Arachidonate 12-lipoxygenase and 12-hydroxyeicosatetraenoic acid contribute to stromal aging-induced progression of pancreatic cancer.
The incidence of pancreatic cancer increases with age, suggesting that chronological aging is a significant risk factor for this disease. Fibroblasts are the major nonmalignant cell type in the stroma of human pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated whether the chronological aging of normal human fibroblasts (NHFs), a previously underappreciated area in pancreatic cancer research, influences the progression and therapeutic outcomes of PDAC. Results from experiments with murine xenografts and 2D and 3D co-cultures of NHFs and PDAC cells revealed that older NHFs stimulate proliferation of and confer resistance to radiation therapy of PDAC. MS-based metabolite analysis indicated that older NHFs have significantly increased arachidonic acid 12-lipoxygenase (ALOX12) expression and elevated levels of its mitogenic metabolite, 12-(S)-hydroxy-5,8,10,14-eicosatetraenoic acid (12-(S)-HETE) compared with their younger counterparts. In co-cultures with older rather than with younger NHFs, PDAC cells exhibited increases in mitogen-activated protein kinase signaling and cellular metabolism, as well as a lower oxidation state that correlated with their enhanced proliferation and resistance to radiation therapy. Expression of ALOX12 was found to be significantly lower in PDAC cell lines and tumor biopsies, suggesting that PDAC cells rely on a stromal supply of mitogens for their proliferative needs. Pharmacological (hydroxytyrosol) and molecular (siRNA) interventions of ALOX12 in older NHFs suppressed their ability to stimulate proliferation of PDAC cells. We conclude that chronological aging of NHFs contributes to PDAC progression and that ALOX12 and 12-(S)-HETE may be potential stromal targets for interventions that seek to halt progression and improve therapy outcomes.


Felty's syndrome and hypofibrinogenemia: an unusual target for anti-cyclic citrullinated peptide antibodies?
Rheumatoid arthritis (RA) is a risk factor for the development of Felty's syndrome and large granular lymphocyte (LGL) leukemia. Anti-cyclic citrullinated peptide (CCP) antibodies are considered highly specific for RA and are directed against various citrullinated antigens, including citrullinated fibrinogen. Anti-CCP antibodies may interfere with the detection of citrullinated proteins and their function. In this article, we describe the possible inhibition of fibrinogen by anti-CCP antibodies with clinical consequences which have never been reported in the literature to our best knowledge. We present the case of a 79-year-old Caucasian woman with a longstanding history of untreated seropositive RA and who had been investigated for severe neutropenia since several months. The association of splenomegaly led to suspicion of Felty's syndrome. Flux cytometry was compatible with T-cell LGL leukemia. In addition, severe hypofibrinogenemia was detected. The later finding has not been consistently associated with the former clinical entities. Further investigations demonstrated that the anti-CCP antibodies of the patient also recognized the P41 peptide of citrullinated fibrinogen. The patient deceased of intracranial hemorrhage. It is likely, yet not definite, that high anti-citrullinated fibrinogen titers may contribute to low fibrinogen levels and could have contributed to the fatal hemorrhagic event.


Oral habits in a population of Albanian growing subjects.
The aim of this study was to assess the prevalence of oral habits in an Albanian population of schoolchildren. A sample of 2617 subjects, aged 7-15, was examined by clinical observation without radiograms. The sample comprised 1257 males and 1360 females, with no history of orthodontic treatment. Aestethical frontal and profile analysis, intraoral and functional analysis were performed. Gender and age differences were compared by chi-square test. The relationship between malocclusions and oral habits was assessed by t-test and the level of significance was assessed at 0.01. The findings indicated that oral habits were present in 2225 subjects (85.0%), 1103 males (87.7%) and 1121 females (82.4%); the most frequent oral habit was pacifier sucking (30%) and it was mostly present in the 7-11 years group. It was observed a significant correlation between oral habits and dental malocclusions, open bite, altered overjet and maxillary contraction. CONCLUSION The high number of oral habits observed in the studied sample suggest that prevention strategies adopted in other countries could be successfully integrated in the development of an effective national programme in Albania aimed at reducing malocclusion risk factors.


