infusion of mixed amino acids (Aminosyn 15, 44-261 mg kg-1 h-1) in 21 healthy subjects, (11 men 10 women, aged 29 +/- 2 years) and measured the rate of incorporation of D5-phenylalanine or D3-leucine into muscle protein and blood and intramuscular amino acid concentrations. The relationship between the fold increase in MPS and blood essential amino acid concentration ([EAA], mM) was hyperbolic and fitted the equation MPS = (2.68 x [EAA])/(1.51 + [EAA]) (P < 0.01). The pattern of stimulation of myofibrillar, sarcoplasmic and mitochondrial protein was similar. There was no clear relationship between the rate of MPS and the concentration of intramuscular EAAs; indeed, when MPS was increasing most rapidly, the concentration of intramuscular EAAs was below basal levels. We conclude that the rates of synthesis of all classes of muscle proteins are acutely regulated by the blood [EAA] over their normal diurnal range, but become saturated at high concentrations. We propose that the stimulation of protein synthesis depends on the sensing of the concentration of extracellular, rather than intramuscular EAAs.


Suggested Cut-Off Values for Vitamin D as a Risk Marker for Total and Cardiac Death in Patients with Suspected Acute Coronary Syndrome.
Several studies have demonstrated an association between low vitamin D levels and cardiovascular risk. Vitamin D cut-off levels are still under debate. To assess two cut-off levels, 40 and 70 nmol/L, respectively, for vitamin D measured as 25-hydroxyvitamin D in chest pain patients with suspected acute coronary syndrome. We investigated 1853 patients from coastal-Norway and inland Northern-Argentina. A similar database was used for pooling of data. Two-year follow-up data including all-cause mortality, cardiac death, and sudden cardiac death in the total patient population were analyzed, applying univariate and multivariable analysis. Two hundred fifty-five patients with known vitamin D concentrations died. In the multivariable analysis, there was a decrease in total mortality above a cut-off level of 40 nmol/L and a decrease in cardiac death above a cut-off level of 70 nmol/L [HRs of 0.66 (95% CI, 0.50-0.88), p = 0.004 and 0.46 (95% CI, 0.22-0.94), p = 0.034, respectively]. Vitamin D cut-off levels of 40 and 70 nmol/L were related to total mortality and cardiac death, respectively.


Irisin-pretreated BMMSCs Secrete Exosomes to Alleviate Cardiomyocytes Pyroptosis and Oxidative Stress to Hypoxia/reoxygenation Injury.
The cardiomyocytes pyroptosis and bone marrow-derived mesenchymal stem cells have been well considered as novel therapies to attenuate myocardial ischemia/reperfusion injury, however, the relationship has not yet been determined. We aim to evaluate whether pre-treatment bone marrow-derived mesenchymal stem cells protect against myocardial ischemia/reperfusion injury by repressing cardiomyocytes pyroptosis, as well as to further elucidate the potential mechanisms. Cardiomyocytes were treated with hypoxia, followed by reoxygenation to mimic myocardial ischemia/reperfusion injury. Pre-treatment bone marrow-derived mesenchymal stem cells or their exosomes were co-cultured with cardiomyocytes following hypoxia/reoxygenation. Cell Counting Kit-8 assay was used to determine cell viability. Reactive oxygen species production was determined by dihydroethidium stain. Enzyme-linked immunosorbent assays were used to detect IL-1β and IL-18. We observed that Irisin pre-treatment bone marrow-derived mesenchymal stem cells protected cardiomyocytes against hypoxia/reoxygenation-induced injuries. The underlying molecular mechanism was further identified. Irisin-BMMSCs were found to secrete exosomes, which repressed cardiomyocytes pyroptosis and oxidative stress response by suppressing NLRP3 under hypoxia/reoxygenation conditions. Based on our findings, we revealed a promising target that exosomes derived from bone marrow-derived mesenchymal stem cells with Irisin treatment to elevate the therapeutic benefits for hypoxia/ reoxygenation injury.


Primary structure of sarcotoxin I, an antibacterial protein induced in the hemolymph of Sarcophaga peregrina (flesh fly) larvae.
The primary structure of sarcotoxin I, a potent bactericidal protein induced in the hemolymph of larvae of Sarcophaga peregrina (flesh fly), was investigated. Sarcotoxin I was a mixture of three proteins (sarcotoxins IA, IB, and IC) with almost identical primary structures. These proteins were found to consist of 39 amino acid residues and to differ in only 2-3 amino acid residues. The amino-terminal half of the molecules was rich in charged amino acids and was hydrophilic, whereas the carboxyl-terminal half was hydrophobic. It is suggested that the carboxyl-terminal half of sarcotoxin I penetrates into the bacterial membrane and that its amino-terminal half rich in basic amino acid residues interacts with acidic phospholipids in the bacterial membrane, resulting in perturbation of the membrane and loss of viability of the bacteria.


California Collaborative Center for Substance Abuse Policy Research: a history and update.
The California Collaborative Center for Substance Abuse Policy Research is engaged in policy research, training, and information dissemination on substance abuse policy in and for the state of California. As such it is a cosponsor of the recent Therapeutic Jurisprudence conference with Haight Ashbury Free Clinics. The following recoups a presentation made by Richard B. Seymour on behalf of Center codirector Carroll Estes at that conference on the nature, history, and future priorities of the Center.


The distribution of vasoactive intestinal peptide2 receptor messenger RNA in the rat brain and pituitary gland as assessed by in situ hybridization.
The distribution of rat vasoactive intestinal peptide2 (VIP2) receptor messenger RNA in the brain and the pituitary gland was examined by in situ hybridization and by ribonuclease protection assay. labelled cells were found chiefly in the suprachiasmatic nucleus, the central nucleus of the amygdala and the thalamus (the lateral geniculate nucleus, and the paraventricular, mediodorsal and ventral nuclei of the thalamus). The distribution of the VIP2 receptor overlaps only in part with that of the VIP1 receptor, for example in the hippocampus, where VIP2 receptor messenger RNA was found in the pyramidal cells of the CA1-CA3 subfields and in the granule cells of the dentate gyrus. Small numbers of neurons containing high concentrations of VIP2 receptor messenger RNA were present in the brainstem in the principal sensory trigeminal nucleus and in the substantia gelatinosa of the spinal cord, suggesting a role for the VIP2 receptor in the processing of sensory information. The presence of the VIP2 receptor in the suprachiasmatic nucleus suggests that it is this receptor subtype which is involved in the control of circadian rhythms.


Simulation of the influences of bathing solution and crosslink density on the swelling equilibrium of ionic thermo-sensitive hydrogels.
The influences of the bathing solution and crosslink density on the swelling equilibrium of ionic thermo-sensitive hydrogels due to temperature stimulus are studied by mathematical modeling. The model used is termed the multi-effect-coupling thermal-stimulus (MECtherm) model with consideration of multiphases and multiphysics. It is used for the steady-state numerical simulation of the hydrogels in swelling equilibrium after it is verified well by comparison with available experimental data concerning the variation of volume swelling ratio with temperature. The phenomenon of volume phase transition is simulated for the thermal-stimulus responsive hydrogel. Simulations predict well the influences of the bathing solution concentration and crosslink density of polymeric network on the swelling equilibrium of the hydrogels.


Manipulation of mobile phase parameters for the HPLC separation of endogenous monoamines in rat brain tissue.
Multi-component mobile phases are common in ion pair reverse phase high performance liquid chromatography for the analysis of endogenous monoamines in rat brain tissue. By examining the effects of each component of a mobile phase on the separation of a number of monoamines and their metabolites, we show how optimization of parameters can achieve and/or maintain a separation both within and between different octadecyl columns. The assay itself is rapid, sensitive, demands minimal sample preparation, and results in complete resolution of the amines. More importantly, the basis for the manipulation of mobile phase components is discussed with regard to practical utilization in selective amine separation. We conclude that knowledge of mobile phase parameters, their mechanism, and manipulation is as important as the assay itself.


Lacosamide in monotherapy in BTRE (brain tumor-related epilepsy): results from an Italian multicenter retrospective study.
Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients. We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints). Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence. This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.


Serotonin inhibits apoptosis of pulmonary artery smooth muscle cell by pERK1/2 and PDK through 5-HT1B receptors and 5-HT transporters.
Decreased apoptosis of pulmonary artery smooth muscle cells (PASMCs) plays a key role in pulmonary vascular remodeling in pulmonary hypertension (PH). However, the cause and mechanism of this decrease in apoptosis are still unclear. Serotonin (5-HT) has been shown to be involved in PH by inducing PASMC proliferation through the activation of 5-HT1B receptors (5-HT1BR) and 5-HT transporter (5-HTT). 5-HT1BR and 5-HTT are also involved in abnormal apoptosis in many other pathological processes. Therefore, we hypothesized that 5-HT induces decreases in PASMC apoptosis through 5-HT1BR and 5-HTT. PASMCs were treated with 5-HT, and their proliferation and apoptosis were assayed. 5-HT1BR agonists, 5-HT1BR antagonist, 5-HTT antagonist, combined 5-HT1BR/5-HTT antagonists, extracellular signal-regulated kinase (ERK1/2) activation inhibitor peptide I (EPI) and pyruvate dehydrogenase kinase (PDK) inhibitor sodium dichloroacetate (DCA) were used to explore the mechanism by which 5-HT induce decrease in PASMC apoptosis. PASMCs stimulated by 5-HT showed an increase in proliferation and a decrease in apoptosis, accompanied by increase in pERK1/2, PDK, and mitochondrial transmembrane potential. The effects of 5-HT on the proliferation and apoptosis of PASMCs were similar to those of 5-HT1BR agonists and were markedly prevented by 5-HT1BR antagonist, 5-HTT antagonist, combined 5-HT1BR/5-HTT antagonists, EPI, or DCA. 5-HT inhibits PASMC apoptosis through 5-HT1BR or 5-HTT. pERK1/2 and PDK are involved in the process of 5-HT inhibition PASMC apoptosis through 5-HT1BR or 5-HTT.


