Metabolic inversion of stereoisomeric ibuprofen in man.
Metabolic stereoisomeric inversion of ibuprofen has both toxicological and clinical implications, and may represent a potential pitfall for patients with metabolic disorders. For those patients, reduced renal clearance in conjunction with metabolic bioactivation resulting from inversion may increase the plasma levels of the active species to an unpredictable degree. This will give rise to enhanced adverse consequences from the same mechanism as its antiinflammatory action, via inhibition of prostaglandin formation. In this study, an enantioselective HPLC technique has been established to scrutinize this unique biotransformation. It was found that ibuprofen epimerization in humans in virtually irreversible, from R to S, which is in agreement with the previous reports. Also, using rats as a model, we have prepared active subcellular hepatic preparations to effect this biotransformation. The "2-arylpropionyl-CoA epimerase" readily converts R-ibuprofen-CoA into its S-counterpart. Examination of the epimerase activity in various tissues indicated that this metabolism mainly occurred in the liver and kidney.


Activation of TAFI on the surface of Streptococcus pyogenes evokes inflammatory reactions by modulating the kallikrein/kinin system.
Bacteria-controlled regulation of host responses to infection is an important virulence mechanism that has been demonstrated to contribute to disease progression. Here we report that the human pathogen Streptococcus pyogenes employs the procarboxypeptidase TAFI (thrombin-activatable fibrinolysis inhibitor) to modulate the kallikrein/kinin system. To this end, bacteria initiate a chain of events starting with the recruitment and activation of TAFI. This is followed by the assembly and induction of the contact system at the streptococcal surface, eventually triggering the release of bradykinin (BK). BK is then carboxyterminally truncated by activated TAFI, which converts the peptide from a kinin B(2) receptor ligand to a kinin B(1) receptor (B1R) agonist. Finally, we show that streptococcal supernatants indirectly amplify the B1R response as they act on peripheral blood mononuclear cells to secrete inflammatory cytokines that in turn stimulate upregulation of the B1R on human fibroblasts. Taken together our findings implicate a critical and novel role for streptococci-bound TAFI, as it processes BK to a B1R agonist at the bacterial surface and thereby may redirect inflammation from a transient to a chronic state.


Cloning and expression studies of the Dunaliella salina UDP-glucose dehydrogenase cDNA.
The enzyme UDP-glucose dehydrogenase (EC 184.108.40.206) converts UDP-glucose to UDP-glucuronate. Plant UDP-glucose dehydrogenase (UGDH) is an important enzyme in the formation of hemicellulose and pectin, the components of primary cell walls. A cDNA, named DsUGDH, (GeneBank accession number: AY795899) corresponding to UGDH was cloned by RT-PCR approach from Dunaliella salina. The cDNA is 1941-bp long and has an open reading frame encoded a protein of 483 amino acids with a calculated molecular weight of 53 kDa. The derived amino acids sequence shows high homology with reported plants UGDHs, and has highly conserved amino acids motifs believed to be NAD binding site and catalytic site. Although UDP-glucose dehydrogenase is a comparatively well characterized enzyme, the cloning and characterization of the green alga Dunaliella salina UDP-glucose dehydrogenase gene is very important to understand the salt tolerance mechanism of Dunaliella salina. Northern analyses indicate that NaCl can induce the expression the DsUGDH.


[An autopsy case with progressive muscular atrophy: an subtype of lower motor predominant amyotrophic lateral sclerosis].
We report an autopsy case with progressive muscular atrophy of 6 years' duration. The patient was a Japanese woman without any hereditary predisposition to neuropathy. She developed muscle weakness of the upper extremities at 66 years of age, followed by muscle weakness of the lower extremities, fasciculation, and atrophy of the tongue. She died at 72 years of age from fat embolism of the lung. During the clinical course of her illness, neither Babinski sign nor hyperreflexia were present on neurological examination. No respirator support was necessary at any time throughout the clinical course. Neuropathological examinations on autopsy disclosed neuronal loss with gliosis in the hypoglossal nucleus and anterior horns of the spinal cord, but there was no apparent atrophy of the motor cortex or degeneration of the corticospinal tract. No Bunina bodies were detected. Skein-like neuronal cytoplasmic inclusions and glial cytoplasmic inclusions positive for phosphorylated TDP-43 were found in the anterior spinal horn. Grouped muscle fiber atrophy of the tongue indicated neurogenic changes. Based on these clinicopathological findings, our diagnosis for this woman was progressive muscular atrophy, which is defined by progressive degeneration of lower motor neurons. We and other experts believe this represents a lower motor neuron-predominant phenotype of ALS.


Differential Response to NaCl Osmotic Stress in Sequentially Harvested Hydroponic Red and Green Basil and the Role of Calcium.
Basil (Ocimum basilicum L.) is a heterogeneous reservoir of bioactive compounds that provide recognized benefits to human health, rendering it a model aromatic herb. Notwithstanding the application of nutritional stress, such as sodium chloride (NaCl) salinity, which mainly affects the primary metabolism, it also triggers adaptive mechanisms that involve the production of bioactive secondary metabolites. Genotype selection and the exogenous application of calcium chloride (CaCl2) help minimize salinity's suppressive effects on growth. In the present study, we hypothesize that the ratio of different salt types may induce differential responses in the function of preharvest factors in hydroponic basil culture. In this perspective, the stock nutrient solution (Control) was supplemented with 12.5 mm NaCl + 8.33 mm CaCl2 (Moderate Mix), 25 mm NaCl (Moderate NaCl), 25 mm NaCl + 16.66 of CaCl2 (High Mix), or 50 mM of NaCl (High NaCl) with the objective of evaluating the different impact of salinity on yield, sensory quality (color and aroma profile), and the accumulation of minerals and bioactive compounds in two successive harvests of green and red basil cultivars. Although more productive (+39.0% fresh weight) than the red one, the green cultivar exhibited higher susceptibility to salinity, especially under the High Mix and High NaCl treatments. The addition of CaCl2 to the High Mix solution reduced the sodium by 70.4% and increased the total polyphenols by 21.5% compared to the equivalent isomolar solution (High NaCl). The crop performance in terms of fresh and dry yield improved for both cultivars at the second cut. Regardless of cultivar and salt treatment, successive harvests also increased the concentration of phenols and vitamin C (29.7 and 61.5%, respectively) while reducing (-6.9%) eucalyptol, the most abundant aromatic compound in both cultivars. Salinity, as well as the mechanical stress induced by cutting, improved the functional quality of basil. However, the productive responses to the conditions imposed in our work once again highlighted the importance of genetic background. Specifically, CaCl2 in the Moderate Mix solution preserved fresh leaf weight in the most stress-sensitive green cultivar.


The missed opportunities to diagnose and treat iron deficiency in patients hospitalized with heart failure.
Iron Deficiency (ID) is common in heart failure (HF), and is an independent contributor to mortality and morbidity. We examined whether patients with previously known HF who were recently hospitalized, had previous treatment for ID, were investigated for it at the time of hospitalization, and, if ID was found, were prescribed iron on discharge. We examined the records of 76 consecutive patients admitted to our hospital medical wards with a primary diagnosis of HF. Anemia (Hb<12 g/dl) was found in 42/76 patients (55.3%). In 55/76 patients (72.4%) there was no iron workup, in 6 (7.9%) an incomplete iron workup with serum iron, transferrin or ferritin lacking and in 15/76 (19.7%) a complete iron workup. If ID was defined as either a serum ferritin of <100 μg/l or a serum ferritin of 100-299 μg/l and a %Transferrin Saturation of <20% it was found in 12/15 (80%) of those with a complete workup; in 9 of 10 (90%) of the anemic patients and in 3 of 5 (60%) of those non-anemic patients. At discharge 11/15 (73.3%) of those with a complete iron workup were given iron, 10 orally and 1 IV. In those 6 with an incomplete workup 2 were started on oral iron (33.3%) and in those without any workup, 1 of 55 (1.8%) was given oral iron. ID is common in hospitalized HF patients but is usually not sought after by physicians at the time of admission. However if detected the physicians usually treated it.


A new indole alkaloid from the stems of Glycosmis puberula var. craibii.
A phytochemical investigation on the stems of Glycosmis puberula var. craibii led to the isolation of a new indole alkaloid (named glycosmiscrol A, 1), together with four known compounds (2-5). The new structure was elucidated by detailed analysis of comprehensive spectroscopic methods. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1-5 showed significant antiproliferative effects with IC50 values ranging from 0.16 to 8.58 µM.


New paradigm for auditory paired pulse suppression.
Sensory gating is a mechanism of sensory processing used to prevent an overflow of irrelevant information, with some indexes, such as prepulse inhibition (PPI) and P50 suppression, often utilized for its evaluation. In addition, those are clinically important for diseases such as schizophrenia. In the present study, we investigated long-latency paired-pulse suppression of change-related cortical responses using magnetoencephalography. The test change-related response was evoked by an abrupt increase in sound pressure by 15 dB in a continuous sound composed of a train of 25-ms pure tones at 65 dB. By inserting a leading change stimulus (prepulse), we observed suppression of the test response. In Experiment 1, we examined the effects of conditioning-test intervals (CTI) using a 25-ms pure tone at 80 dB as both the test and prepulse. Our results showed clear suppression of the test response peaking at a CTI of 600 ms, while maximum inhibition was approximately 30%. In Experiment 2, the effects of sound pressure on prepulse were examined by inserting prepulses 600 ms prior to the test stimulus. We found that a paired-pulse suppression greater than 25% was obtained by prepulses larger than 77 dB, i.e., 12 dB louder than the background, suggesting that long latency suppression requires a relatively strong prepulse to obtain adequate suppression, different than short-latency paired-pulse suppression reported in previous studies. In Experiment 3, we confirmed similar levels of suppression using electroencephalography. These results suggested that two identical change stimuli spaced by 600 ms were appropriate for observing the long-latency inhibition. The present method requires only a short inspection time and is non-invasive.


Factors regulating competence in transformation of streptococci.
Pakula, Roman (University of Toronto, Toronto, Ontario, Canada). Factors regulating competence in transformation of streptococci. J. Bacteriol. 90:1320-1324. 1965.-The highly transformable group H Streptococcus strain Challis produced an exocellular competence-provoking enzyme capable of converting to the state of competency incompetent cells of the homologous strain, and of the very poorly transformable strain Wicky. The competence-provoking activities of culture filtrates of strain Challis prepared at various periods of growth were tested on cells of strain Wicky. In the first 3 hr of growth, a strict correlation was found between the degree of competence and the competence-provoking activity. The period of maximal competency was followed by a rapid decline, although the competence-provoking activity of the filtrates remained at a maximum. The decay of competence was caused by a change in the structure of the cells which rendered them nonreceptive to the action of the competence-provoking enzyme.