Eph receptors and ephrin signaling pathways: a role in bone homeostasis.
The maintenance of bone homeostasis is tightly controlled, and largely dependent upon cellular communication between osteoclasts and osteoblasts, and the coupling of bone resorption to bone formation. This tight coupling is essential for the correct function and maintenance of the skeletal system, repairing microscopic skeletal damage and replacing aged bone. A range of pathologic diseases, including osteoporosis and cancer-induced bone disease, disrupt this coupling and cause subsequent alterations in bone homeostasis. Eph receptors and their associated ligands, ephrins, play critical roles in a number of cellular processes including immune regulation, neuronal development and cancer metastasis. Eph receptors are also expressed by cells found within the bone marrow microenvironment, including osteoclasts and osteoblasts, and there is increasing evidence to implicate this family of receptors in the control of normal and pathological bone remodeling.


Earliest evidence of dental caries manipulation in the Late Upper Palaeolithic.
Prehistoric dental treatments were extremely rare, and the few documented cases are known from the Neolithic, when the adoption of early farming culture caused an increase of carious lesions. Here we report the earliest evidence of dental caries intervention on a Late Upper Palaeolithic modern human specimen (Villabruna) from a burial in Northern Italy. Using Scanning Electron Microscopy we show the presence of striations deriving from the manipulation of a large occlusal carious cavity of the lower right third molar. The striations have a "V"-shaped transverse section and several parallel micro-scratches at their base, as typically displayed by cutmarks on teeth. Based on in vitro experimental replication and a complete functional reconstruction of the Villabruna dental arches, we confirm that the identified striations and the associated extensive enamel chipping on the mesial wall of the cavity were produced ante-mortem by pointed flint tools during scratching and levering activities. The Villabruna specimen is therefore the oldest known evidence of dental caries intervention, suggesting at least some knowledge of disease treatment well before the Neolithic. This study suggests that primitive forms of carious treatment in human evolution entail an adaptation of the well-known toothpicking for levering and scratching rather than drilling practices.


Transaxillary robotic thyroidectomy: Belgian team learning from the first 50 cases.
In search for less invasive operative techniques, the da Vinci Robot System was introduced in thyroid surgery. Previous studies have reported on safety, effectiveness and improved cosmetics of transaxillary endoscopic thyroidectomy procedures in selected cases. We report on the first 50 patients that have been treated with a gasless transaxillary robot-assisted thyroidectomy in a Belgian institution. We describe the implementation, the operative technique and results of robotic thyroid surgery. 48 hemithyroidectomy and 2 total thyroidectomy procedures were performed. The mean ultrasound dimensions of the nodules were 3.4 ± 1.0 cm (range 1.0-8.0 cm). The mean operative time was significantly longer than with a conventional open approach: 215 min ± 55 min (range 133 min-347 min). No major complications were observed. All patients were "satisfied" about the cosmetic outcome. Transaxillary robotic thyroid surgery is demanding, but feasible. Selected patients can benefit from this technique with an optimal cosmetic outcome. Ideal indication in the hand of our team is a hemithyroidectomy for benign nodules ranging up to 5 cm.