Diaphyseal lengthening for brachymetatarsia.
The authors present a case report of brachymetatarsia. The literature is reviewed, various surgical treatments are discussed, and the preferred surgical procedure that relieved symptoms and achieved cosmetic approval is described.


CCK-octapeptide injected into cerebral ventricles of sheep decreases plasma insulin level.
Cholecystokinin-8 (CCK-8) was injected into the lateral cerebral ventricles (LV) of conscious sheep to determine its effect on secretion of three hormones important in regulation of peripheral metabolism: growth hormone (GH), glucagon, and insulin. Three hr continuous LV injection of 0.64 pmol/min CCK-8 decreased plasma insulin concentration approximately 30% throughout the three hr period, compared to control injection, and this effect occurred independently of whether or not the sheep were permitted to eat during injection. Only high doses of desulfated CCK-8 affected plasma insulin levels, thus suggesting the involvement of specific CCK receptors. Plasma glucose and GH concentrations were unaffected by LV injections, but plasma glucagon concentration was also decreased by CCK-8. LV injection of 0.64 pmol/min CCK-8 in sheep given an IV bolus injection of glucose (1.0 g/kg body mass) resulted in significantly lower plasma insulin and higher plasma glucose concentrations than during control LV injections; thus CCK-8 is capable of suppressing insulin secretion even under stimulated conditions. Since cisterna magna injections of CCK-8 were not effective in suppressing insulin secretion, more rostral brain sites are probably responsible for mediating this effect.


Sarcoid polyneuropathy responsive to intravenous immunoglobulin.
We describe a 38-year-old woman with a predominantly sensory axonal polyneuropathy in whom a nerve biopsy demonstrated sarcoid granulomas. The neuropathy did not respond to oral steroid therapy but there was a rapid and repeated response to intravenous immunoglobulin, which gradually diminished over subsequent treatments, but remained beneficial. The systemic sarcoidosis remained active.


Clinical comparison of the selective serotonin3 antagonists ramosetron and granisetron in treating acute chemotherapy-induced emesis, nausea and anorexia.
The efficacies of the selective 5-hydroxytryptamine3 (5-HT3) antagonists--ramosetron (0.3 mg) and granisetron (3 mg) in treating acute chemotherapy-induced digestive system dysunction were compared. A total of 111 patients were enrolled in a single-blind, randomised crossover study; with data from 98 were used to assess efficacy and data from 110 to assess the safety profile. Ramosetron or granisetron was given intraveneously 15 min befire chemotherpy. The ability of ramosetron to prevent emesis, nausea and anorexia was similar to granisetron during the first 6 h following the administration of chemotherapy, ciplatin or doxorubicin. However, during the first 24 h after chemotherapy, significant differences between ramosetron and granisetron appeared: emetic episode (P = 0.068), nausea (P = 0.006), and anorexia (P = 0.048) remained lower in ramosetron-treated patients. The safety profile of ramosetron was similar to that of granisetron and adverse events in both groups were generally mild and transient. Ramosetron is more potent and longer-lasting than granisetron in preventing chemotherapy-induced digestive disturbances.


Dimethyl itaconate induces long-term innate immune responses and confers protection against infection.
Itaconate is an immunomodulatory metabolite produced by immune cells under microbial stimulation and certain pro-inflammatory conditions and triggers antioxidant and anti-inflammatory responses. We show that dimethyl itaconate, a derivative of itaconate previously linked to suppression of inflammation and widely employed as an alternative to the endogenous metabolite, can induce long-term transcriptional, epigenomic, and metabolic changes, characteristic of trained immunity. Dimethyl itaconate alters glycolytic and mitochondrial energetic metabolism, ultimately leading to increased responsiveness to microbial ligand stimulation. Subsequently, mice treated with dimethyl itaconate present increased survival to infection with Staphylococcus aureus. Additionally, itaconate levels in human plasma correlate with enhanced ex vivo pro-inflammatory cytokine production. Collectively, these findings demonstrate that dimethyl itaconate displays short-term anti-inflammatory characteristics and the capacity to induce long-term trained immunity. This pro-and anti-inflammatory dichotomy of dimethyl itaconate is likely to induce complex immune responses and should be contemplated when considering itaconate derivatives in a therapeutic context.


Decreased serum 5-oxoproline in TB patients is associated with pathological damage of the lung.
Tuberculosis (TB) is a serious world-wide health problem, causing millions of deaths every year. Metabolomics is a relatively new approach to identify disease specific biomarkers. However, there is little information available on metabolite biomarkers in TB. In this study, we used gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS) to identify serum metabolite biomarkers associated with the active state of TB. Potential biomarkers were selected by comparing serum metabolites in 10 healthy donors with 10TB patients, and in 6TB patients before and after treatment. Selected biomarkers were then validated using a larger population of samples from 120 healthy donors and 120TB patients derived from different clinical backgrounds The 5-oxoproline level was consistently low in patients with active TB. Further validation in larger population of clinical samples showed that 5-oxoproline was associated with pathological damage of the lung but not with age, sex, or bacterial burden in TB patients. Serum 5-oxoproline may be a useful biomarker for active TB and pathological damage of the lung.


The quest for precision in transanal total mesorectal excision.
Transanal total mesorectal excision (TME) is an emerging minimally invasive approach to rectal cancer, with encouraging preliminary results. However, the new surgical anatomy of the bottom-up approach complicates surgical understanding and increases the risks of inadvertent injuries to crucial anatomical structures, including nerves. Key elements to improve the safety and stimulate interest in such a complex technique might be robotics and image guidance, to enhance the level of precision. In this editorial, some of the technologies that could be used for precision TME are outlined, in light of the experience of our Institute for Image-Guided Surgery.


Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute pancreatitis induced by cerulein.
In the present study, we investigated the effects of rosiglitazone (10 mg/kg, i.p.), a PPAR-gamma agonist, on the development of acute pancreatitis. Intraperitoneal injection of cerulein in mice induced an acute pancreatitis characterized by edema, neutrophil infiltration elevated serum levels of amylase and lipase. This experimental model was performed to test the anti-inflammatory activity of rosiglitazone. SETTING. University research laboratory. Male CD mice (20-22 g) were allocated into four groups (n=10 for each group): (a) Cerulein+vehicle group. Mice were treated hourly (x 5) with cerulein (50 microg/kg, in saline solution, i.p.); (b) Rosiglitazone group (same as the Cerulein+vehicle group but were administered rosiglitazone, 10 mg/kg bolus, 30 min prior to cerulein); (c) Sham+saline group. Mice were treated with saline instead of cerulein; (d) Sham+Rosiglitazone. Identical to Rosiglitazone group except that the saline was administered instead of cerulein. Mice were killed at 6 h after the induction of pancreatitis. Blood samples, pancreas, and lungs were collected. Infiltration of pancreatic and lung tissue with neutrophils was associated with enhanced lipid peroxidation. Immunohistochemical examination demonstrated a marked increase in immunoreactivity for nitrotyrosine and for ICAM-1 in the pancreas of cerulein-treated mice. In contrast, the degree of (a) pancreatic inflammation and tissue injury, (b) upregulation/formation of ICAM-1 and nitrotyrosine, and (c) neutrophils infiltration was markedly reduced in pancreatic tissue obtained from rosiglitazone-treated mice. These findings support the view that rosiglitazone and other potent PPAR-gamma agonists may be useful in the therapy of acute pancreatitis.


Arf-dependent regulation of Pdgf signaling in perivascular cells in the developing mouse eye.
We have established that the Arf tumor suppressor gene regulates mural cell biology in the hyaloid vascular system (HVS) of the developing eye. In the absence of Arf, perivascular cells accumulate within the HVS and prevent its involution. We now demonstrate that mural cell accumulation evident at embryonic day (E) 13.5 in Arf(-/-) mice was driven by excess proliferation at E12.5, when Arf expression was detectable in vitreous pericyte-like cells. Their expression of Arf overlapped with Pdgf receptor beta (Pdgfrbeta), which is essential for pericyte accumulation in the mouse. In cultured cells, p19Arf decreased Pdgfrbeta and blocked Pdgf-B-driven proliferation independently of Mdm2 and p53. The presence of a normal Arf allele correlated with decreased Pdgfrbeta in the embryonic vitreous. Pdgfrbeta was required for vitreous cell accumulation in the absence of Arf. Our findings demonstrate a novel, p53- and Mdm2-independent function for p19Arf. Instead of solely sensing excessive mitogenic stimuli, developmental cues induce Arf to block Pdgfrbeta-dependent signals and prevent the accumulation of perivascular cells selectively in a vascular bed destined to regress.