Pre-operative localization of hyperfunctioning parathyroid tissue by parathyroid scintigraphy.
In 22 patients who underwent surgery suspected of primary hyperparathyroidism, the surgical findings were compared with the results obtained by pre-operative parathyroid scanning and biochemical screening. Thirteen of 15 parathyroid adenomas were localized by pre-operative scanning, but in five of them a false positive focus was also described. The technique was less useful in primary hyperplasia. Comparable results were reported by other investigators. In both instances the best results were obtained in patients with high parathyroid activity as measured by plasma calcium, plasma alkaline phosphatase and tubular reabsorption of phosphorus (TRP). Parathyroid scintigraphy was especially helpful in the presence of ectopic adenomas and in patients who had undergone previous parathyroid surgery. Unfortunately, the possibility of false positive results makes it unreliable for the diagnosis of primary hyperparathyroidism.


Rapid turnover of myosin light chain phosphate during cross-bridge cycling in smooth muscle.
The rate of phosphatase-mediated dephosphorylation of the regulatory light chain of smooth muscle myosin was determined under nearly steady-state conditions in permeabilized muscles, from the time course of incorporation of 33P-labeled phosphate into the light chain after the photolytic release of [gamma-33P]ATP from high specific activity caged [gamma-33P]ATP. The extent of myosin light chain phosphorylation is unchanged, and, if the kinase and phosphatase reactions are irreversible, the rate constant for the exponential increase in 33P in the light chain is equal to the rate constant for the phosphatase reaction. Under activated conditions (pCa 4.5) at 20 degrees C, the incorporation of 33P into approximately 80% of the phosphorylated light chain is fit by a single exponential with a rate constant of 0.37 s-1. ATP usage due to phosphorylation and dephosphorylation of the light chain is about one-third of the suprabasal energy requirement. The high phosphatase rate constant suggests that dephosphorylation of the light chain is rapid enough to interact with and potentially modify the completion of the cross-bridge cycle.


Gadkin negatively regulates cell spreading and motility via sequestration of the actin-nucleating ARP2/3 complex.
Regulation of actin dynamics is key to many cell physiological processes, ranging from protrusion formation and control of cell shape to cellular motility, endocytosis, and vesicle movement. The actin-related protein (ARP)2/3 complex is a major actin nucleator organizing branched filament networks in lamellipodial protrusions and during cell migration downstream of nucleation-promoting factors (NPFs). Although many NPFs have been characterized in detail, only few ARP2/3 inhibitors are known. Here, we identify the trans-Golgi network (TGN)/endosomally localized adaptor protein (AP)-1-associated adaptor protein Gadkin as a negative regulator of ARP2/3 function. Loss of Gadkin is associated with a partial redistribution of ARP2/3 to the plasma membrane and with increased cell spreading and migration, phenotypes that depend on the presence of a functional ARP2/3 complex. Gadkin directly binds to ARP2/3 via a conserved tryptophan-based acidic cluster motif reminiscent of ARP2/3-binding sequences of NPFs but fails to facilitate ARP2/3-mediated actin assembly. Consistent with an inhibitory role of Gadkin on ARP2/3 function, ARP2/3 is found on motile Gadkin-containing endosomal vesicles under migration-inhibiting conditions from where it relocalizes to the plasma membrane following activation of NPFs. Together with the observation that Gadkin-mediated inhibition of cell spreading requires its binding to ARP2/3, these data indicate that Gadkin is a negative regulator of ARP2/3 function present on intracellular membranes.


Genotoxicity assessment of vaccine adjuvant squalene.
The genotoxic potential of the vaccine adjuvant Squalene was assessed by the chromosomal aberrations (CAs), sister chromatid exchanges (SCEs) and micronucleus (MNs) tests in human lymphocytes and comet assay in both human and rat lymphocytes. Five different concentrations of squalene (1250-20,000 μg/ml for human lymphocytes and 0.07-1.12 mg/kg for rat lymphocytes) were studied. Squalene did not affect the CAs and MN frequency, in all treatments in vitro. A significant increase in SCEs was observed in almost all concentrations at 24 h treatment. Squalene did not affect significantly the comet tail length (CTL) (except 2500 μg/ml) and comet tail intensity (CTI) at all treatments in vitro. In rats, squalene significantly increased and decreased CTL and CTI in some doses. Although there are increasing and reduction in the effect, squalene cannot be regarded as genotoxic in human lymphocytes. However, further in vivo studies are required to be sure on the effect.


Selective gene transfer into the liver of non-human primates with E1-deleted, E2A-defective, or E1-E4 deleted recombinant adenoviruses.
Preclinical studies were designed to investigate the feasibility and safety of recombinant adenoviruses transduced into the hepatic artery of nonhuman primates. The vectors used are recombinant adenoviruses deleted in E1 and contain either a temperature-sensitive mutation in the E2a gene, which encodes a defective DNA-binding protein at nonpermissive temperatures, or a deletion of the E4 region, including open reading frame (ORF) 6. Six 8- to 10-kg baboons underwent femoral artery cannulation, and angiographic techniques were used to introduce vector selectively into either a portion of the right lobe of the liver via a branch of the right hepatic artery or the common hepatic artery. Necropsies were performed at 4, 29, or 61 days. Serial sequential liver biopsies were performed in the baboons that survived 29 or 61 days. In the 2 baboons with vector transduction into the right hepatic artery, X-Gal histochemical analysis of the liver showed evidence of quantitatively increased gene transfer in the targeted lobe; however, gene transfer was present throughout the liver. Quantitative analysis of histopathology showed that portal inflammation was present throughout both livers transduced with the highest dose of vector. No differences were seen in the level of portal inflammation in targeted and untargeted lobes despite the observed qualitative and quantitative differences in gene expression. Southern blot analysis of total cellular DNA isolated from targeted and nontargeted lobes showed similar levels of viral DNA throughout the liver. Polymerase chain reaction (PCR) analysis was able to detect viral DNA sequence in gonads and brain as well as many other tissues in baboons treated with high-dose vector. In baboons treated with lower doses of an E1-E4 deleted vector expressing the human ornithine transcarbamylase (OTC) gene, DNA was detectable by nested PCR in liver but not gonads at days 29 and 61. The data suggest that intraarterial administration of recombinant adenoviral E1-E4 deleted vector is feasible and safe. At high doses of vector, widespread dissemination of vector DNA is seen. At low doses, hepatic gene transfer is not associated with vector DNA dissemination to gonads.


Headspace single drop microextraction versus dispersive liquid-liquid microextraction using magnetic ionic liquid extraction solvents.
A headspace single drop microextraction (HS-SDME) method and a dispersive liquid-liquid microextraction (DLLME) method were developed using two tetrachloromanganate ([MnCl42-])-based magnetic ionic liquids (MIL) as extraction solvents for the determination of twelve aromatic compounds, including four polyaromatic hydrocarbons, by reversed phase high-performance liquid chromatography (HPLC). The analytical performance of the developed HS-SDME method was compared to the DLLME approach employing the same MILs. In the HS-SDME approach, the magnetic field generated by the magnet was exploited to suspend the MIL solvent from the tip of a rod magnet. The utilization of MILs in HS-SDME resulted in a highly stable microdroplet under elevated temperatures and long extraction times, overcoming a common challenge encountered in traditional SDME approaches of droplet instability. The low UV absorbance of the [MnCl42-]-based MILs permitted direct analysis of the analyte enriched extraction solvent by HPLC. In HS-SDME, the effects of ionic strength of the sample solution, temperature of the extraction system, extraction time, stir rate, and headspace volume on extraction efficiencies were examined. Coefficients of determination (R2) ranged from 0.994 to 0.999 and limits of detection (LODs) varied from 0.04 to 1.0μgL-1 with relative recoveries from lake water ranging from 70.2% to 109.6%. For the DLLME method, parameters including disperser solvent type and volume, ionic strength of the sample solution, mass of extraction solvent, and extraction time were studied and optimized. Coefficients of determination for the DLLME method varied from 0.997 to 0.999 with LODs ranging from 0.05 to 1.0μgL-1. Relative recoveries from lake water samples ranged from 68.7% to 104.5%. Overall, the DLLME approach permitted faster extraction times and higher enrichment factors for analytes with low vapor pressure whereas the HS-SDME approach exhibited better extraction efficiencies for analytes with relatively higher vapor pressure.


Targeting aberrant sialylation and fucosylation in prostate cancer cells using potent metabolic inhibitors.
Aberrant glycosylation is a hallmark of cancer and is not just a consequence, but also a driver of a malignant phenotype. In prostate cancer, changes in fucosylated and sialylated glycans are common and this has important implications for tumour progression, metastasis, and immune evasion. Glycans hold huge translational potential and new therapies targeting tumour-associated glycans are currently being tested in clinical trials for several tumour types. Inhibitors targeting fucosylation and sialylation have been developed and show promise for cancer treatment, but translational development is hampered by safety issues related to systemic adverse effects. Recently, potent metabolic inhibitors of sialylation and fucosylation were designed that reach higher effective concentrations within the cell, thereby rendering them useful tools to study sialylation and fucosylation as potential candidates for therapeutic testing. Here, we investigated the effects of global metabolic inhibitors of fucosylation and sialylation in the context of prostate cancer progression. We find that these inhibitors effectively shut down the synthesis of sialylated and fucosylated glycans to remodel the prostate cancer glycome with only minor apparent side effects on other glycan types. Our results demonstrate that treatment with inhibitors targeting fucosylation or sialylation decreases prostate cancer cell growth and downregulates the expression of genes and proteins important in the trajectory of disease progression. We anticipate our findings will lead to the broader use of metabolic inhibitors to explore the role of fucosylated and sialylated glycans in prostate tumour pathology and may pave the way for the development of new therapies for prostate cancer.


Nuclear Organization in Stress and Aging.
The eukaryotic nucleus controls most cellular processes. It is isolated from the cytoplasm by the nuclear envelope, which plays a prominent role in the structural organization of the cell, including nucleocytoplasmic communication, chromatin positioning, and gene expression. Alterations in nuclear composition and function are eminently pronounced upon stress and during premature and physiological aging. These alterations are often accompanied by epigenetic changes in histone modifications. We review, here, the role of nuclear envelope proteins and histone modifiers in the 3-dimensional organization of the genome and the implications for gene expression. In particular, we focus on the nuclear lamins and the chromatin-associated protein BAF, which are linked to Hutchinson-Gilford and Nestor-Guillermo progeria syndromes, respectively. We also discuss alterations in nuclear organization and the epigenetic landscapes during normal aging and various stress conditions, ranging from yeast to humans.