Neuronal soluble factors differentially regulate the expression of the GLT1 and GLAST glutamate transporters in cultured astroglia.
The glutamate transporters in the plasma membranes of neural cells secure termination of the glutamatergic synaptic transmission and keep the glutamate levels below toxic concentrations. Astrocytes express two types of glutamate transporters, GLAST (EAAT1) and GLT1 (EAAT2). GLT1 predominates quantitatively and is responsible for most of the glutamate uptake activity in the juvenile and adult brain. However, GLT1 is severely down-regulated in amyotrophic lateral sclerosis, a progressive neurodegenerative disease. Furthermore, selective loss of this transporter occurs in cultured astroglia. Expression of GLAST, but not of GLT1, seems to be regulated via the glutamate receptor signalling. The present study was undertaken to examine whether neuronal factors, other than glutamate, influence the expression of astroglial glutamate transporters. The expression of GLT1 and GLAST was examined in primary cultures of cerebellar granule neurons, cortical neurons, and astrocytes under different experimental conditions, including those that mimic neuron-astrocyte interactions. Pure astroglial cultures expressed only GLAST, whereas astrocytes grown in the presence of neurons expressed both GLAST (at increased levels) and GLT1. The induction of GLT1 protein and its mRNA was reproduced in pure cortical astroglial cultures supplemented with conditioned media from cortical neuronal cultures or from mixed neuron-glia cultures. This treatment did not change the levels of GLAST. These results suggest that soluble neuronal factors differentially regulate the expression of GLT1 and GLAST in cultured astroglia. Further elucidation of the molecular nature of the secreted neuronal factors and corresponding signalling pathways regulating the expression of the astroglial glutamate transporters in vitro may reveal mechanisms important for the understanding and treatment of neurological diseases.


Intact verbal description of letters with diminished awareness of their forms.
Visual processing and its conscious awareness can be dissociated. To examine the extent of dissociation between ability to read characters or words and to be consciously aware of their forms, reading ability and conscious awareness for characters were examined using a tachistoscope in an alexic patient. A right handed woman with 14 years of education presented with incomplete right hemianopia, alexia with kanji (ideogram) agraphia, anomia, and amnesia. Brain MRI disclosed cerebral infarction limited to the left lower bank of the calcarine fissure, lingual and parahippocampal gyri, and an old infarction in the right medial frontal lobe. Tachistoscopic examination disclosed that she could read characters aloud in the right lower hemifield when she was not clearly aware of their forms and only noted their presence vaguely. Although her performance in reading kanji was better in the left than the right field, she could read kana (phonogram) characters and Arabic numerals equally well in both fields. By contrast, she claimed that she saw only a flash of light in 61% of trials and noticed vague forms of stimuli in 36% of trials. She never recognised a form of a letter in the right lower field precisely. She performed judgment tasks better in the left than right lower hemifield where she had to judge whether two kana characters were the same or different. Although dissociation between performance of visual recognition tasks and conscious awareness of the visual experience was found in patients with blindsight or residual vision, reading (verbal identification) of characters without clear awareness of their forms has not been reported in clinical cases. Diminished awareness of forms in our patient may reflect incomplete input to the extrastriate cortex.


Quality and safety of minimally invasive surgery: past, present, and future.
Adverse events because of medical errors are a leading cause of death in the United States (US) exceeding the mortality rates of motor vehicle accidents, breast cancer, and AIDS. Improvements can and should be made to reduce the rates of preventable surgical errors because they account for nearly half of all adverse events within hospitals. Although minimally invasive surgery (MIS) has proven patient benefits such as reduced postoperative pain and hospital stay, its operative environment imposes substantial physical and cognitive strain on the surgeon increasing the risk of error. To mitigate errors and protect patients, a multidisciplinary approach is needed to improve MIS. Clinical human factors, and biomedical engineering principles and methodologies can be used to develop and assess laparoscopic surgery instrumentation, practices, and procedures. First, the foundational understanding and the imperative to transform health care into a high-quality and safe system is discussed. Next, a generalized perspective is presented on the impact of the design and redesign of surgical technologies and processes on human performance. Finally, the future of this field and the research needed to further improve the quality and safety of MIS is discussed.


Call to Integrate Content Related to Disabilities Into Contemporary Pharmacy Curricula.
The curricula of US schools and colleges of pharmacy provide students with only a cursory introduction to patients with disabilities, and this is usually achieved through didactic content. These brief introductions are considered helpful; however, pedagogical approaches do not provide comprehensive content for mastery of skills and strategies for delivering accessible healthcare services to patients with disabilities. Student pharmacists' need to obtain the requisite education, knowledge, and skills to provide effective healthcare to patients with disabilities. Accordingly, it is essential that schools and colleges of pharmacy prepare student pharmacists to be competent and confident in providing effective and accessible care to this underserved patient population.