Increasing abscisic acid levels by immunomodulation in barley grains induces precocious maturation without changing grain composition.
Abscisic acid (ABA) accumulates in seeds during the transition to the seed filling phase. ABA triggers seed maturation, storage activity, and stress signalling and tolerance. Immunomodulation was used to alter the ABA status in barley grains, with the resulting transgenic caryopses responding to the anti-ABA antibody gene expression with increased accumulation of ABA. Calculation of free versus antibody-bound ABA reveals large excess of free ABA, increasing signficantly in caryopses from 10 days after fertilization. Metabolite and transcript profiling in anti-ABA grains expose triggered and enhanced ABA-functions such as transcriptional up-regulation of sucrose-to-starch metabolism, storage protein synthesis and ABA-related signal transduction. Thus, enhanced ABA during transition phases induces precocious maturation but negatively interferes with growth and development. Anti-ABA grains display broad constitutive gene induction related to biotic and abiotic stresses. Most of these genes are ABA- and/or stress-inducible, including alcohol and aldehyde dehydrogenases, peroxidases, chaperones, glutathione-S-transferase, drought- and salt-inducible proteins. Conclusively, ABA immunomodulation results in precocious ABA accumulation that generates an integrated response of stress and maturation. Repression of ABA signalling, occurring in anti-ABA grains, potentially antagonizes effects caused by overshooting production. Finally, mature grain weight and composition are unchanged in anti-ABA plants, although germination is somewhat delayed. This indicates that anti-ABA caryopses induce specific mechanisms to desensitize ABA signalling efficiently, which finally yields mature grains with nearly unchanged dry weight and composition. Such compensation implicates the enormous physiological and metabolic flexibilities of barley grains to adjust effects of unnaturally high ABA amounts in order to ensure and maintain proper grain development.


Values, attitudes and perceptions of managers as predictors of corporate environmental responsiveness.
We examine whether managers' values, attitudes, and perceptions influence the greening of organizations. To that purpose, we specify and test a model of corporate environmental responsiveness (CER), drawing upon a modified version of the theory of planned behavior and the value-belief-norm theory. Based on survey data from 142 Greek companies, we find that top managers' personal values influence responses indirectly, through shaping their environmental attitudes, while direct relationship is not significant. Subjective norms, expressing stakeholder expectations, do affect CER, with their effect being stronger than that of attitudes. Managers' perceived ability to handle environmental issues also appears to influence responses. Results have theoretical implications, indicating the significant role of managers' values, attitudes and perceptions in a firm's environmental response. Practical implications are discussed in relation to selection of managers and training.


[Development of immunochromatographic test system for the rapid detection of lipopolysaccharide antigen and cells of causative agent of bovine brucellosis].
A rapid method for detection of the surface lipopolysaccharide antigen and the cells of the causative agent of bovine brucellosis was developed. The method represents a sandwich format immunochromatographic assay. The contact between the sample and the test strip with immobilized immunoreagents initiates the fluid movement along the membrane components of the test strip, immunochemical reactions, and the formation of colored bands. The novel method requires 10 minutes to determine the lipopolysaccharide antigen of the cell wall of the brucellosis causative agent at concentrations down to 10 ng/mL and the Brucella abortus cells at concentrations down to 10(6) cells/mL (5 x 10(4) cells in the sample). The specificity of the immunodetection was confirmed. The designed test system can be used for the rapid field diagnosis of brucellosis in cattle.


Purification of single-strand DNA binding protein from an Escherichia coli lysate using counter-current chromatography, partition and precipitation.
Single-strand DNA binding protein (SSB) from Escherichia coli lysate was purified by counter-current chromatography (CCC) using the ammonium sulfate precipitation method in a coiled column. About 5 ml of E. coli lysate was separated by CCC using a polymer phase system composed of 16% (w/w) polyethylene glycol (PEG) 1000 and 17% (w/w) ammonium sulfate aqueous polymer two-phase solvent system. The precipitation of proteins in the lysate took place in the CCC column, and the SSB protein was eluted in the fraction 51-56. Many other impurities were either eluted immediately after the solvent front or precipitated in the column. The identities of the proteins in the fractions and in the precipitate were confirmed by SDS-polyacrylamide gel electrophoresis with Coomassie Brilliant Blue staining.


Tumor suppressors govern insulin-like growth factor signaling pathways: implications in metabolism and cancer.
The insulin-like growth factor (IGF) axis mediates growth, differentiation and developmental processes, and is also involved in control of metabolic activities. Deregulation of IGF axis expression and action is linked to a number of pathologies, ranging from metabolic disorders to growth deficits and cancer development. Activation of the IGF signaling pathway is a crucial prerequisite for malignant transformation. In addition, overexpression of the IGF-1 receptor (IGF-1R) constitutes a typical hallmark of most types of cancer. A series of tumor suppressors have been identified whose mechanisms of action involve transcriptional suppression of the IGF-1R gene. These tumor suppressors include the p53/p63/p73 family, breast cancer gene-1, von-Hippel Lindau protein, Wilms' tumor-1 and others. Comprehensive analyses have identified a complex bidirectional interplay between the IGF and tumor-suppressor signaling pathways. These interactions are of major importance in terms of cancer development and may also predict responsiveness to IGF-1R-targeted therapies. Furthermore, the insulin/IGF system has a pivotal role in the regulation of cancer cell metabolism. Deregulation of IGF axis components by mutated tumor-suppressor proteins may lead to metabolic perturbations, with ensuing pathological consequences.


What seals the inflammation in acute coronary syndromes?
Inflammation plays a key role in the development of acute coronary syndromes and its consequences. Coronary stenting provides improved mortality and morbidity in appropriate cases by several routes. However the beneficial effects of the coronary stenting on inflammation remain controversial as the coronary stenting might lead to--systemically detected--local inflammatory reaction.


Denaturation manner of sarcoplasmic proteins in Pale, Soft and Exudative meat determines their positive impacts on myofibrillar water-holding capacity.
The aim of the study was to investigate the denaturation manner of sarcoplasmic proteins (SP) under PSE condition to explain their positive impacts on water-holding compacity. We found that the SP precipitation under PSE-like condition (pH 5.5, 40 °C) and heating conditions (pH 5.5, 7.0, 8.0, 55 °C) were similar, but the myofibrillar water-holding capacity was improved only under PSE-like condition (pH 5.5, 40 °C). To understand the denaturation mechanism of SP, their physicochemical properties were examined. Results demonstrated that PSE-denaturation and heat-denaturation of SP were two different processes. At pH 7.0 and 8.0, the unfolding of SP due to temperature elevation did not alter the overall net surface negative charges but only increased hydrophobicity, whereas at pH 5.5, the net surface positive charges and hydrophobicity increased dramatically. We hypothesized that in PSE meat, denatured SP became highly positively charged and hydrophobic and easier to bind to the negatively charged MF, which is related to the improvement on water-holding capacity.


Optimization of cultural and nutritional conditions for accumulation of poly-beta-hydroxybutyrate in Synechocystis sp. PCC 6803.
Poly-beta-hydroxybutyrate (PHB) accumulation in the unicellular cyanobacterium, Synechocystis sp. PCC 6803, was studied under various cultural and nutritional conditions. Under controlled condition, cells harvested at the stationary phase of growth depicted maximum accumulation of PHB, i.e., 4.5% (w/w of dry cells) as compared to lag (1.8%) or logarithmic (2.9%) phases of cultures. A temperature range of 28-32 degrees C and pH between 7.5 and 8.5 were preferred for PHB accumulation. Cells cultivated under regular light-dark cycles accumulated more PHB (4.5%) than those grown under continuous illumination (2.4%). Nitrogen and phosphorus starvation stimulated PHB accumulation up to the tune of 9.5 and 11% (w/w of dry cells), respectively. Synechocystis cells pre-grown in glucose (0.1%)-supplemented BG-11 medium when subjected to P-deficiency in presence of acetate (0.4%), PHB accumulation was boosted up to 29% (w/w of dry cells), the value almost 6-fold higher with respect to photoautotrophic condition. Fishpond discharges were found as suitable media for PHB accumulation in the test cyanobacterium.


[Suicidality in German-speaking school psychiatry : Thematization in textbooks from 1803 until the present].
This chronology gives an overview about continuities and changes in the perception of suicidality in German-speaking school psychiatry over the past 200+ years. This study was guided by the following questions: has suicidality been perceived as regularly being connected to certain mental illnesses? Which other possible causes have been discussed by psychiatrists from the nineteenth century to the beginning of the twenty-first century? What approaches have major psychiatrists adopted towards suicidal patients and threatened suicide? What treatment and preventive strategies have been suggested? First, we compiled a list of the, in our view, most influential textbooks on psychiatry of German-speaking school psychiatry from 1803 until the present. These textbooks were then skim-read for relevant passages on suicidality. The material gained was elicited, classified and analyzed in relation to the questions at hand. Futhermore, an attempt was made to arrive at contextual estimations. Several authors named a certain set of psychiatric illnesses that are assumed to involve or increase the risk of suicide. These illnesses include depression, schizophrenia and also physical illnesses. In nineteenth century textbooks heredity, anatomical anomalies and nationality were discussed as potential influencing factors. In contrast, more recent books discuss models of how suicidal behavior emerges and often refer to the Werther effect. With respect to therapy there is a trend towards therapeutic discussions and modern psychopharmacotherapy. Over time, there have been continuities and changes in psychiatrists' approach to suicidality not only as far as clinical aspects are concerned but also the general approach to and management of suicidal patients.


Zinc complexes of salicylaldehydes: synthesis, characterization and DNA-binding properties.
The neutral mononuclear zinc complexes with substituted salicylaldehydes, in the absence or presence of a nitrogen donor heterocyclic ligand 2,2'-bipyridine or 1,10-phenanthroline or 2,2'-dipyridylamine, have been synthesized and characterized by IR, UV and NMR spectroscopies. The experimental data suggest that salicylaldehyde is on deprotonated mode acting as a bidentate ligand coordinated to the metal ion through the phenolato and one aldehydo oxygen atoms. The crystal structures of bis(5-nitro-salicyladehydato)(2,2'-dipyridylamine)zinc(II), bis(5-chloro-salicylaldehydato)(2,2'-bipyridine)zinc(II) monohydrate and bis(5-bromo-salicyladehydato)bis(methanol)zinc(II) have been determined with X-ray crystallography. The ability of the complexes to bind to calf-thymus DNA (CT DNA) has been studied by UV and fluorescence spectroscopy and viscosity measurements. UV studies of the interaction of the complexes with DNA have shown that they can bind to CT DNA. The calculated binding constants of the complexes to DNA reveal tight binding to DNA. The complexes can probably bind to CT DNA via intercalation as concluded by studying the viscosity of a DNA solution in the presence of the complexes. Competitive studies with ethidium bromide (EB) have shown that the complexes can displace the DNA-bound EB suggesting strong competition with EB for the intercalation site of DNA.