Chloride-activated passive potassium transport in human erythrocytes.
Passive K+ transport in human erythrocytes (defined as ouabain-insensitive transport) was inhibited 70% by replacement of Cl- by several permeant monovalent anions. The Vmax of Cl--dependent K+ influx was 1.14 mmol . liter-1, hr-1; its apparent Km for K+ was 4.7 mM. There was a much smaller component of Na+ influx dependent on Cl- (Vmax, 0.23 mmol . liter-1 . hr-1). Furosemide and other inhibitors of Cl- transport inhibited passive K+ transport to the same extent as replacement of Cl-, but 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid, a specific inhibitor of anion exchange in erythrocytes, was ineffective. The Cl--dependent K+ transport, which may be K+/Cl- cotransport, could reflect a mechanism for regulating cell volume.


Seasonal Flight, Optimal Timing and Efficacy of Selected Insecticides for Cabbage Maggot (Delia radicum L., Diptera: Anthomyiidae) Control.
In order to describe seasonal flight activity of the cabbage maggot Delia radicum (L.) adults in relation to Julian days (JD), degree-day accumulations (DDA) and precipitation, flight dynamics were followed weekly with the use of yellow sticky traps (YST). Climatic data were collected and DDA were calculated using the lower developmental threshold of 4.3 °C. The efficacy of four insecticides applied either as standard foliar treatment or through dipping the seedlings before transplanting was determined. Seasonal flight activity during the cultivation season of a mid-early variety of white cabbage was correlated with DDA and JD and was characterized by having two peaks. The first peak occurred between 119 ± 7.5 JD and 125.5 ± 8 JD when DDA was 471.35 ± 74.97 °C. The second occurred between 172.8 ± 6.1 JD and 179.3 ± 6.7 JD when DDA was 1,217.28 ± 96.12 °C. The DDA, cumulative capture of flies and JD are suitable for predicting the timing of insecticide application. Spraying with insecticides should be applied when the cumulative capture of flies reaches 100 flies/YST and when DDA reaches 400 °C. If only one parameter reaches the threshold, additional visual surveys should be employed to establish the level of infestation. Insecticides were able to ensure only partial control. In the future, alternative control tactics which employ seed treatments and nonpesticide measures should be investigated in Croatia.


Chromosome instability syndromes.
The chromosome instability syndromes, ataxia telangiectasia (A-T), Fanconi anaemia (FA) and Bloom syndrome (BS) have been known for many years. More recently Nijmegen breakage syndrome (NBS) and ataxia telangiectasia-like disorder (ATLD) have been identified. A-T, ATLD and NBS form a group of disorders all of which show very similar cellular features that result from the consequences of increased sensitivity to ionizing radiation (IR). They also share some clinical features, particularly A-T and ATLD, and all show an immunodeficiency. A-T and NBS both show a predisposition to lymphoid tumours. Fanconi anaemia can be caused by mutations in eight different genes, although the majority of mutations are accounted for by FANCA and FANCC. The very rare Bloom syndrome is caused by mutation in a single gene, BLM. An important feature which all of these disorders have in common is that the genes identified are involved in aspects of recombination repair of DNA damage.


[An unusual case of extensive false aneurysm of the superior gluteal artery].
The authors describe an uncommon case of a false aneurysm of the superior gluteal artery, most probably of post-traumatic aetiology. The condition was resolved by exclusion of the aneurysm from the circulation. In the available literature no reference to a similar clinical finding and its treatment was found.


Syntheses, structures, and magnetic properties of mononuclear CuII and tetranuclear CuII3MII (M = Cu, Co, or Mn) compounds derived from N,N'-ethylenebis(3-ethoxysalicylaldimine): cocrystallization due to potential encapsulation of water.
Syntheses, structures, and magnetic properties of one mononuclear inclusion compound [CuIIL1 within (H2O)] (1) and three tetrametal systems of the composition [{CuIIL1}2{CuIIL1MII(H2O)3}]ClO4)2 (M = Cu (2), M = Co (3), M = Mn (4)) derived from the hexadentate Schiff base compartmental ligand N,N'-ethylenebis(3-ethoxysalicylaldimine) (H2L1) have been described. Compounds 1 and 2 crystallize in orthorhombic Pbcn and monoclinic P21/c systems, respectively, and the space group of the isomorphous compounds 3 and 4 is monoclinic C2/c. The water molecule in 1 is encapsulated in the vacant O4 compartment because of the hydrogen bonding interactions with the ether and phenolate oxygens, resulting in the formation of an inclusion product. The structures of 2-4 consist of the [CuIIL1MII(H2O)3]2+ cation and two mononuclear [CuIIL1] moieties. In the dinuclear [CuIIL1MII(H2O)3]2+ cation, the metal centers are doubly bridged by the two phenolate oxygens. The second metal center, MII (Cu in 2, Co in 3, and Mn in 4), in the [CuIIL1MII(H2O)3]2+ cation is pentacoordinated by the two phenoxo oxygens and three water molecules. Two of these three coordinated water molecules interact, similar to that in 1, with two mononuclear [CuIIL1] moieties, resulting in the formation of the tetrametal [{CuIIL1}2{CuIIL1MII(H2O)3}]2+ system that consists of the cocrystallized dinuclear (one) and mononuclear (two) moieties. Evidently, the cocrystallization observed in 2-4 is related to the tendency of a water molecule to be encapsulated in the vacant O4 compartment of the mononuclear [CuIIL1] species. In the case of 2, there are two independent [CuIIL1CuII(H2O)3]2+ units. The tau ((beta-alpha)/60, where beta and alpha are the largest and second largest bond angles, respectively) values in the pentacoordinated environment of the two copper(II) centers in 2 are 0.04 and 0.37, indicating almost ideal and appreciably distorted square pyramidal geometry, respectively. In contrast, the tau values (0.54 for 3 and 0.49 for 4) indicate that the coordination geometry around the cobalt(II) and manganese(II) centers in 3 and 4 is intermediate between square pyramidal and trigonal bipyramidal. The variable-temperature (2-300 K) magnetic susceptibilities of compounds 2-4 have been measured. The magnetic data have been analyzed in the model of one exchange-coupled dinuclear CuIIMII moiety and two noninteracting CuII centers. In all three cases, the metal ions in the dinuclear core are coupled by a weak antiferromagnetic interaction (J = -17.4 cm-1, -8 cm-1, and -14 cm-1 for 2, 3, and 4, respectively). The observation of a weak interaction has been explained in terms of the structural parameters and symmetry of the magnetic orbitals.


Extending the platinum-free interval with a non-platinum therapy in platinum-sensitive recurrent ovarian cancer. Results from the SOCRATES Retrospective Study.
It has been proposed that extending the platinum-free interval with intervening non-platinum therapy increases the efficacy of a later re-treatment with platinum in platinum-sensitive recurrent ovarian cancer. This hypothesis is based on data from small series and although it has not been validated prospectively, this strategy has entered general practice in Italy in the last years. The SOCRATES study retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000-2002 in 37 Italian centres. Data were collected between April and September 2005. Patients with recurrent ovarian cancer with a platinum-free interval >6 months were eligible. 493 patient files were collected and 428 were eligible and analyzed. The interval from the end of the 1st line to relapse was 6-12 months in 164 patients (39.5%) and >12 months in 251 cases (60.5%). Patients received a 2nd (100%), 3rd (80.1%), 4th (50.2%), 5th (28.3%), and 6th (11.9%) line of chemotherapy. At 2nd line 282 (65.9%) received platinum (group A), while 146 (34.1%) received non-platinum chemotherapy (group B). In the latter group, 67 patients received platinum at later progression (group B1), while 79 never received platinum (group B2). Median time to platinum re-treatment was 20 and 23.1 months in patients of groups A and B1, respectively. The response rate to the first platinum received was 74.4 and 57.4% in groups A and B1, respectively (p = 0.02). Group B2 was characterized by the worst response rate and survival. At multivariate analysis time of first platinum re-treatment (2nd line vs. later; p = 0.0132; OR = 2.34) and age (p = 0.0029; OR = 2.41) was independently associated with a higher possibility of response to platinum. With the limits of a retrospective study, our data question the hypothesis that extending the platinum-free interval with an intervening non-platinum therapy in patients with recurrent platinum-sensitive ovarian cancer improves the response rate of a further platinum re-treatment.


Association Between Grading of Oral Submucous Fibrosis With Frequency and Consumption of Areca Nut and Its Derivatives in a Wide Age Group: A Multi-centric Cross Sectional Study From Karachi, Pakistan.
Oral submucous fibrosis (OSMF) is a chronic, premalignant condition of the oral mucosa and one of the commonest potentially malignant disorders amongst the Asian population. The objective of this study was to investigate the association of etiologic factors with: age, frequency, duration of consumption of areca nut and its derivatives, and the severity of clinical manifestations. A cross-sectional, multi centric study was conducted over 8 years on clinically diagnosed OSMF cases (n = 765) from both public and private tertiary care centers. Sample size was determined by World Health Organization sample size calculator. Consumption of areca nut in different forms, frequency of daily usage, years of chewing, degree of mouth opening and duration of the condition were recorded. Level of significance was kept at P ≤ 0.05. A total of 765 patients of OSMF were examined, of whom 396 (51.8%) were male and 369 (48.2%) female with a mean age of 29.17 years. Mild OSMF was seen in 61 cases (8.0%), moderate OSMF in 353 (46.1%) and severe OSMF in 417 (54.5%) subjects. Areca nut and other derivatives were most frequently consumed and showed significant risk in the severity of OSMF (P ≤ 0.0001). Age of the sample and duration of chewing years were also significant (P = 0.012). The relative risk of OSMF increased with duration and frequency of areca nut consumption especially from an early age of onset.


Initial placement and secondary displacement of a new suture-method catheter for sciatic nerve block in healthy volunteers: a randomised, double-blind pilot study.
We performed a randomised double-blind pilot study in 16 healthy volunteers to investigate the success rate for placing a new suture-method catheter for sciatic nerve block. A catheter was inserted into both legs of volunteers and each was randomly allocated to receive 15 ml lidocaine 2% through the catheter in one leg and 15 ml saline in the other leg. Successful placement of the catheter was defined as a 20% decrease in maximum voluntary isometric contraction for dorsiflexion of the ankle. Secondary outcomes were maximum voluntary isometric contraction for plantar flexion at the ankle, surface electromyography and cold sensation. After return of motor and sensory function, volunteers performed standardised physical exercises; injection of the same study medication was repeated in the same leg and followed by motor and sensory assessments. Fifteen of 16 (94%; 95%CI 72-99%) initial catheter placements were successful. The reduction in maximum voluntary isometric contraction and surface electromyography affected the peroneal nerve more often than the tibial nerve. Eleven of 15 (73%; 95%CI 54-96%) catheters remained functional with motor and sensory block after physical exercise, and the maximal displacement was 5 mm. Catheters with secondary block failure were displaced between 6 and 10 mm. One catheter was displaced 1.8 mm that resulted in a decrease in maximum voluntary isometric contraction of less than 20%. After repeat test injection, 14 of the 16 volunteers had loss of cold sensation. Neither motor nor sensory functions were affected in the legs injected with placebo. We conclude that the suture-method catheter can be placed with a high success rate, but that physical exercise may cause displacement.


Migration and HIV: an epidemiological study of Montrealers of Haitian origin.
We aimed to determine the prevalence of HIV infection and associated risk factors among Montrealers of Haitian origin. We carried out a voluntary, anonymous survey in 7 primary care medical clinics in Montreal among 5039 persons aged 15 to 49 years born in Haiti or with at least one parent born in Haiti. The participation rate was 94.3%. Overall, HIV prevalence was 1.3% (1.6% in men and 1.1% in women). The HIV prevalence was lower among those born in Canada or who had resided in Canada longer. The prevalence among subjects who had travelled to Haiti in the previous 5 years was 2.0%, twice the rate of those who had not. The adjusted population attributable fraction of HIV infections associated with having had unprotected sex in Haiti was 10.2%. This study identified risk factors which will help in the design of more effective prevention programmes among Montrealers of Haitian origin.


[Diagnosis of ductal carcinoma in situ with interruption of the anterior border of the mammary gland by ultrasonography-a case report].
We report a case of ductal carcinoma in situ( DCIS) with interruption of the anterior border of the mammary gland by ultrasonography. The patient was a 41-year-old woman. The patient was identified by a focal asymmetric density on her left breast by screening mammography. Ultrasonography showed an ill-defined low echoic mass, 25 mm in diameter, in the A area of her left breast. The tumor had features consistent with the interruption of the anterior border of the mammary gland. Therefore, she was diagnosed with invasive ductal carcinoma of the breast. We performed a modified radical mastectomy with sentinel lymph node biopsy. A resected specimen led to a diagnosis of DCIS positive for estrogen receptor and progesterone receptor, and negative for HER2/neu protein expression. After surgery, she was administered tamoxifen. One year and 6 months after the operation, she is well without metastases. Ultrasonography is generally useful to differentiate between a DCIS lesion or an invasive ductal carcinoma lesion. However, in this case, we could not diagnose the tumor as DCIS by ultrasonography because the tumor was interrupted by the anterior border of the mammary gland. This case suggests that we should be cautious when diagnosing low echoic tumors with interruption of the anterior border of the mammary gland by ultrasonography.


Surface and tissue forces, surfactant protein A, and the phospholipid components of pulmonary surfactant in bleomycin-induced pulmonary fibrosis in the rat.
Administration of bleomycin to animals results in an alteration of the pressure-volume relationship of the lungs with an increased elastic recoil at any given volume. We sought to evaluate the relative importance of surface forces to elastic recoil by comparing the differences between the air and saline pressure-volume curves. The difference in elastic recoil between air- and saline-filled lungs was altered in bleomycin-treated rats when elastic recoil was compared at 35% of predicted TLC or at 80% of observed TLC. This pressure difference was present both during the early phase (Days 4 and 7) of the injury and acute inflammation as well as during the later phase (Days 14 to 28) when there was chronic inflammation and an elevation in the lung hydroxyproline content. The total amount of phospholipids recovered in lavage was decreased at Day 4 and increased more than 2.5-fold over saline-instilled control animals at Days 21 and 28. The percentage of phosphatidylglycerol was reduced and that of phosphatidylinositol increased. There was no consistent change in the percentage of phosphatidylcholine that was disaturated. The amount of surfactant protein A (SP-A) did not change during the course of the experiment and was not a useful independent marker of alveolar injury or changes in pulmonary compliance. The ratio of SP-A to total phospholipid decreased 14 to 28 days after instillation of bleomycin. These results support the hypothesis that individual components of surfactant are independently regulated and indicate that SP-A content in lavage is insensitive to lung injury and repair.


[Exploring the impact of a group-based tablet-PC training program in older adults].
There are several barriers to older adults using internet and information and communication technology (ICT). It has been suggested that appropriate training is necessary to support the learning process and is an important issue with regards to digital inclusivity for older adults. This study explored the impact of a tablet-PC training program for older adults, provided in a group setting. Thirteen community-dwelling older adults attended the program (ten one and half hour training sessions, taking place once every 2 weeks) and completed pre- and post- assessments. After the intervention, participants showed significantly higher levels of ICT acceptance (87.6 vs. 113.5, p=0.002) and proficiency (109.5 vs. 132.7, p=0.003) than before the intervention. However, they did not showed improvement in feelings of loneliness, symptoms of depression and global cognitive function. Qualitative analyses indicated that the intervention enabled older adults to become more up to date with the information society and promoted tablet-PC acceptance. Although it helped older adults to feel less isolated, it did not enable them to form genuine friendships. The intervention was effective in improving older adults' digital literacy and promoting ICT acceptance, allowing the digital divide to be narrowed.


Decorin interferes with platelet-derived growth factor receptor signaling in experimental hepatocarcinogenesis.
Decorin, a secreted small leucine-rich proteoglycan, acts as a tumor repressor in a variety of cancers, mainly by blocking the action of several receptor tyrosine kinases such as the receptors for hepatocyte, epidermal and insulin-like growth factors. In the present study we investigated the effects of decorin in an experimental model of thioacetamide-induced hepatocarcinogenesis and its potential role in modulating the signaling of platelet-derived growth factor receptor-α (PDGFRα). Genetic ablation of decorin in mice led to enhanced tumor prevalence and a higher tumor count compared with wild-type mice. These findings correlated with decreased levels of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) and concurrent activation (phosphorylation) of PDGFRα in the hepatocellular carcinomas generated in the decorin-null vis-à-vis wild-type mice. Notably, in normal liver PDGFRα localized primarily to the membrane of nonparenchymal cells, whereas in the malignant counterpart PDGFRα was expressed by the malignant cells at their cell surfaces. This process was facilitated by a genetic background lacking endogenous decorin. Double immunostaining of the proteoglycan and the receptor revealed only minor colocalization, leading to the hypothesis that decorin would bind to the natural ligand PDGF rather than to the receptor itself. Indeed, we found, using purified proteins and immune-blot assays, that decorin binds to PDGF. Collectively, our findings support the idea that decorin acts as a secreted tumor repressor during hepatocarcinogenesis by hindering the action of another receptor tyrosine kinase, such as the PDGFRα, and could be a novel therapeutic agent in the battle against liver cancer.


Four channel high power rf source with beam steering based on gyromagnetic nonlinear transmission lines.
The synchronized operation of four gyromagnetic nonlinear transmission lines (NLTLs) was tested with a pulse repetition frequency up to 1 kHz during 1 s bursts. High voltage pulses with a duration of ∼5 ns from the solid state driver S-500 were split into four 48 Ω channels reaching about -200 kV in each channel with ∼10% variation in the amplitude. The maximum peak voltage at the NLTL output was within 220-235 kV with the maximum modulation depth of decaying oscillations up to 90% at the center frequency near 2.1 GHz. The relative delay between channels reached the half-period of the center frequency of oscillations. The associated beam steering by four element array of conical helical antennas was demonstrated in a horizontal plane at 17°. The effective potential of radiation reached 360 kV at the radiation axis. The effect of ferrite temperature on the shock wave velocity in gyromagnetic NLTL is observed.


Accelerating invasion potential of disease vector Aedes aegypti under climate change.
Vector-borne diseases remain a major contributor to the global burden of disease, while climate change is expected to exacerbate their risk. Characterising vector development rate and its spatio-temporal variation under climate change is central to assessing the changing basis of human disease risk. We develop a mechanistic phenology model and apply it to Aedes aegypti, an invasive mosquito vector for arboviruses (e.g. dengue, zika and yellow fever). The model predicts the number of life-cycle completions (LCC) for a given location per unit time based on empirically derived biophysical responses to environmental conditions. Results suggest that the world became ~1.5% more suitable per decade for the development of Ae. aegypti during 1950-2000, while this trend is predicted to accelerate to 3.2-4.4% per decade by 2050. Invasion fronts in North America and China are projected to accelerate from ~2 to 6 km/yr by 2050. An increase in peak LCC combined with extended periods suitable for mosquito development is simulated to accelerate the vector's global invasion potential.


[Early postnatal proliferation of the retinal pigment epithelium cells in the mouse].
A burst of proliferative activity with a maximum of DNA-synthesizing cells on the first day after birth was found in the central zone of the retinal pigment epithelium (RPE) in albino mice from the moment of birth to 9 days of life using radioautography with 3H-thymidine pulse labelling. During this period the central RPE zone, which consists in newborns of mononuclear cells by 95%, gradually transforms in a population with predominance of binuclear cells and fluctuations in the index of labelled nuclei (after the kinetics of cell population in the central RPE zone is similar in mice and rats both in accumulation of binuclear cells and fluctuations in the index of labelled nuclei (after pulse labelling), except that in mice the peak of the index of labelled nuclei is observed earlier than in rats.


Cross-cultural adaptation of the Brazilian version of the Vocal Fatigue Index - VFI.
The purpose of this study was to perform the cultural adaptation of the Brazilian version of the Vocal Fatigue Index (VFI). Two Brazilian bilingual speech-language pathologists (SLP) translated the original version of the VFI in English into Portuguese. The translations were reviewed by a committee of five voice specialist SLPs resulting in the final version of the instrument. A third bilingual SLP back-translated this final version and the same committee reviewed the differences from its original version. The final Portuguese version of the VFI, as in the original English version, was answered on a categorical scale of 0-4 indicating the frequency they experience the symptoms: 0=never, 1=almost never, 2=sometimes, 3=almost always, and 4=always. For cultural equivalence of the Portuguese version, the option "not applicable" was added to the categorical scale and 20 individuals with vocal complaints and dysphonia completed the index. Questions considered "not applicable" would be disregarded from the Brazilian version of the protocol; no question had to be removed from the instrument. The Brazilian Portuguese version was entitled "Índice de Fadiga Vocal - IFV" and features 19 questions, equivalent to the original instrument. Of the 19 items, 11 were related with tiredness of voice and voice avoidance, five concerned physical discomfort associated with voicing, and three were related to improvement of symptoms with rest or lack thereof. The Brazilian version of the VFI presents cultural and linguistic equivalence to the original instrument. The IFV validation into Brazilian Portuguese is in progress.