A label-free signal amplification assay for DNA detection based on exonuclease III and nucleic acid dye SYBR Green I.
We have developed a new fluorescence method for specific single-stranded DNA sequences with exonuclease III (Exo III) and nucleic acid dye SYBR Green I. It is demonstrated by a reverse transcription oligonucleotide sequence (target DNA, 27 bases) of RNA fragment of human immunodeficiency virus (HIV) as a model system. In the absence of the target DNA, the hairpin-probe is in the stem-closed structure, the fluorescence of SYBR Green I is very strong. In the presence of the target DNA, the hairpin-probe hybridizes with the target DNA to form double-stranded structure with a blunt 3'-terminus. Thus, in the presence of Exo III, only the 3'-terminus of probe is subjected to digestion. Exo III catalyzes the stepwise removal of mononucleotides from this terminus, releasing the target DNA. The released target DNA then hybridizes with another probe, whence the cycle starts anew. The signal of SYBR Green I decreases greatly. This system provides a detection limit of 160 pM, which is comparable to the existing signal amplification methods that utilized Exo III as a signal amplification nuclease. Due to the unique property of Exo III, this method shows excellent detection selectivity for single-base discrimination. More importantly, superiors to other methods based on Exo III, these probes have the advantages of easier to design, synthesize, purify and thus are much cheaper and more applicable. This new approach could be widely applied to sensitive and selective nucleic acids detection.


Content and activity of human liver microsomal protein and prediction of individual hepatic clearance in vivo.
The lack of information concerning individual variation in content and activity of human liver microsomal protein is one of the most important obstacles for designing personalized medicines. We demonstrated that the mean value of microsomal protein per gram of liver (MPPGL) was 39.46 mg/g in 128 human livers and up to 19-fold individual variations existed. Meanwhile, the metabolic activities of 10 cytochrome P450 (CYPs) were detected in microsomes and liver tissues, respectively, which showed huge individual variations (200-fold). Compared with microsomes, the activities of liver tissues were much suitable to express the individual variations of CYP activities. Furthermore, individual variations in the in vivo clearance of tolbutamide were successfully predicted with the individual parameter values. In conclusion, we offer the values for MPPGL contents in normal liver tissues and build a new method to assess the in vitro CYP activities. In addition, large individual variations exist in predicted hepatic clearance of tolbutamide. These findings provide important physiological parameters for physiologically-based pharmacokinetics models and thus, establish a solid foundation for future development of personalized medicines.


Constructing Co3S4 Nanosheets Coating N-Doped Carbon Nanofibers as Freestanding Sulfur Host for High-Performance Lithium-Sulfur Batteries.
Lithium-sulfur batteries (LSBs) have shown great potential as a rival for next generation batteries, for its relatively high theoretical capacity and eco-friendly properties. Nevertheless, blocked by the shuttle effect of lithium polysulfides (LPSs, Li2S4-Li2S8) and insulation of sulfur, LSBs show rapid capacity loss and cannot achieve the practical application. Herein, a composite of carbon nanofibers coated by Co3S4 nanosheets (denoted as CNF@Co3S4) is successfully synthesized as freestanding sulfur host to optimize the interaction with sulfur species. The combination of the two materials can lead extraordinary cycling and rate performance by alleviating the shuttle of LPSs effectively. N-doped carbon nanofibers serve as long-range conductive networks and Co3S4 nanosheets can accelerate the conversion of LPSs through its electrocatalytic and chemical adsorption ability. Benefiting from the unique structure, the transporting rate of Li+ can be enhanced. Distribution of Li+ is uniform for enough exposed negative active sites. As a result, the cell with CNF@Co3S4 as sulfur host is able to stabilize at 710 mA h g-1 at 1 C after 200 cycles with average coulombic efficiency of 97.8% in a sulfur loading of 1.7 mg cm-2 and deliver 4.1 mA h cm-2 at 0.1 C even in 6.8 mg cm-2 for 100 cycles.


Agomelatine(S 20098) antagonizes the penile erections induced by the stimulation of 5-HT2C receptors in Wistar rats.
Agomelatine, an antidepressant with melatonin agonist and 5-HT(2C) antagonist properties, as well as two of its main metabolites, S 21517 (N-[2-(7-hydroxy-1-naphtyl)ethyl]acetamide) and S21540 (N-[2-(3-hydroxy-7-methoxynaphtalen-1-yl)ethyl]acetamide), have been assessed in vitro on pig choroid plexus preparations to determine their affinities for 5-HT(2C) receptors and their effects on inositol phosphate production. These compounds were also tested for their ability to inhibit the penile erections induced by the 5-HT(2C) receptor agonists, m-(chlorophenyl)piperazine (mCPP, 0.75 mg/kg, SC) and Ro 60-0175 (2.5 mg/kg, SC) in Wistar rats. These in vivo effects were compared to those of melatonin and the 5-HT antagonists pizotifen and SB 206,553. Agomelatine and S 21517 had moderate affinity for 5-HT(2C) receptors and behaved in vitro as weak antagonists at this receptor subtype. S 21540 had a 10-fold lower affinity. Pizotifen and SB 206,553 antagonized mCPP- and Ro 60-0175-induced penile erections, suggesting that penile erections induced by mCPP or Ro 60-0175 resulted from the stimulation of 5-HT(2C) receptors. Whereas increasing doses (from 1.25 to 40 mg/kg, IP) of melatonin were unable to modify the penile erections induced by mCPP and Ro 60-0175, agomelatine (from 1.25 to 40 mg/kg, IP) dose-dependently decreased mCPP- as well Ro 60-0175-induced penile erections. Furthermore, increasing doses (from 1.25 to 40 mg/kg, IP) of S 21517 and S 21540, the two main metabolites of agomelatine, did not affect the penile erections induced by mCPP and Ro 60-0175. Considering the similar activity of melatonin and agomelatine at melatonin receptors, these data suggested that the reported effects were not due to the stimulation of melatonin receptors and that, contrary to melatonin, agomelatine exerted 5-HT(2C) receptor antagonist properties in addition to its agonist activity at melatonin receptors. Finally, neither S 21517 nor S 21540 seemed to participate to the observed inhibition of penile erections by agomelatine.


Epitopes specificity of antibodies to thyroid peroxidase in patients with Graves' disease, Hashimoto's thyroiditis and overlap-syndrome.
Antibodies against thyroid peroxidase (anti-TPO) serve as clinical markers of thyroid autoimmune diseases (TAIDs). By trying to elucidate the causes of heterogeneity in autoantibody levels among patients with different TAIDs it becomes possible to clarify the pathophysiology of GD and HT. To investigate the heterogeneity of epitopes recognized by anti-TPO in patients with Hashimoto's thyroiditis (HT), Graves' disease (GD) and overlap-syndrome. We carried out a cross-sectional study on 398 patients with GD, HT and overlap syndrome and analyzed the specificity of epitopes and binding constants of TPO with monoclonal antibodies (MAbs). Ten MAbs to TPO were used, of which five were reactive with native TPO and the rest were reactive with denaturated TPO. The autoantibodies in blood serum of HT patients inhibited the binding of MAb63 more significantly than those in serum of GD patients: 59.62 % versus 54.02 %, respectively (p = 0.001). The anti-TPOs in serum of GD patients inhibited the binding of MAb77 more significantly than those in serum of HT patients: 54.36 % versus 51.13 %, respectively (p = 0.047). The binding of MAb45 was more inhibited in serum of patients with anti-TPO concentration over 1000 IU/ml (58.36 %). The blood serum of patients with overlap-syndrome showed less significant inhibition of MAb63 binding than that of patients with no overlap-syndrome: 52.47 % versus 58.81 %, respectively (p = 0.043). Mapping the epitopes to TPO with the help of MAbs may improve the differential diagnosis between different thyroid autoimmunities.


Hypothalamic self-stimulation and operant activity in the mottled mutant mouse.
Some behavioural effects of the mottled mutation were studied in the variegated heterozygote female. In mutants, compared to normals, operant activity was increased, whereas hypothalamic self-stimulation was always decreased. These results are discussed relative to the excepted central catecholaminergic disturbances resulting from the mutant gene.


Gradient domestication of Haematococcus pluvialis mutant with 15% CO2 to promote biomass growth and astaxanthin yield.
In order to increase biomass yield and reduce culture cost of Haematococcus pluvialis with flue gas from coal-fired power plants, a screened mutant by nuclear irradiation was gradually domesticated with 15% CO2 to promote biomass dry weight and astaxanthin yield. The biomass yield of mutant after 10 generations of 15% CO2 domestication increased to 1.3 times as that with air. With the optimization of nitrogen and phosphorus concentration, the biomass dry weight was further increased by 62%. The astaxanthin yield induced with 15% CO2 and high light of 135 μmol photons m(-2) s(-1) increased to 87.4mg/L, which was 6 times higher than that induced with high light in air.