On the significance of long-term trends in tree-ring N isotopes - The interplay of soil conditions and regional NOx emissions.
As anthropogenic nitrogen (N) emissions have been rising for decades, it is critical to develop natural archives that help understand how natural processes were modified in the past. Tree-ring δ15N values may represent such an indicator but its validity as faithful record of N cycling changes is still debated. Here we produce long-tree-ring δ15N series for five white spruce stands from two boreal regions submitted to moderate industrial N inputs. The obtained δ15N series show sharp differences among stands, even from the same region, despite the fact that they show similar increases in intrinsic water use efficiency (iWUE), a proxy for foliar strategies derived from δ13C values. The statistical modeling of these series and the basal area increment (BAI) of the trees allow to suggest that the mechanisms controlling the isotopic fractionation of N assimilated by tree rings are decoupled from the foliar strategies under the anthropogenic N emissions. The iWUE trends mainly reflect rise of pCO2 and changes in air quality. The long-term δ15N trends echo different biogeochemical processes responding to N deposition due to distinct original soil pH at the various sites. We contend that tree-ring δ15N series can record changes in the forest N cycle, but their rigorous interpretation requires laborious work, particularly an understanding of the biogeochemistry in the soil immediately around the investigated trees. "Seek simplicity and distrust it", Alfred North Whitehead.


Cholesterol plays a decisive role in tetraspanin assemblies during bilayer deformations.
The tetraspanin family plays key roles in many physiological processes, such as, tumour invasion, cell motility, virus infection, cell attachment and entry. Tetraspanins function as molecular scaffolds organized in microdomains with interesting downstream cellular consequences. However, despite their relevance in human physiology, the precise mechanisms of their various functions remain elusive. In particular, the full-length CD81 tetraspanin has interesting cholesterol-related properties that modulate its activity in cells. In this work, we study the opening transition of CD81 under different conditions. We propose that such conformational change is a collaborative process enhanced by simultaneous interactions between multiple identical CD81 tetraspanins. With molecular dynamics simulations we describe the crucial role of a ternary lipid bilayer with cholesterol in CD81 conformational dynamics, observing two emergent properties: first, clusters of CD81 collectively segregate one tetraspanin while favouring one opening transition, second, cumulative cholesterol sequestering by CD81 tetraspanins inhibits large membrane deformations due to local density variations.


A maxillary screw-retained, implant-supported diagnostic wax pattern.
This article describes the fabrication of a screw-retained, implant-supported wax pattern that enables the restorative dentist to predict the outcome of the final prosthesis. The wax pattern also affords the patient an opportunity to evaluate and approve the design of the planned prosthesis, thereby enhancing communication between the dentist and patient.


The Relationship Between Atrial Cardiopathy Biomarkers and Prognosis of Patients With Embolic Stroke of Undetermined Source.
To compare the proportion of atrial cardiopathy in patients with embolic stroke of undetermined source (ESUS) and other non-cardiac strokes, and to evaluate the prognostic value of atrial cardiopathy biomarkers in patients with ESUS. This retrospective study enrolled patients with ischemic stroke from January 2018 to April 2020 in a single stroke center, and compared the proportion of atrial cardiopathy in (1) ESUS group, (2) large artery atherosclerosis (LAA) group, and (3) small-vessel occlusion (SVO) group. Then, it compared the baseline characteristics between ESUS patients with atrial cardiopathy and cardioembolism (CE) group. In addition, the relationship was compared between the biomarkers of atrial cardiopathy and prognosis in patients with ESUS. In total, 316 patients with ischemic stroke were included that included 105 (33.23%) ESUS, 84 (26.58%) LAA, 73 (23.10%) SVO, and 54 (17.09%) CE. Among these patients, patients with ESUS were younger, and had lower triglyceride, lower low-density lipoprotein than non-ESUS group. The proportion of atrial cardiopathy in ESUS group was higher than LAA group or SVO group (42.86 vs. 17.86 vs. 8.22%, p < 0.001). Compared with non-atrial cardiopathy group, patients with atrial cardiopathy were older, had lower EF value, larger left ventricular diameter, and longer PR interval. Among 105 patients with ESUS, 11 (10.78%) cases died, 32 (31.37%) cases had poor functional outcome (mRS >2). In the multivariable model, the risk factor associated with the death risk of patients with ESUS was N-terminal pro-B-type natriuretic peptide (NT-proBNP) >250 pg/ml [p = 0.025, hazard ratio (HR) = 4.626, 95% CI: 1.212-17.652] after a 1-year follow-up. Atrial cardiopathy is more common in patients with ESUS, and the characteristics of ESUS patients with atrial cardiopathy are similar to those in patients with CE. NT-proBNP >250 pg/ml is related to the risk of death in patients with ESUS.


Tyrosine kinase domain mutations of EGFR gene in head and neck squamous cell carcinoma.
Epidermal growth factor receptor (EGFR) is a commonly altered gene that is identified in various cancers, including head and neck squamous cell carcinoma (HNSCC). Therefore, EGFR is a promising molecular marker targeted by monoclonal antibodies and small molecule inhibitors targeting the tyrosine kinase (TK) domain. The objective of this study was to investigate the spectrum of mutations in exons 18, 19, 20, and 21 of the EGFR gene in HNSCC patients. This retrospective study included 47 confirmed HNSCC cases. Mutations in the TK domain, exons 18, 19, 20, and 21 of the EGFR gene, were detected by Scorpion® chemistry and ARMS® technologies on Rotor-Gene Q real-time polymerase chain reaction. The tumors exhibited EGFR-TK domain mutations in 57% of cases. Four cases of T790M mutations were reported for the first time among HNSCC patients. Out of the total mutations, L861Q (exon 21), exon 20 insertions and deletions of exon 19 accounted for the majority of mutations (21%, 19%, and 17%, respectively). EGFR mutation status was correlated with the higher grade (P=0.026) and advanced stage (P=0.034) of HNSCC tumors. Higher frequency of EGFR-TK domain mutations together with the presence of the T790M mutation suggests that identification of these mutations might streamline the therapy and provide a better prognosis in HNSCC cases.


Physical activity containing behavioural interventions for adults living with modifiable chronic non-communicable diseases in Africa: a systematic mixed-studies review.
Physical activity improves physiological, cognitive and psychosocial functioning in chronic non-communicable diseases (NCDs). This study reviewed papers on the effects and patients' experiences of physical activity interventions for chronic NCDs in Africa. We conducted a systematic review of clinical and qualitative studies by searching eight bibliographic databases and grey literature until 19 April 2017. The mixed-methods appraisal and Cochrane Collaboration's tools were used for quality and risk of bias assessments. Three-stage sequential explanatory syntheses were done. One randomized controlled trial (RCT), two non-controlled before and after studies and two qualitative studies of diabetic South African and Reunion patients were included. Exercise and sports unrelated to home and occupational activities were increased in the long term (1 year, moderate quality evidence) and short term immediately after a 4-week intervention (low quality evidence). There was conflicting evidence of intervention effects on home and occupational physical activities. Behaviour-change techniques improving chronic disease knowledge, addressing environmental barriers and stimulating/supporting physical activity were important to patients. Procedure-related components-health professional training and adequate health facilities-were important to patients, but were not addressed. High quality RCTs are needed to confirm the intervention components for improving physical activity for chronic NCD management in Africa.


Modified PAMAM vehicles for effective TRAIL gene delivery to colon adenocarcinoma: in vitro and in vivo evaluation.
TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) gene therapy is considered as one of the promising approaches for cancer treatment. Polyamidoamine (PAMAM) is one of the most extensively applied polymeric vector in gene delivery. In the current study, PAMAM (G4 and G5) dendrimers were modified with alkyl-carboxylate chain, PEG and cholesteryl chloroformate in order to enhance transfection efficiency through overcoming extracellular and intracellular barriers while reducing PAMAM cytotoxicity. Gene delivery efficiency of synthetized vectors was evaluated by both GFP (green fluorescent protein) reporter gene and TRAIL plasmid in colon cancer cells, in vitro and in vivo. The obtained results demonstrated that PAMAM G4-alkyl-PEG (3%)-Chol (5%)-TRAIL complexes at C/P ratio 4 could significantly increase cell death (29.45%) in comparison with unmodified PAMAM vector (15.5%). Moreover, in vivo study in C26 tumor-bearing BALB/c mice suggested that the prepared non-toxic safe vector could inhibit the tumor growth. This study represented the potent vehicle based on cholesterol-grafted PAMAM dendrimers with alkyl-PEG modification for efficient gene delivery in vitro and in vivo.


Targeted inhibition of histone deacetylase 6 in inflammatory diseases.
Targeting epigenetic modification of gene expression represents a promising new approach under investigation for the treatment of inflammatory diseases. Accumulating evidence suggests that epigenetic mechanisms, such as histone modification, play a crucial role in a number of inflammatory diseases, including rheumatoid arthritis, asthma, and contact hypersensitivity. Consistent with this role, histone deacetylase (HDAC) inhibitors have shown efficacy in the treatment of inflammatory diseases. In particular, selective inhibitors of HDAC6, a cytoplasmic member of the HDAC family that contains two deacetylase domains, are under investigation as a potential treatment strategy for inflammatory diseases due to their ability to regulate inflammatory cells and cytokines. Here, we review recent findings highlighting the critical roles of HDAC6 in a variety of inflammatory diseases, and discuss the therapeutic potential of HDAC6 inhibitors in these settings.


Phenotypic and functional characterization of pharmacologically expanded Vγ9Vδ2 T cells in pigtail macaques.
While gaining interest as treatment for cancer and infectious disease, the clinical efficacy of Vγ9Vδ2 T cell-based immunotherapeutics has to date been limited. An improved understanding of γδ T cell heterogeneity across lymphoid and non-lymphoid tissues, before and after pharmacological expansion, is required. Here, we describe the phenotype and tissue distribution of Vγ9Vδ2 T cells at steady state and following in vivo pharmacological expansion in pigtail macaques. Intravenous phosphoantigen administration with subcutaneous rhIL-2 drove robust expansion of Vγ9Vδ2 T cells in blood and pulmonary mucosa, while expansion was confined to the pulmonary mucosa following intratracheal antigen administration. Peripheral blood Vγ9Vδ2 T cell expansion was polyclonal, and associated with a significant loss of CCR6 expression due to IL-2-mediated receptor downregulation. Overall, we show the tissue distribution and phenotype of in vivo pharmacologically expanded Vγ9Vδ2 T cells can be altered based on the antigen administration route, with implications for tissue trafficking and the clinical efficacy of Vγ9Vδ2 T cell immunotherapeutics.


Pathogenicity & virulence of Histoplasma capsulatum - A multifaceted organism adapted to intracellular environments.
Histoplasmosis is a systemic mycosis caused by the thermally dimorphic fungus Histoplasma capsulatum. Although healthy individuals can develop histoplasmosis, the disease is particularly life-threatening in immunocompromised patients, with a wide range of clinical manifestations depending on the inoculum and virulence of the infecting strain. In this review, we discuss the established virulence factors and pathogenesis traits that make H. capsulatum highly adapted to a wide variety of hosts, including mammals. Understanding and integrating these mechanisms is a key step toward devising new preventative and therapeutic interventions.


Identification of novel RARbeta2 transcript variants with short 5'-UTRs in normal and cancerous breast epithelial cells.
Functional significance of RARbeta2 as a putative tumor suppressor gene has been studied in breast cancer and other tumors. The long 5'-untranslated region (5'-UTR) of its transcript with multiple open-reading frames (uORFs) is considered as a regulatory unit for translation. Here, for the first time we identified RARbeta2 transcript variants with short 5'-UTRs in both normal and malignant breast epithelial cells. The 5'-RACE analysis of RARbeta2 mRNA in these cells demonstrated the existence of short RARbeta2 transcript variants that are identical to the sequence of known RARbeta2, but lack all the uORFs present in the full-length 5'-UTR. By RT-PCR analysis, we found that the expression of both transcripts with short and full-length 5'-UTR is mediated by retinoic acid, while cellular sensitivity is preferentially correlated to upregulation of short RARbeta2 transcript variants in response to retinoic acid. The transfection and in vitro translation assay indicated that the short 5'-UTR has no inhibitory effects on translation, while the presence of full-length 5'-UTR inhibited translation by 60%. In addition, no promoter activity was detectable in RARbeta2 full-length 5'-UTR region. Our data suggest that the RARbeta2 transcript variants with short 5'-UTR may serve as major transcripts for RARbeta2 protein translation as well as potential targets for retinoids in breast cancer prevention and therapy studies.


Description of Pintomyia salomoni sp. n., a new phlebotomine species from northwest Argentina.
A new species of phlebotomine sandfly is described and illustrated using male and female specimens collected in the provinces of Jujuy and Tucumán, Argentina. Both male and female morphological characters allow the inclusion of the new species within the Pintomyia genus, Pifanomyia subgenus, serrana series (Diptera: Psychodidae). The species was denominated as Pintomyia salomoni n. sp., and is closely related to Pintomyia (Pifanomyia) torresi and Pintomyia (Piffanomyia) boliviana.


Applicational possibilities of linear and non-linear (polynomial) regression and analysis of variance. III. Stability determination of pharmaceutical preparations: stability of diclofenac-sodium in Diclofen injections.
This paper presents the application of the regression analysis program and the program for comparing linear regressions (modified method for one-way, analysis of variance), writtens in BASIC program language, for instance, determination of content of Diclofenac-Sodium (active ingredient in DIKLOFEN injections, ampules á 75 mg/3 ml). Stability testing of Diclofenac-Sodium was done by isothermic method of accelerated aging at 4 different temperatures (30 degrees, 40 degrees, 50 degrees and 60 degrees C) as a function of time (4 different duration of treatment: (0-155, 0-145, 0-74 and 0-44 days). The decrease in stability (decrease in the mean value of the content of Diclofenac-Sodium (in %), at different temperatures as a function of time, is possible to describe by, linear dependance. According to the value for regression equation values, the times are assessed in which the content of Diclofenac-Sodium (in %) will decrease by 10%, of the initial value. The times are follows at 30 degrees C 761.02 days, at 40 degrees C 397.26 days, at 50 degrees C 201.96 days and at 60 degrees C 58.85 days. The estimated times (in days) in which the mean value for Diclofenac-Sodium content (in %) will by 10% of the initial values, as a junction of time, are most suitably described by 3rd order parabola. Based on the parameter values which describe the 3rd order parabola, the time was estimated in which Diclofenac-Sodium content mean value (in %) will fall by 10% of the initial one at average ambient temperatures of 20 degrees C and 25 degrees C. The times are: 1409.47 days (20 degrees C) and 1042.39 days (25 degrees C). Based on the value for Fischer's coefficien (F), the comparison of trenf of Diclofenac-Sodium content (in %) shows that, under the influence of different temperatures as a function of time, among them, depending on temperature value, there is: statistically very significant difference (P << .05) at 50 degrees C and lower toward 60 degrees C, i.e. statistically probably significant difference (P > 0.01) at 40 degrees C and lower towards 50 degrees C and there is no statistically significance difference (P >> 0.05) at 30 degrees C towards 40 degrees C.


Management of functional, hepatic damage after chemotherapy with Liverubin (pharma-standard silymarin).
Mild, temporary hepatic failure (MTHF) after chemotherapy is a common clinical problem; in case of repeated episodes MTHF may cause chronic impairment. This registry has evaluated post- chemotherapy (PC)-MTHF in subjects using Liverubin (standardized Silymarin) for 8 weeks (3 capsules/day). PC-MTHF was evaluated in a registry study. Hepatitis markers were negative at inclusion and at end-registry. In the final registry there were results concerning 18 Liverubin-supplemented patients and 19 controls completing the 8-week period. Signs/symptoms. The distribution of the most common symptoms and signs with ultrasound scans were comparable. Symptoms were mostly minimal or subclinical. Most symptoms observed at inclusion were completely disappeared or greatly attenuated after 8 weeks. The improvement produced by Liverubin induced a better and faster disappearance of symptoms. The results of the blood tests (at inclusion and at 8 weeks showed the increase in albumin, significantly (P<0.05) faster with the final values higher in the supplement group. Total bilirubin was reduced with the supplement better than in controls (P<0.05). Direct bilirubin values improved more in the supplement (P<0.05) group. The decrease in SGPT and AST-ASAT was more evident with the supplement (P<0.05). Improvement in controls was more limited. Alkaline phosphatase was significantly lower (than in controls) with Liverubin at 8 weeks (p<0.05). Gamma GT also decreased more and faster with the supplement. The ESR (erythrocytes sedimentation rate) was decreased in both groups, more in the Liverubin group (P<0.05). There was a more limited decrease in controls with persisting higher values at 8 weeks. The white cell count was also better at 3 months (with a larger decrease with the supplement; P<0.05). Oxidative stress. Plasma free radicals (PFR) were elevated in both groups at inclusion. A more significant decrease in the supplement group was observed at 8 weeks. Persisting elevation in values was seen in controls (P<0.05). Platelets values improved better with Liverubin (P<0.05). Safety and tolerability were optimal (no side effect was registered). In conclusion, results from this pilot registry indicate a significant activity of Liverubin associated with a very good safety profile, in patients with post-chemotherapy hepatic failure. The recovery of hepatic function is faster and more effective with Liverubin in comparison with the best "standard" management.


Comparative Study of Four Chemometric Methods for the Quantitative Analysis of the Carbon Content in Coal by Laser-Induced Breakdown Spectroscopy Technology.
Coal is a heterogeneous mineral substance mainly composed of carbon, along with various amounts of other elements. The carbon content is an important and pertinent parameter for coal quality. To achieve the rapid and accurate online measurement of the carbon content in coal, four different calibration strategies are applied to coal analysis by laser-induced breakdown spectroscopy (LIBS). Four calibration models based on support vector regression (SVR), back-propagation training (BP), random forest (RF), and partial least-squares regression (PLSR) were proposed, and the prediction accuracy, prediction precision, model stability, and training velocity of the four calibration models were compared for the quantitative analysis of the carbon content. A total of 65 coal samples were ablated, and the plasma spectra were used as the input data. Among the four calibration models, the results indicate that SVR and BP are the most promising calibration models for finding a better optimized model with a better prediction accuracy and prediction precision, and PLSR has a better prediction stability and a faster training velocity; however, RF has a prediction performance worse than those of the other three models.


The Information-Motivation-Behavioral Skills Model Revisited: A Network-Perspective Structural Equation Model Within a Public Sexually Transmitted Infection Clinic Sample of Hazardous Alcohol Users.
The information-motivation-behavioral skills (IMB) model is useful for understanding sexual risk behavior, but has not been tested with hazardously-drinking sexually transmitted infection (STI) clinic patients, a subpopulation at greater HIV risk, or with a network-perspective sexual risk behavior outcome. Participants (N = 569) were STI clinic patients who screened positive for hazardous drinking and risky sexual behavior. Sexual risk behavior (SRB) was operationalized as a latent variable with three indicators: (1) number of sexual partners, (2) number of unprotected sex occasions with primary partner, and (3) number of unprotected sex occasions with non-primary partner(s). Preliminary analyses suggested SRB was best operationalized as a latent variable with two indicators, while unprotected sex with primary partners should be considered separately. In structural models with good fit, the IMB model was generally supported. The IMB model functioned differently for non-primary and multiple partners compared to primary partners in STI clinic patients with hazardous alcohol use.


Plunging ranula: surgical management of case series and the literature review.
Plunging ranulas are rare; report of this condition is particularly limited in our environment. We present case series in children; with all cases having both oral and cervical components. It is important to note this type of presentation of plunging ranula and their appropriate management.


The tetraspanin CD9 mediates lateral association of MHC class II molecules on the dendritic cell surface.
We have found that MHC class II (MHC II) molecules exhibit a distinctive organization on the dendritic cell (DC) plasma membrane. Both in DC lysates and on the surface of living cells, I-A and I-E molecules engaged in lateral interactions not observed on other antigen-presenting cells such as B blasts. Because DCs and B blasts express MHC II at comparable surface densities, the interaction was not due to simple mass action. Instead, it reflected the selective expression of the tetraspanin CD9 at the DC surface. I-A and I-E molecules coprecipitated with each other and with CD9. The association of heterologous MHC II molecules was abrogated in DCs from CD9(-/-) mice. Conversely, expression of exogenous CD9 in B cells induced MHC II interactions. CD9 is thus necessary for the association of heterologous MHC II, a specialization that would facilitate the formation of MHC II multimers expected to enhance T cell receptor stimulation by DCs.