Prevalence and burden of gastrointestinal helminthes among local chickens, in northern Jordan.
We conducted a cross-sectional study from December 2004 to February 2005 and from June 2005 to August 2005. The study aimed to determine the prevalence of gastrointestinal and tracheal helminthes among local chickens in northern Jordan. A total of 208 male and female local scavenging chickens were selected randomly. We examined the trachea and gastrointestinal tract of each bird for the presence of helminthes. We recovered three nematode and eight cestode species. No trematodes were found. One hundred and fifty-two birds (73.1%) (95% CI: 67, 79) were infected. The prevalences of different species were as follows: Ascaridia galli female 28%, male 43%; Capillaria obsignata 0.5%; Heterakis gallinarum 33%; Amoebotaenia cuneata 4.3%; Choanotaenia infundibulum female 23%, male 13%; Davainea proglottina 1.4%; Hymenolepsis cantaniana 11%; Hymenolepsis carioca female 35%, male 24%; Raillietina cesticillius female 5%, male 11%; Raillietina echinobothrida 16%; and Raillietina tetragona 18%. The prevalences of A. galli and R. cesticillus were higher in male than female hosts while those of C. infundibulum and H. carioca were higher in females. The median worm burden was 7 (range 0-168) worms per chicken.


Safety profile of the intravenous administration of brain-targeted stable nucleic acid lipid particles.
In a clinical setting, where multiple administrations of the therapeutic agent are usually required to improve the therapeutic outcome, it is crucial to assess the immunogenicity of the administered nanoparticles. In this data work, we investigated the safety profile of the repeated intravenous administration of brain-targeted stable nucleic acid lipid particles (RVG-9r-targeted SNALPs). To evaluate local activation of the immune system, we performed analysis of mouse tissue homogenates and sections from cerebellum. To investigate peripheral activation of the immune system, we used serum of mice that were intravenously injected with RVG-9r-targeted SNALPs. These data are related and were discussed in the accompanying research article entitled "Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype" (Conceição et al., in press) [1].


Polypharmacy and elderly patients.
Medication therapy in elderly patients is difficult to manage and always has the potential of being hazardous. With the age-related changes that affect the pharmacokinetics and pharmacodynamics of a medication, prescribing medications is further complicated. Similarly, assessment of a medication's efficacy is difficult. The situation becomes more complicated when the patient is taking multiple medications. Nurses in the perioperative area need to be cognizant of a patient's preoperative medication regime and the medications that have been prescribed in the perioperative setting. As medication interactions increase substantially with the number of medications taken, the most pertinent nursing intervention is accurate assessment of the patient. Early recognition of potentially harmful medication effects is critical.


A change in the timing of the Bacillus Calmette-Guérin vaccination in 2013 was associated with an increase in the incidence rate of infants with latent tuberculosis infection.
A change in the timing of the Bacillus Calmette-Guérin (BCG) vaccination among infants in Japan appears to be associated with an increase in the incidence rate of latent tuberculosis infection (LTBI). Data on both active and latent tuberculosis (TB) infections from 2007 to 2019, which were reported by the Japan Anti-Tuberculosis Association, were statistically analyzed by comparing TB incidence rates in 2007-2012 and 2013-2019. Although the incidence rate for active TB disease did not statistically increase nor decrease in the infant age group for either sex (and in fact decreased for some of the other age groups), the incidence rates of LTBI for both sexes were increased in the infant age group, while the incidence rates decreased in the other age groups. Between 2007 and 2012, the incidence rate of LTBI in females was statistically greater than those of males in the 1-4-year-old age group. From 2013 to 2019, the incidence rates of females were greater than those of males in both the infant and 1-4-year-old age groups, suggesting a growing preponderance of infections among female children in the youngest age groups. It may be that the change of BCG vaccination timing in Japan which took place in 2013 affected the infant incidence rate of LTBI, with a more prominent effect on females than males. In order to control TB infection, the ramifications of a change in vaccination timing therefore need careful exploration, as one such change appears associated with increased numbers of infants with LTBI, with disproportionate effects on females.


Tumors in the cauda equina: A SEER analysis of tumor types and predictors of outcome.
Caudaequinatumors are histologically diverse. International Classification of Diseases for Oncology (ICD-O3) confers dedicated site code (C72. 1) for cauda equina. This code is excluded during analyses of other primary spinal cord tumors. In this retrospective study, the Surveillance, Epidemiology and End Results (SEER) data for primary cauda equina tumors (PCET, C72. 1) excluding the tumors of spinal meninges (C70. 1) from 1992 to 2015 were reviewed. Demographic characteristics, tumor types, and clinical outcomes were analyzed using univariable analysis. Overall survival was estimated using Kaplan-Meier methods and compared for age, histology and treatment type. 293 patients with PCET met inclusion criteria. The most common tumors comprised schwannoma (32%), myxopapillary ependymoma (21%), malignant ependymoma (22%). The median age at diagnosis was 50 years (range < 1 year to 98 years), 57% of patients were males. 77% of the patients underwent surgery. Median follow up time for these patients was 70 months. Of the 293 patients, 250 (85%) were living at the end of 2015. The cause of death was tumor or CNS related in 15 patients. 136 patients were followed for <5 years, of which 102 were censored and 34 died (11.6%) before 5 years. Using univariable analysis, age at diagnosis (Hazard Ratio, HR 1.05; confidence interval, CI 1.03-1.07; p < 0.001), malignant tumor type (HR 2.88, CI 1.15-7.19, p = 0.0239) and absence of surgical intervention (HR 2.54, CI1.26-5.11, p = 0.0092) were predictors of increased mortality. Although most patients did well, older age and lack of surgical intervention were associated with worse survival.


Ethno-medicinal uses of plants growing in the Bulandshahr district of northern India.
A medico-botanical study was carried out in certain villages of the Bulandshahr district in Uttar Pradesh, India, on the traditional uses of medicinal plants by the rural population for curing human diseases. Certain plants were considered useful in only one disease whereas a few had multiple uses. Recipes with a suitable dose, precautions, if any, and mode of administering the drugs are suggested.


Initial characterization of a polyclonal antibody to an insulin-sensitive glycophospholipid.
This paper describes the production of a rabbit polyclonal antibody against an insulin-sensitive glycophospholipid from rat liver membranes. The immunogen was a highly purified glycophospholipid-tetanus toxoid conjugate. Immunoglobulin purified from immune serum reacted with a glycophospholipid-ovalbumin conjugate, indicating specificity for the glycophospholipid hapten and not the protein carrier. By radioimmunoassay the antibody recognized the purified glycophospholipid antigen but not other phospholipids including phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and phosphatidylinositol. The antigenic site appears to be the carbohydrate portion of the glycophospholipid. The antibody also reacted with glycophospholipid purified from two rat hepatoma cell lines. Analysis of partially purified liver glycophospholipid by thin-layer chromatography revealed over 20 orcinol- or fluorescamine-positive bands, but immunostaining identified only 1 band. The latter had an Rf identical to those of the original glycophospholipid isolated from rat liver and metabolically labeled material isolated from hepatoma cells. The antibody should prove useful in determining the role of the glycophospholipid and its metabolites in insulin action.


Stress, affective disorders, and immune function.
Increasing scientific evidence supports age-old observations that psychosocial factors are closely associated with the pathogenesis of certain physical and mental illnesses. The immune system appears to play a primary mediating role. Whereas acute stress may initiate a transient immunologically protective response, prolonged or poorly controlled psychosocial stressors may result in depression of different components of the immune system. These responses may be related to, or independent of, changes in the neuroendocrine system. As the rather prolific literature in this infant area of psychoneuroimmunology reveals, there are many complex levels of interaction that require further investigation. There is clearly a need for long-term prospective studies that will identify individuals at risk for those numerous diseases in which psychosocial factors and impaired immune function play a pathogenic role. In addition to correlating altered immune function over time with changes in the physical environment, these studies should include psychologic profiles, life-event inventories, and psychiatric interviews in an effort to delineate the role of psychosocial factors as the stimulus for and as the response to the disease process. One of the many positive outcomes of this multifactorial approach to illness is that it will alter the physician's approach to disease and thus to patients as they are evaluated and treated in the psychosocial context in which they live. As Hippocrates said, "It is more important to know what sort of a person has a disease than to know what sort of disease a person has."


Mosquito-transmitted malaria in New York City, 1993.
In August, 1993, 3 cases of Plasmodium falciparum malaria in people without recent travel histories or bloodborne exposure were reported in New York City. An epidemiological investigation confirmed the absence of risk factors for acquisition of malaria in two cases. The third case could not be definitively classified as locally acquired malaria because the patient had travelled to Thailand two years before malaria was diagnosed. The 3 individuals lived in separate houses in the same neighbourhood of Queens, New York and had onset of illness within a day of each other. The investigation consisted of patient interviews, active case finding, reviewing recent New York flight and shipping arrivals, and an entomological survey for anopheline mosquitoes and breeding sites. No other cases were identified. The 3 patients lived several miles from air and sea ports and prevailing winds would have carried any mosquitoes at those sites away from the patient's homes. By the time of the environmental investigation (September, 1993), the area was dry and neither adult nor larval anophelines were found. However, weather conditions at the probable time of infection (July, 1993) were very different. Malaria was probably transmitted to these 2 patients by local anopheline mosquitoes that had fed on infected human hosts. Mosquito-control measures were not implemented because there was no evidence of ongoing transmission. The occurrence of mosquito-transmitted malaria in New York City demonstrates the potential for reintroduction of malaria transmission into areas that are no longer endemic and emphasises the need for continued surveillance and prompt investigations, if cases without risk factors are reported.


MRI anatomy of the nerves of the upper limb.
In view of the good anatomic definition of the images obtained by magnetic resonance imaging (MRI), we have defined MRI sections allowing study of the nerves of the upper limb.


Structures of poly(dA-dT, ip5dU) containing various small amounts of the antiherpetic 5-isopropyl-2'-deoxyuridine.
Three different concentrations of the antiherpetic agent 5-isopropyl-2'-deoxyuridine (ip5dU) were introduced into the synthetic DNA poly(dA-dT) to analyze resulting copolymers by electron microscopy, UV absorption and CD spectroscopy. The poly(dA-dT, ip5dU) containing 1.3 and 4.3% ip5dU did not much differ from the parent poly(dA-dT) but poly (dA-dT, ip5dU) with 7.1% ip5dU behaved in an unusual way. Results are explained by the notion that if bulky isopropyls occur sufficiently close to each other then stable hairpins protruding from the double helix are formed, presumably to accommodate the ip5dU-s into the loops.


Oxygen transfer kinetics of red blood cells of the turtle Pseudemys scripta elegans.
The kinetics of O2 uptake into, and release from, the red blood cells (RBC) of the turtle Pseudemys scripta elegans were determined with a stopped-flow technique at varied temperature (10-30 degrees C) and pH (7.5-7.9). The results were compared to those obtained for RBC of other vertebrates and related to morphometric and physiological data on gas/blood diffusion in turtle lungs. The O2 transfer conductance of RBC, G, for O2 release into high concentrations of dithionite, considered to represent the best estimate of true RBC transfer conductance for O2 uptake and release, averaged 0.17 +/- 0.01 at 30 degrees C, 0.13 +/- 0.01 at 20 degrees C, 0.09 +/- 0.01 at 10 degrees C (mean +/- SD, in mmol.min-1.Torr-1.(mlRBC)-1). These values are about one half the corresponding value for human RBC, and this difference may be due to the larger size of turtle RBC (volume, 327 microns 3) compared to human RBC (90 microns 3). The temperature dependence of G, Q10 = 1.3 indicates that, as in human RBC, diffusion through aqueous media is the main limiting factor for O2 exchange. Morphometric data on the lungs of Pseudemys scripta suggest that the resistance to O2 transfer by RBC is lower than that offered by the gas-blood barrier. The total apparent transfer resistance to CO, obtained from previous measurements of pulmonary diffusing capacity for CO in the same species, is much higher than that predicted from the combination of RBC O2 kinetics and morphometric data on gas-blood barrier.


A study on the evolution of economic patterns and urban network system in Guangdong-Hong Kong-Macao greater bay area.
The COVID-19 pandemic has seriously affected China's macroeconomy, industrial transformation, and high-quality development. Research on economic patterns and urban network systems can provide a reference for healthy development of the regional economic system. The evolution of the economic pattern and urban network system of Guangdong-Hong Kong-Macao Greater Bay Area (GBA) from 2010 to 2020 is investigated using methods (e.g., the gravity center model, the gravitational force model, social network analysis, and geographic information system). (1) The gravity center of gross domestic product (GDP) of the GBA is located in Nansha district, Guangzhou, with a skewing direction northwest-east-northwest and a movement rate of "large-small-large." The center of import and export and the center of consumption show a "zigzagging migration" in which the center of investment shows an "irregular (random) migration". (2) The economic connection degree of cities in the GBA exhibits a high ascending velocity, and the whole area tends to be mature, with a significant effect of spatial proximity. With the steady increase in network density, there is significant polarization of network centrality in the region. The four major cohesive subgroups have been relatively stable and consistent with the degree of geographic proximity of the cities. The center-periphery structure is more significant, in which the core area is extended to the cities on the east coast of the Pearl River Estuary, thus forming the core cluster of "Hong Kong-Shenzhen-Guangzhou-Dongguan." In this study, the evolution of economic patterns and urban network systems in the GBA over the past decade is analyzed using multiple methods (i.e., gravity model, urban network system analysis, and geographic information system) based on urban socioeconomic data by starting from various spatial elements (e.g., "points, lines, and networks") to gain insights into and optimize research on regional economic development after the COVID-19 pandemic.


Mechanisms of petroleum hydrocarbon toxicity: destruction of liver microsomal and mitochondrial calcium pump activities by a Prudhoe Bay crude oil.
Administration of Prudhoe Bay crude oil (PBCO) to rats resulted in an abrupt drop in liver mitochondrial and microsomal ATP-dependent calcium uptake activity. Also, in vitro incubations of either mitochondria or microsomes in the presence of a dimethyl sulfoxide (DMSO) extract of PBCO resulted in a dose-dependent inhibition of calcium influx. The release of calcium from calcium-loaded mitochondria and microsomes was also observed in the presence of the PBCO extract. At concentrations which effect calcium sequestration, the PBCO extract produced swelling of mitochondria. Microsomal ATPase activity in the presence or absence of calcium was unaffected by PBCO. The results indicate that increased permeability of the membranes to calcium is a contributory factor in the inhibition of calcium uptake by PBCO.


Aging and pancreatic exocrine function. Studies in female conscious rats.
Basal pancreatic exocrine functions as well as responses to endogenous (BPJ diversion) and exogenous (injection of CCK-8 or secretin) stimulations were examined in young (6- and 12-month-old) and old (24- to 26-month old) female Fischer 344 rats. Basal secretions were not significantly different between young and old rats. BPJ diversion significantly stimulated pancreatic secretions of fluid, bicarbonate, and protein in all animals. The pancreatic protein response (mg/kg/hr) to BPJ diversion was significantly attenuated with respect to age [57.59 +/- 16.16, 43.73 +/- 6.94, and 20.75 +/- 3.95, for 6-, 12-, 24- to 26-month-old rats, respectively, mean +/- SE, F(2,20) = 3.49, P less than 0.05]. The pancreatic responses to secretin (0.086, 0.432, and 1.728 nmol/kg) were not significantly different between young and old rats. Intravenous injection of CCK-8 (0.033, 0.167, and 0.667 nmol/kg) produced a significant increase in protein output in all age groups. In young animals, stepwise increases in protein output were observed, whereas, in old rats, increments in response to the larger two doses of CCK-8 (0.167 and 0.667 nmol) were smaller than that produced by 0.033 nmol/kg of CCK-8. In conclusion, the basal secretions in old rats were comparable with those in young ones, but the reserve capacity for protein secretion appears to decrease in old compared to young rats.


Expression of Bcl-XS alters cytokinetics and decreases clonogenic survival in K12 rat colon carcinoma cells.
bcl-XS, a member of the bcl-2 family, has been shown to induce and/or sensitize some cells to undergo programmed cell death, and to negate the anti-apoptotic activity of bcl-XL and bcl-2 by mechanisms which are still uncertain. To help understand these mechanisms we have established stable derivatives of the K12 rat colon carcinoma cell line that express bcl-XS in a tetracycline-regulated manner, using an autoregulatory retroviral cassette. When bcl-XS expression is induced, we observe two phenotypic responses. A small fraction of cells appear to undergo spontaneous apoptosis while the majority of cells undergo a form of cytostasis. In the latter case, the cells stop dividing (or divide a limited number of times at a retarded rate) and swell to many times their original size. These cells can take on a ghostlike appearance and subsequently detach from the culture plates and die or they may remain intact in a hindered state of proliferation. Doubling times were calculated to be 31.4 h in the presence of tetracycline and 50.4 h without tetracycline, bcl-XS expression also causes dramatic alterations in the cell cycle distribution of K12 cells manifesting as a substantial decrease (approximately 50%) in the fraction of S phase cells with a concomitant increase in the G1 population. Continuous expression of bcl-XS, at levels approximately equal to that of bcl-XL, decreased the viability of K12 cells as demonstrated by a log decline in clonogenic survival. This decrease occurred without considerable apoptosis or a compensatory increase in the level of bcl-XL. None of these phenotypes were present in control cells expressing beta-galactosidase in a similar retroviral cassette. These observations demonstrate that bcl-XS can have substantial cytokinetic effects under circumstances that produce relatively little apoptosis.


[Elderly arrested people in correctional facilities Challenge for health care].
At present there is no systematic, nationwide collection of data about the health status and health care of elderly persons imprisoned in Germany. The health status is highly significant with regard to the (re)socialization of elderly prisoners. From an ethical point of view a highly developed country should provide a good quality health care even in prisons. Using the example of male prisoners in the Federal State of Rhineland-Palatinate, a survey was carried out on the health status of elderly prisoners and the presence of functional handicaps. A total of 222 elderly male prisoners in Rhineland-Palatinate who were at least 50 years old at the time of the quantitative analyses participated in the anonymous comprehensive survey by completing a questionnaire. The elderly prisoners in Rhineland-Palatinate are concerned by age-related chronic diseases and functional handicaps significantly more often than the general extramural population. The data obtained in this survey are essential for the development and implementation of targeted strategies of prevention and health promotion and for improvement in the health care of elderly prisoners.


Prospective, randomized trial comparing diathermy excision and diathermy coagulation for symptomatic, prolapsed hemorrhoids.
This study was designed to compare diathermy excision and diathermy coagulation in the treatment of symptomatic prolapsed piles. Forty-five consecutive patients were randomly assigned to diathermy excision hemorrhoidectomy (Group A, n = 25) and diathermy coagulation (Group B, n = 20) under general anesthesia. The median duration of surgery was ten minutes for both groups. There was no statistical difference in the severity of postoperative pain at rest between the two groups, but Group A patients felt less pain during defecation on the third postoperative day (median, 5 (interquartile range, 3-7) vs. 8 (4-9); P = 0.04) and on the sixth postoperative day (median, 5 (interquartile range, 2-6) vs. 9 (5-10); P = 0.02). There was, however, no statistical difference in postoperative oral analgesics use and patients' satisfaction scores between the two groups. Complication rates were similar except that diathermy coagulation tended to leave some residual skin components of external hemorrhoid especially in very large prolapsed piles. Group A patients resumed work earlier (mean, 12 (range, 4-20) vs. 17 (11-21) days); however, this was not statistically significant ( P = 0.1). Diathermy coagulation of hemorrhoids is a simple technique and may be considered in suitable cases.