Role of CD10 Immunoexpression in Grading Phyllodes Tumour of the Breast.
Fibroepithelial tumours are a heterogeneous group of biphasic neoplasms consisting of a proliferation of both epithelial and stromal components. Fibroadenoma (FA) and Phyllodes Tumour (PT) constitute the major entities. It is crucial to distinguish benign from borderline PT (low grade malignant PT), because the former do not metastasize, have a lesser risk of local recurrence and initial local recurrences are histologically benign in almost all instances. Multiple Immunohistochemical (IHC) markers are being studied to find their utility in grading the PT accurately for planning proper treatment. To study, the IHC expression of CD10 in the stromal cells of a series of PTs and FA, with the aim of determining whether the degree of CD10 expression in the stromal cells is related to the grade of the tumour. Records of 28 cases of PT and 35 cases of FA received in the Department of Pathology in a tertiary care hospital were obtained. Histopathology reports and slides of all the cases were reviewed and clinical data such as age and histomorphological features such as tumour cellularity, stromal overgrowth, mitotic count and nuclear atypia were noted. Representative block of the tumour with maximum cellularity was subjected to CD10 staining. For FA and benign PT a technique of tissue microarray was used. For borderline and malignant PT, representative section was used. Stromal cell staining was assessed, using cytoplasmic staining of the breast myoepithelium as internal control. Present study included 35 cases of FA, 20 cases of benign PT, five cases of borderline PT and three cases of malignant PT. The mean age of the patients increased with the increasing tumour grade of PT and this was also observed for FA and benign PT. The mean age increased with increase in tumour grade of PT and was statistically significant (p<0.05). The mean size did not increase with the increasing tumour grade of PT and was statistically insignificant (p=0.0429). Mean tumour size was more in benign PT as compared to FA and was highly statistically significant (p<0.01). CD10 staining was diffuse (Grade-3) and strong in malignant PT. The staining intensity was strong but patchy (Grade-2) in borderline PT. Weak and patchy (Grade-1) CD10 staining was seen in four benign PT and six FA. Other cases of benign PT and FA were negative for CD10 immunoreactivity. Our study showed that CD10 expression strongly correlates with the PT grade, which can help in the differentiation between benign and malignant variants of PT.


Cost-effectiveness analysis of liver transplantation in biliary atresia according to the severity of end-stage liver disease.
Timing for liver transplantation (LT) in biliary atresia (BA) children with end-stage liver disease (ESLD) is associated with all-cause mortality. The cut-off value of pediatric end-stage liver disease (PELD) score for LT consideration varies across institutions. We aimed to determine the cost-effectiveness of LT to prevent death among BA children registered on the waiting list with different severities of ESLD. Subjects were BA children aged < 12 years at a transplant center between 2010 and 2021. A decision tree was developed for cost-effectiveness analysis from a hospital perspective to compare all-cause death between patients initially registered with a low PELD score (< 15) and a high PELD score (≥ 15). Each patient's direct medical cost was retrieved from the beginning of registration until 5 years after LT, adjusted with an inflation rate to 2022 Thai Baht (THB). Among 176 children, 138 (78.4%) were initially registered with the high PELD score. The cost and mortality rate of the low PELD score group (THB1,413,424 or USD41,904 per patient and 31.6% mortality) were less than the high PELD score group (THB1,781,180 or USD52,807 per patient and 47.9% mortality), demonstrating the incremental cost-effectiveness ratio (ICER) of THB2,259,717 or USD66,994 per death prevented. The cost of early post-operative admission had the highest effect on the ICER. Considering the break-even analysis, cost among children initially registered at the low PELD score was also less expensive over time. Registration for LT at PELD score < 15 was more cost-effective to prevent death among BA children with ESLD.


Electron microscopy of Friend murine leukemia virus in the mid-gut of experimentally infected mosquitoes.
After 30 and 78 hr, Friend murine leukemia virus (FLV) particles were detected by electron microscopy in the mid-gut lumen of the mosquitoes Aedes aegypti (Linnaeus) and Anopheles stephensi Liston which had fed on leukemia BALB/c mice infected with FLV. Various developmental stages of the virions were observed within and on the surface of ingested blood cells, particularly young erythroblasts, as well as free in the lumen after budding. These preliminary findings indicate that FLV continues to multiply in the mid-gut of these species for at least 3 days despite the action of digestive enzymes. Detailed studies are in progress to determine the fate of FLV in these mosquito species.


[Blood transfusion and ethics: new questions].
Chairman to the French Institutional Review Board, Professor Didier Sicard raises blood donation issues from an ethical standpoint. The contaminated blood scandal focused on the necessity of reducing transfusion risks and regarded blood safety as an ethical mandatory requirement, a debatable subject to deal with. The author proposes to reconsider the nature of unpaid blood donations while advising not to scorn the remunerated gift when such is the case. As for the use of blood, he questions the solutions based on a zero risk perspective, in particular an excessive auto-transfusional practice or a restrictive use of blood, lately regarded as essential. Starting from the blood donation concern this article leads us to think over both our society's fears and the precautionary principle abuses.


Graphitic Carbon Nitride Polymers toward Sustainable Photoredox Catalysis.
As a promising two-dimensional conjugated polymer, graphitic carbon nitride (g-C3 N4 ) has been utilized as a low-cost, robust, metal-free, and visible-light-active photocatalyst in the field of solar energy conversion. This Review mainly describes the latest advances in g-C3 N4 photocatalysts for water splitting. Their application in CO2 conversion, organosynthesis, and environmental purification is also briefly discussed. The methods to modify the electronic structure, nanostructure, crystal structure, and heterostructure of g-C3 N4 , together with correlations between its structure and performance are illustrated. Perspectives on the challenges and opportunities for the future exploration of g-C3 N4 photocatalysts are provided. This Review will promote the utilization of g-C3 N4 materials in the fields of photocatalysis, energy conversion, environmental remediation, and sensors.


Risk assessment for invasive species produces net bioeconomic benefits.
International commerce in live organisms presents a policy challenge for trade globalization; sales of live organisms create wealth, but some nonindigenous species cause harm. To reduce damage, some countries have implemented species screening to limit the introduction of damaging species. Adoption of new risk assessment (RA) technologies has been slowed, however, by concerns that RA accuracy remains insufficient to produce positive net economic benefits. This concern arises because only a small proportion of all introduced species escape, spread, and cause harm (i.e., become invasive), so a RA will exclude many noninvasive species (which provide a net economic benefit) for every invasive species correctly identified. Here, we develop a simple cost:benefit bioeconomic framework to quantify the net benefits from applying species prescreening. Because invasive species are rarely eradicated, and their damages must therefore be borne for long periods, we have projected the value of RA over a suitable range of policy time horizons (10-500 years). We apply the model to the Australian plant quarantine program and show that this RA program produces positive net economic benefits over the range of reasonable assumptions. Because we use low estimates of the financial damage caused by invasive species and high estimates of the value of species in the ornamental trade, our results underestimate the net benefit of the Australian plant quarantine program. In addition, because plants have relatively low rates of invasion, applying screening protocols to animals would likely demonstrate even greater benefits.


Systematic review of errors on beta-2 transferrin gel electrophoresis testing of rhinorrhea and otorrhea.
Beta-2 transferrin (B2-Tf) gel electrophoresis (GE) is the preferred non-invasive diagnostic modality for confirming cerebrospinal fluid (CSF) in body fluids. While B2-Tf GE testing is highly sensitive and specific for CSF, false-positive (FP) and false-negative (FN) results can lead to diagnostic and therapeutic dilemmas. Several series have demonstrated potential causes of false B2-Tf GE results, but few studies have reported reasons for these errors. The purpose of this systematic review was to describe sources of B2-Tf GE errors. A systematic review was performed by searching OVID, EMBASE, and Web of Science databases for B2-Tf GE studies. After applying exclusion criteria, original research studies directly addressing erroneous B2-Tf GE results underwent qualitative analysis. Of the 243 abstracts screened, 71 underwent full-text review and 18 studies reporting B2-Tf GE errors were included for analysis. There were 15 potential FPs, 12 actual FPs, 12 potential FNs, 19 actual FNs, and 14 indeterminate results. There were also 246 potentially indeterminate results from in vitro studies. Reasons for B2-Tf GE errors included serum transferrin alterations (n = 17; all potential), infection related (n = 13; 9 potential), orbital or salivary contamination (n = 2; 1 potential), and collection related (n = 255; 246 potential). There were 31 false or indeterminate results with unspecified reasons. There were no reported errors due to laboratory processing. Multiple potential or actual reasons for false or indeterminate results have been reported for B2-Tf GE testing of rhinorrhea and otorrhea. Future studies should explore reasons for B2-Tf testing errors and how these may affect clinical decision making.


Antiviral properties of copper and its alloys to inactivate covid-19 virus: a review.
Copper (Cu) and its alloys are prospective materials in fighting covid-19 virus and several microbial pandemics, due to its excellent antiviral as well as antimicrobial properties. Even though many studies have proved that copper and its alloys exhibit antiviral properties, this research arena requires further research attention. Several studies conducted on copper and its alloys have proven that copper-based alloys possess excellent potential in controlling the spread of infectious diseases. Moreover, recent studies indicate that these alloys can effectively inactivate the covid-19 virus. In view of this, the present article reviews the importance of copper and its alloys in reducing the spread and infection of covid-19, which is a global pandemic. The electronic databases such as ScienceDirect, Web of Science and PubMed were searched for identifying relevant studies in the present review article. The review starts with a brief description on the history of copper usage in medicine followed by the effect of copper content in human body and antiviral mechanisms of copper against covid-19. The subsequent sections describe the distinctive copper based material systems such as alloys, nanomaterials and coating technologies in combating the spread of covid-19. Overall, copper based materials can be propitiously used as part of preventive and therapeutic strategies in the fight against covid-19 virus.