Rate and Predictors of Acute Care Encounters in the First Month After Stroke.
The purpose of this quality improvement project is to understand the burden of acute care, including inpatient readmission and emergency department (ED) visits, in the month following hospital discharge after stroke. We identified patients discharged from our hospitals between 2015 and 2018 with any stroke diagnosis who had an unplanned readmission or ED visit within the first month after discharge, and those who had primary care (PC) visits before or after their stroke. Patients were compared regarding demographics, clinical characteristics, and PC visits. Independent predictors of acute care encounters were examined using logistic regression. A total of 166 patients (19%) had an acute care encounter one month after discharge. Eighty-eight (10%) patients were readmitted and 78 (9%) patients had an ED visit. Encounter diagnoses were different between the two groups; inpatient readmission had more frequent acute stroke/TIA and pneumonia/pulmonary indications, while ED visits had more non-specific neurologic symptoms and more frequent cardiovascular complaints. Independent predictors of any acute care encounter and inpatient readmission were younger age, longer length of stay (LOS), and lack of PC visit after discharge. Predictors of ED visits were the same except for LOS. 30-day acute care encounters after stroke hospitalization are common, affecting 19% of patients and usually occurring in the first week after discharge. Post discharge PC visit was associated with a decreased need for acute care. Efforts should be made to facilitate a PC visit within a week after discharge, especially in high risk patients.


An Exposition on Surgical Experiences in Identification, Exposure, and Injuries of Recurrent Laryngeal Nerve (RLN) During Thyroid Operations: Gleanings, Narrative, and the Reflections.
Identifying and preserving the recurrent laryngeal nerve (RLN) is of paramount importance during thyroid surgeries. Iatrogenic injuries to RLN (RLNI) are considered one of the most serious and feared complications of thyroidectomies. Surgically, there are four routes/approaches (lateral, inferior, superior, and medial) for localizing and identifying the RLN. This study aims to estimate the incidence of RLNI in the context of various approaches taken intra-operatively for nerve localization and identification. This retrospective analytical study included 54 cases of thyroidectomies operated for various benign and malignant thyroid disorders in a tertiary care center from January 2018 to December 2020. Intraoperative search, identification, and dissection of the nerve were done with superior, inferior, medial, and lateral approaches. The chi-square test and exact test were used to analyze the data and p-value < 0.05 was considered significant. Pre- and post-operative recurrent laryngeal nerve evaluation was done with 90 degrees Hopkins laryngoscope. Overall in this series, the incidence of post-thyroidectomy RLNI was 3.7% and 3.7% for permanent and temporary nerve insults, respectively. Non-recurrent RLN on the right side was identified in one case and extra-laryngeal branching of RLN was identified in two cases. There was no statistically significant difference (p = 0.929) between the different approaches taken and the incidence of RLNI. The type of surgery and pathology also expressed no statistically significant relevance with the incidence of RLNI (p = 0.463 and p = 0.277, respectively). Adoption of a particular surgical approach to localize and identify RLN during thyroid surgery carries no statistically significant difference between RLNI and approaches taken. Meticulous handling and dissection of the tissue in the correct surgical plane are crucial determinants in preventing RLNIs.


Parathyroidectomy: extent of resection and late results.
Opinion is divided as to the necessary extent of parathyroid resection in primary hyperparathyroidism. Some surgeons urge that subtotal parathyroidectomy be performed routinely, while others reserve subtotal resections for patients with parathyroid hyperplasia. In a review of 102 patients treated by parathyroidectomy for primary hyperparathyroidism and subsequently followed up for an average of 6 years, there were 73 patients with parathyroid adenoma, 26 with hyperplasia and 3 with carcinoma. The adenoma was not found at the first operation in only 3 cases; in the other 70 after removal of the adenoma no further hypercalcaemia was observed during the follow-up period. Persistent or recurrent hypercalcaemia was a problem in 9 out of the 26 patients with primary hyperplasia who had inadequate resection at the first operation, and also in the 3 patients with carcinoma. Experience shows that peroperative biopsy with frozen section of all the parathyroids is useful in confirming their identity and can be a guide to the type of disease present and the appropriate extent of resection.


Isolation and identification of cutaneous leishmaniasis species by PCR-RFLP in Ilam province, the west of Iran.
Cutaneous leishmaniasis (CL) is one of the most common parasitic diseases and public health problems in Iran. CL is endemic in most parts of Ilam province, in the west of Iran. The distance from the center of country, the great number of divers rural areas, and lack of specialists and laboratory facilities have been the major causes of Leishmania species remaining unknown in this region. Polymerase chain reaction followed by restriction fragment length polymorphism was performed to identify the Leishmania species in 61 patients with cutaneous lesions. Eventually L. major was confirmed as the cause of cutaneous leishmaniasis in Ilam province, the west of Iran.


Discovery of the imidazole-derived GPR40 agonist AM-3189.
As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.


Direct measurement of protein dynamics inside cells using a rationally designed photoconvertible protein.
All biological reactions depend on the diffusion and re-localization of biomolecules. Our understanding of biological processes requires accurate measurement of biomolecule mobility in living cells. Currently, approaches for investigating the mobility of biomolecules are generally restricted to measuring either fast or slow diffusion kinetics. We describe the development and application of a photoconvertible fluorescent protein, Phamret, that can be highlighted by UV light stimulation inducing a change in fluorescence emission from cyan fluorescent protein (CFP) to photoactivated GFP (PA-GFP). Phamret can be monitored by single excitation-dual emission mode for visualization of molecular dynamics for a broad range of kinetics. We also devised a microscopy-based method to measure the diffusion coefficient from the fluorescence decay after photostimulation of Phamret, enabling analysis of diffusion kinetics ranging from less than 0.1 microm2/s up to approximately 100 microm2/s, and found significant changes in free protein movement during cell-cycle progression.


Future opportunities of the Gynecological Cancer Intergroup.
The Gynecologic Cancer Intergroup (GCIG) is an international collaboration of cooperative clinical trials groups who conduct randomized phase III clinical trials in the population of women affected by gynecologic cancer. This collaboration amongst 18 member groups allows for rapid accrual of women to such trials with outcomes that are rapidly generated and readily generalizable to a broad population. Future considerations should include studies in prevention and translational research through improved processes and new global partnerships.


Bacillary angiomatosis presenting as a soft-tissue tumor without skin involvement.
A patient with human immunodeficiency virus infection presented with a soft-tissue mass which histologically and clinically mimicked an angiosarcoma. Ultrastructural study, however, revealed bacteria identical to those seen in cutaneous bacillary angiomatosis, but the patient had no skin lesions. To our knowledge, this represents the first report of soft tissue involvement by bacillary angiomatosis without the presence of skin lesions.


[Implementation and evaluation of error prevention measures in surgical clinics: Results of a current online survey].
In the autumn of 2014, more than 3,000 surgeons completed an online questionnaire asking for the prevalence and efficiency of instruments to prevent adverse events within surgical departments in Germany. About 90 % of the respondents stated that perioperative checklists, preoperative marking of the surgical site and the documentation of hospital infections had been implemented in their institution; and 75 % of the institutions had introduced critical incident reporting systems (CIRS), morbidity and mortality conferences and identification bracelets for patients. The surgeons were asked to rank the different instruments for the prevention of adverse events. According to the respondents, preoperative marking of the surgical site and the use of checklists were at the top of the efficacy ranking, followed by an introductory course for surgeons starting work in a hospital or when new devices became available. Only 50 % of the responding surgeons perceived CIRS as being efficient. Overall, the answers showed that instruments to increase patient safety were commonly available in surgical departments. On the other hand, there is still room for improvement in daily practice.


Very-low-calorie ketogenic diet for the management of obesity, overweight and related disorders.
Very-low-calorie ketogenic diet (VLCKD) is a promising lifestyle intervention for the management of overweight and obesity. It is characterized by a restriction of both calories and carbohydrates, while assuring the adequate proteins, fats and micronutrients intake. Significant results in terms of excess body weight loss have been reported and this strategy considered also in the preoperative settings. Improvements in hypertension, type 2 diabetes and dyslipidemia follows. PubMed and Google Scholar were searched for papers reporting data on VLCKD as a strategy for the management of overweight, obesity and related disorders in adults. Four main documents are available in the literature and were included in the present narrative review. The present review discusses available evidence and provides practical recommendations for the management of VLCKD.


Studies on photosynthetic oxygen-evolving complex by means of Fourier transform infrared spectroscopy: calcium and chloride cofactors.
Structural roles of functional Ca2+ and Cl- ions in photosynthetic oxygen-evolving complexes (OEC) were studied using low- (640-350 cm-1) and mid- (1800-1200 cm-1) frequency S2/S1 Fourier transform infrared (FTIR) difference spectroscopy. Studies using highly active Photosystem (PS) II core particles from spinach enabled the detection of subtle spectral changes. Ca2+-depleted and Ca2+-reconstituted particles produced very similar mid- and low-frequency spectra. The mid-frequency spectrum was not affected by reconstitution with 44Ca isotope. In contrast, Sr2+-substituted particles showed unique spectral changes in the low-frequency Mn-O-Mn mode at 606 cm-1 as well as in the mid-frequency carboxylate stretching modes. The mid-frequency spectrum of Cl- -depleted OEC exhibited marked changes in the carboxylate stretching modes and the suppression of protein modes compared with that of Cl- -reconstituted OEC. However, Cl- -depletion did not exert significant effects on the low-frequency spectrum.