Donor failure after corneal transplantation surgery.
Donor failure refers to graft edema present within the first 24 h after penetrating keratoplasty that persists in spite of maximal medical therapy. We reviewed the case histories of 1,351 penetrating keratoplasties. Of these, 17 (1.2%) were considered donor failures. Five cases were histopathologically consistent with Fuchs' dystrophy. Seven cases demonstrated mechanical stripping of the endothelium. Five cases, all from the same eye bank, revealed an absence of posterior stromal keratocytes. Storage medium at the eye bank of origin was found to have an alkaline pH. Careful preoperative evaluation of donor corneas is emphasized, but if an apparent "epidemic" of donor failure occurs, a thorough investigation of the eye bank methodology should be initiated.


Prognostic significance of personality profiles in patients with chronic migraine.
The aim of this study was to assess whether the psychological profile may have prognostic significance in chronic migraine patients. The Minnesota Multiphasic Personality Inventory-2 was used for the psychological assessment of patients with chronic migraine to explore personality traits. Patients with psychiatric disease and medication overuse were excluded. One hundred and two patients completed the study. Migraine-related disability was measured using the Migraine Disability Assessment questionnaire at baseline (T(0)) and again after 2 years (T(1)), during which patients received prophylactic treatment for migraine. At T(1) patients were classified into those exhibiting significant improvement (group 1: scores reduced by at least 50%) and those with unsatisfactory changes in headache-related disability (group 2: scores reduced by less than 50%). At T(1) 49 patients were in group 1 and 53 in group 2; at T(0), group 1 patients had significantly lower Minnesota Multiphasic Personality Inventory-2 scores in the neurotic (hypochondriasis: P < .01; depression: P < .001; hysteria: P < .01) and schizophrenia (P < .05) scales. None of the other variables studied, ie, age, sex, age at migraine onset, number of years from chronic migraine onset, T(0) Migraine Disability Assessment score, T(0) headache frequency, severity and temporal pattern (continuous vs intermittent) differed significantly between the groups. Findings suggest that psychological factors can influence the clinical course of chronic migraine and that psychological evaluation with Minnesota Multiphasic Personality Inventory-2 may be a reliable approach to obtain prognostic data and information for therapy planning in patients with chronic migraine.


Synergistic Activity of an Antimetabolite Drug and Tyrosine Kinase Inhibitors against Breast Cancer Cells.
Antimetabolite drugs, including the adenosine deaminase inhibitor cladribine, have been shown to induce apoptosis in a variety of cancer cells, and have been widely used in clinical trials of various cancers in conjunction with tyrosine kinase inhibitors (TKIs). Combination treatment with cladribine and gefitinib or dasatinib is expected to have a synergistic inhibitory effect on breast cancer cell growth. Our results demonstrated that the combination treatment had synergistic activity against human breast cancer (MCF-7) cells, enhanced G2/M cell arrest and reactive oxygen species (ROS) generation, and increased the loss of mitochondrial membrane potential and cell apoptosis. In addition, the combination treatment decreased Bcl-2 expression. Our results demonstrated that cladribine in combination with gefitinib or dasatinib exerted synergistic anticancer effects on MCF-7 cells by inducing cell cycle arrest, ROS production and apoptosis through the mitochondria-mediated intrinsic pathway.


Palliative social work in the emergency department.
Recognizing that seriously ill patients and their families utilize emergency departments (EDs) for distressing symptoms, changing goals of care, or at the end of life, palliative care and emergency medicine departments are partnering to enhance the care provided to patients with life-limiting illnesses and their families. A social work model for identifying patients with unmet palliative care needs in the ED is included to illustrate the process as well as specific psychosocial interventions that palliative social workers can provide in this environment. As increasing numbers of palliative and emergency medicine departments partner to both improve ED care for patients with life-threatening illness and initiate palliative care consults earlier in hospitalizations, palliative and ED social workers have an opportunity to join their physician and nurse colleagues who are making inroads in this important and growing area.


A threat-detection advantage in those with autism spectrum disorders.
Identifying threatening expressions is a significant social perceptual skill. Individuals with autism spectrum disorders (ASD) are impaired in social interaction, show deficits in face and emotion processing, show amygdala abnormalities and display a disadvantage in the perception of social threat. According to the anger superiority hypothesis, angry faces capture attention faster than happy faces in individuals with a history of typical development [Hansen, C. H., & Hansen, R. D. (1988). Finding the face in the crowd: An anger superiority effect. Journal of Personality and Social Psychology, 54(6), 917-924]. We tested threat detection abilities in ASD using a facial visual search paradigm. Participants were asked to detect an angry or happy face image in an array of distracter faces. A threat-detection advantage was apparent in both groups: participants showed faster and more accurate detection of threatening over friendly faces. Participants with ASD showed similar reaction time, but decreased overall accuracy compared to controls. This provides evidence for less robust, but intact or learned implicit processing of basic emotions in ASD.


Refractory coeliac disease in a country with a high prevalence of clinically-diagnosed coeliac disease.
Refractory coeliac disease (RCD) is thought to be a rare disorder, but the accurate prevalence is unknown. We aimed to identify the prevalence of and the risk factors for developing RCD in a Finnish population where the clinical detection rate of coeliac disease is high. The study involved 11 hospital districts in Finland where the number of treated RCD patients (n = 44), clinically diagnosed coeliac disease patients (n = 12 243) and adult inhabitants (n = 1.7 million) was known. Clinical characteristics at diagnosis of coeliac disease between the RCD patients and patients with uncomplicated disease were compared. The prevalence of RCD was 0.31% among diagnosed coeliac disease patients and 0.002% in the general population. Of the enrolled 44 RCD patients, 68% had type I and 23% type II; in 9% the type was undetermined. Comparing 886 patients with uncomplicated coeliac disease with these 44 patients that developed RCD later in life, the latter were significantly older (median 56 vs 44 years, P < 0.001), more often males (41% vs. 24%, P = 0.012) and seronegative (30% vs. 5%, P < 0.001) at the diagnosis of coeliac disease. Patients with evolving RCD had more severe symptoms at the diagnosis of coeliac disease, including weight loss in 36% (vs. 16%, P = 0.001) and diarrhoea in 54% (vs. 38%, P = 0.050). Refractory coeliac disease is very rare in the general population. Patients of male gender, older age, severe symptoms or seronegativity at the diagnosis of coeliac disease are at risk of future refractory coeliac disease and should be followed up carefully.


Superior anticancer activity is demonstrated by total extract of Curcuma longa L. as opposed to individual curcuminoids separated by centrifugal partition chromatography.
Three curcuminoids: bisdemethoxycurcumin, demethoxycurcumin, and curcumin from turmeric were successfully separated by a high capacity solvent system composed of heptane: chloroform: methanol: water mixture (5: 6: 3: 2 v/v/v/v) tailored for centrifugal partition chromatographs at K-values of 0.504, 1.057, 1.644, respectively. These three ferulic acid derivatives obtained at a purity rate exceeding 95% were analysed by an HPLC-MS spectrometer. Turmeric extract inhibited the proliferation/viability of A549 human lung cancer, HT29 colon cancer, and T98G glioblastoma cell lines in (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay (MTT). Single curcuminoids significantly decreased the viability/proliferation of lung cancer cells in a dose-dependent manner. However, total extract displayed the superior anticancer activity in the investigated cell lines. Crude extract in combination with cisplatin augmented the decrease in the viability of cancer cells compared with single compound treatment in A549 lung cancer cells. Total extract of Curcuma longa could be regarded as being more effective against lung cancer cells in vitro than its separated compounds.


Effects of rumen undegradable protein supplementation on productive performance and indicators of protein and energy metabolism in Holstein fresh cows.
The objective of this study was to determine the effects of feeding increased dietary crude protein (CP) on productive performance and indicators of protein and energy metabolism during 21 d postpartum. Thirty multiparous Holstein dairy cows were balanced by previous lactation milk yield, body condition score (BCS) at calving, and parity and randomly allocated to 1 of 3 dietary treatments from calving until 21 d postpartum. Dietary treatments were 16.0% CP with 5.0% rumen undegradable protein (RUP) based on dry matter (DM) (16CP), 18.7% CP with 7.0% RUP based on DM (19CP), and 21.4% CP with 9.0% RUP based on DM (21CP). Diets were similar in net energy for lactation (approximately 1.7 Mcal/kg of DM) and CP levels were increased with corn gluten meal and fish meal. Dry matter intake (DMI) was increased by increasing dietary CP levels from 16.0 to 19.0% of DM, but dietary CP beyond 19.0% had no effect on DMI. Milk yields were 4.7 and 6.5 kg/d greater in cows fed the 19CP and 21CP diets versus those fed the 16CP diet, whereas 4% fat-corrected milk was greater for cows fed the 21CP than the 16CP diet (36.0 vs. 31.4 kg/d). Milk protein content and yield, lactose yield, and milk urea nitrogen were elevated by increased dietary CP. Milk lactose content and fat yield were not different among dietary treatments, but milk fat content tended to decline with increasing content of CP in diets. High CP levels increased milk N secretion but decreased milk N efficiency. Apparent digestibility of DM, CP, and neutral detergent fiber was greater on the 19CP and 21CP diets compared with the 16CP diet. Cows fed the 19CP and 21CP diets lost less body condition relative to those fed the 16CP diet over 21 d postpartum. Feeding higher CP levels increased the concentrations of serum albumin, albumin to globulin ratio, and urea nitrogen and decreased aspartate aminotransferase, nonesterified fatty acids, and β-hydroxybutyrate, but had no effect on globulin, glucose, cholesterol, or triacylglycerol. These findings indicated that elevating dietary CP up to 19.0% of DM using RUP supplements improved DMI, productive performance and the indicators of protein and energy metabolism from calving to 21 d postpartum.


Influence of blood collection systems on coagulation tests.
Coagulation tests are influenced by pre-analytic conditions such as blood collection systems. Change of glass collection tubes with plastic ones will cause alteration of the test results. The aim of this study was to compare three plastic blood collection tubes with a standard glass blood collection tube and each plastic collection tube with the other two for possible additional tube-to- tube differences. A total of 284 blood samples were obtained from 42 patients receiving warfarin during their routine controls, besides 29 healthy volunteers. Subgroup analyses were done according to health status. Our study demonstrated that different blood collection tubes have a statistically significant influence on coagulation tests. The magnitude of the effect depends on the tube used. However most of the tests performed on samples obtained from any tube correlated significantly with results obtained from other tube samples. Although blood collection tubes with different brands or properties will have distinct effects on coagulation tests, the influence of these blood collection tubes may be relatively small to interfere with decision-making on dose prescription, therefore lack clinical importance. Correlations between the results showed that, one of these plastic blood collection tubes tested in our study, can be used interchangably for a wide variety of coagulation assays. None declared.