Fetal exposure of Aristolochic Acid I undermines ovarian reserve by disturbing primordial folliculogenesis.
The primordial follicle pool established in early life determines the ovarian reserve in the female reproductive lifespan. Premature exhaustion of primordial follicles contributes to primary ovarian insufficiency (POI), that is dependent by the initial size of the primordial follicle pool and by the rate of its activation and depletion. AAI, a powerful nephrotoxin with carcinogenic potential, is present in the Aristolochiaceae species, which can release AAI into soil as a persistent pollutant. In order to assess the potential risk of Aristolochic Acid I (AAI) exposure on mammalian oogenesis, we uncovered its adverse effect on primordial folliculogenesis in the neonatal mouse ovary and its effect on female fertility in adulthood. Pregnant mice were orally administrated with doses of AAI without hepatic or renal toxicity during late-gestation. Ovaries from offspring of administered female displayed gross aberrations during primordial folliculogenesis. Also, unenclosed oocytes in germ-cell cysts showed increased DNA damage. Furthermore, several key factors, including NANOS3, SOX9, KLF4, that govern early gonad's differentiation were abnormally expressed in the exposed ovary, while the follicle formation was partially restored by knockdown of Nanos3 or sox9. In adulthood, these aberrations evolved into a significant reduction in offspring number and impaired ovarian reserve. Together, our results show that AAI influences primordial folliculogenesis and, importantly, affected female fertility. This study shows that administration of drugs herbs or consumption of vegetables that contain AAs during pregnancy may adversely influence the fertility of offspring.


Response to pomalidomide plus fixed low-dose dexamethasone in a case of secondary plasma cell leukaemia.
This is, to our knowledge, the first reported case of secondary Plasma Cell Leukemia that was successfully by pomalidomide plus fixed low-dose dexamethasone. Pomalidomide at a dosage of 4 mg orally on days 1-21 of repeated 28-day cycles associated with fixed low-dose dexamethasone (40 mg on days 1, 8, 15 and 22 of each 28-day cycle), outside of the clinical trials, was started as a final attempt. After the fourth course, the patient achieved an interesting response that included a significant reduction of circulating plasma cells from the peripheral blood, a very important decrease of the M-component, and normalization of haematological value. The toxicities were acceptable. The time to best response was 4 months.


Structural studies on a sulphated glycoprotein preparation isolated from human saliva.
The identity of the sulphated component in a high-molecular-weight glycoprotein preparation (GP) from human whole saliva was investigated. A t0.5 of 96 min for inorganic sulphate release in 0.25 M HCl indicated the presence of O-substituted sulphate, probably associated with hydroxyl groups of sugar residues. This possible association of ester was also inferred from infra-red data of the intact GP, where major absorption bands were detected at 1230-1250 and 828 cm-1. Further a sulphated-monosaccharide derivative was released during acid hydrolysis in 0.1 M HCl at 100 degrees C for 75 min and isolated by gel-filtration on Sephadex G-15. This derivative was separated from a range of non-sulphated sugars by thin-layer chromatography in various solvent systems and possessed the chromatographic characteristics of N-acetylgalactosamine-6-O-sulphate.


Increased speech contrast induced by sensorimotor adaptation to a nonuniform auditory perturbation.
When auditory feedback is perturbed in a consistent way, speakers learn to adjust their speech to compensate, a process known as sensorimotor adaptation. Although this paradigm has been highly informative for our understanding of the role of sensory feedback in speech motor control, its ability to induce behaviorally relevant changes in speech that affect communication effectiveness remains unclear. Because reduced vowel contrast contributes to intelligibility deficits in many neurogenic speech disorders, we examine human speakers' ability to adapt to a nonuniform perturbation field that was designed to affect vowel distinctiveness, applying a shift that depended on the vowel being produced. Twenty-five participants were exposed to this "vowel centralization" feedback perturbation in which the first two formant frequencies were shifted toward the center of each participant's vowel space, making vowels less distinct from one another. Speakers adapted to this nonuniform shift, learning to produce corner vowels with increased vowel space area and vowel contrast to partially overcome the perceived centralization. The increase in vowel contrast occurred without a concomitant increase in duration and persisted after the feedback shift was removed, including after a 10-min silent period. These findings establish the validity of a sensorimotor adaptation paradigm to increase vowel contrast, showing that complex, nonuniform alterations to sensory feedback can successfully drive changes relevant to intelligible communication.NEW & NOTEWORTHY To date, the speech motor learning evoked in sensorimotor adaptation studies has had little ecological consequences for communication. By inducing complex, nonuniform acoustic errors, we show that adaptation can be leveraged to cause an increase in speech sound contrast, a change that has the capacity to improve intelligibility. This study is relevant for models of sensorimotor integration across motor domains, showing that complex alterations to sensory feedback can successfully drive changes relevant to ecological behavior.


Management of asymptomatic severe aortic stenosis.
Patients with symptomatic severe aortic stenosis (AS) benefit from aortic valve replacement (AVR). Management of severe AS in the absence of symptoms is, however, controversial and often challenging. Unselected premature AVR carries the risks of cardiac surgery; delayed AVR due to unrecognized symptoms can result in a dismal outcome. Echocardiography is the standard tool to evaluate and follow patients with AS. Nevertheless, most of the current echocardiographic parameters have limitations in predicting symptom onset and clinical outcome. The same applies to clinical parameters, exercise stress testing, and other imaging modalities used in AS evaluation and serial follow-up. Predictors of outcome could, however, help to identify asymptomatic patients who would benefit from expedited AVR with the goal to reduce mortality. This review will discuss the most relevant clinical studies and guidelines on management of asymptomatic severe AS, with an emphasis on providing concise information for identifying patients at high risk.


Novel ZnO/MgO/Fe2O3 composite optomagnetic nanoparticles.
A facile sol-gel synthesis of novel ZnO/MgO/Fe2O3 nanoparticles (NPs) is reported and their performance is compared to that of ZnO/MgO. Powder x-ray diffraction (XRD) patterns reveal the crystal structure of the prepared samples. The average particle size of the sample was found to be 4.8 nm. The optical properties were determined by UV-vis absorption and fluorescence measurements. The NPs are stable in biologically relevant solutions (phosphate buffered saline (PBS), 20 mM, pH = 7.0) contrary to ZnO/MgO NPs which degrade in the presence of inorganic phosphate. Superparamagnetic properties were determined with a superconducting quantum interference device (SQUID). Biocompatible and stable in PBS ZnO/MgO/Fe2O3 core/shell composite nanocrystals show luminescent and magnetic properties confined to a single NP at room temperature (19-24 ° C), which may render the material to be potentially useful for biomedical applications.


Reliability of common mouse behavioural tests of anxiety: A systematic review and meta-analysis on the effects of anxiolytics.
The validity of widely used rodent behavioural tests of anxiety has been questioned, as they often fail to produce consistent results across independent replicate studies. In this study, we assessed the sensitivity of common behavioural tests of anxiety in mice to detect anxiolytic effects of drugs prescribed to treat anxiety in humans. We conducted a pre-registered systematic review of 814 studies reporting effects of 25 anxiolytic compounds using common behavioural tests for anxiety. Meta-analyses of effect sizes of treatments showed that only two out of 17 commonly used test measures reliably detected effects of anxiolytic compounds. We report considerable between-study variation in size and even direction of effects of most anxiolytics on most outcome variables. Our findings indicate a general lack of sensitivity of those behavioural tests and cast serious doubt on both construct and predictive validity of most of these tests. In view of scientifically valid and ethically responsible research, we call for a revision of behavioural tests of anxiety in mice and the development of more predictive tests.


Independent effects of denervating the cricothyroid muscle and stenting on the anterior cricoid split: canine model.
The anterior cricoid split (ACS) has gained in popularity since its introduction in 1980, for the treatment of the difficult to extubate child. The procedure allows a successful extubation and avoids a tracheotomy about 75% of the time. How the ACS allows extubation remains poorly understood. Animal research has shown that in the canine model the ACS results in a gap in the cricoid cartilage with a subjective increase in the subglottic space (Senders and Eisele, 1978). This gap in the cricoid cartilage develops whether or not an endotracheal tube stent is used. This experiment was designed to quantitatively evaluate the effect of the ACS on the subglottic space with or without the use of the stent, and to evaluate the effect of the cricothyroid muscle on the ACS procedure. The results show that the ACS does result in an increase in the subcricoid space, and that the use of an endotracheal tube stent does result in a larger increase. The cricothyroid muscle has a strong immediate effect on the gap in the cricoid cartilage, which is eliminated by sectioning the external laryngeal nerve. The long-term effects of sectioning the external laryngeal nerve on the gap in the cricoid cartilage were not conclusive.


Platelet a disintegrin and metallopeptidase 10 expression correlates with clock drawing test scores in Alzheimer's disease.
Earlier studies have demonstrated that a disintegrin and metallopeptidase 10 (ADAM10) levels are reduced in Alzheimer's disease (AD) patients compared with healthy subjects. The objective of this study was to evaluate whether platelet ADAM10 levels correlates with the clock drawing test (CDT) scores, which is a simple and a reliable measure of visuospatial ability and executive function in AD patients. Thirty elderly patients with probable AD and 25 healthy patients forming the control group, matched by age, gender, and educational level, were evaluated. Platelet proteins were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, and ADAM10 was identified by western blotting. The Spearman's correlation coefficient between ADAM10 and CDT was obtained for each group. The areas under the curves were used to compare the receiver operating characteristic curves. The CDT scores and platelet ADAM10 expression were significantly different between patients with AD and controls and also along the disease's progression. In AD patients, there was a positive correlation between ADAM10 expression and CDT scores. Among non-AD subjects, no correlation was found. The combination of ADAM10 and CDT was significantly better to confirm the AD diagnosis than the AUCs of ADAM10 and CDT separately. The association of blood-based biomarkers, such as ADAM10, and cognitive tests may be helpful for a more reliable AD diagnosis.