Hanseniaspora nectarophila sp. nov., a yeast species isolated from ephemeral flowers.
Seven apiculate yeast strains that were isolated from the flowers of Syphocampylus corymbiferus Pohl in Brazil are genetically, morphologically and phenotypically distinct from recognized species of the genera Hanseniaspora and Kloeckera. Genetic discontinuities between the novel strains and their closest relatives were found using a networking approach based on the concatenated sequences of the rRNA gene (internal transcribed spacer and D1/D2 of the LSU), and the protein-coding genes for actin and translation elongation factor-1α. Phylogenetic analysis based on the rRNA and the actin gene placed the novel species represented by the strains in close relationship to Hanseniaspora meyeri and Hanseniaspora clermontiae. PCR fingerprinting with microsatellite primers confirmed the genetic heterogeneity of the novel species. The name Hanseniaspora nectarophila sp. nov. is proposed, with UFMG POG a.1(T) ( = ZIM 2311(T) = CBS 13383(T)) as the type strain; MycoBank no. MB807210. As the current description of the genus does not allow the presence of multilateral budding, an emended diagnosis of the genus Hanseniaspora Zikes is proposed.


The effects of feeding and withholding food on the canine small intestinal microbiota.
Prolonged lack of enteral feeding has a negative impact on gut physiology, potentially via microbiota modulation. The aims were to investigate the impact of fasting and post-prandial changes in canine jejunal microbiota. To study post-prandial effects, jejunal brushings were analyzed in 8 healthy fistulated dogs 15 min before feeding (baseline) and hourly for 8 h after feeding. To study effects of withholding food (WF), daily samples were collected for 15 days from 5 dogs. The first 5 days (PRE) dogs were fed regular diet. Food was withheld the next 5 days (days 6-10). For days 11-15 (POST), the original diet was reintroduced. Microbiota was characterized via denaturing gradient gel electrophoresis and 454-pyrosequencing of 16S rRNA genes. In the post-prandial study, no changes in microbiome structure were seen after feeding (ANOSIM, P = 0.28), but Betaproteobacteria (P = 0.04) and Bacteroidales decreased compared to baseline. Species richness decreased by 300 min (P = 0.04). During WF, microbiota structure differed from PRE and POST period (P = 0.001). During WF, species richness did not vary over time (P = 0.69). In conclusion, a prolonged period of food withholding results in altered jejunal microbiota. How these changes affect the microbiota metabolism warrants further studies.


Adaptation to visuomotor rotations remaps movement vectors, not final positions.
When exposed to novel visuomotor rotations, subjects readily adapt reaching movements, such that the virtual display of the hand is brought to the target. Whereas this clearly reflects remapping of the relationship between hand movements and the visual display, the nature of this remapping is not well understood. We now examine whether such adaptation results in remapping of the position of the visually displayed target and the final limb position or between the target vector and the movement vector. The latter is defined relative to a starting position, whereas the former should be independent of the starting position. Subjects first adapted to a 30 degrees rotation during reaching movements made from a single starting location to four different target locations. After adaptation, generalization trials were introduced, during which reaching movements were made under the same visual rotation condition but started from one of two locations outside the practiced workspace. These trials were directed to either the previously practiced targets or new targets that reflected the direction and distance of the practiced trials. Generalization was greatest for movements made in similar directions, regardless of changes in spatial location. Most significantly, when reaching to the previously adapted targets, subjects did not reach to the previously learned limb positions but rather to positions that reflected a near 30 degrees rotation of the new target vector. These results indicate that learned visuomotor rotations remap the representations of movement vectors and not final positions of the limb in the workspace.


Conjoint Analysis of User Acceptability of Sustained Long-Acting Pre-Exposure Prophylaxis for HIV.
Long-acting delivery modalities of HIV pre-exposure prophylaxis (PrEP), such as subdermal implants, are in development. To facilitate end-user uptake and sustained use, it is critical to understand potential consumers' and physician prescribers' preferences about, interest in, and relative importance of different implant features. The ordered identification of these key attributes allows implant developers to incorporate this feedback into product design, which theoretically improves acceptability, feasibility, and user experience with the device. In this study, n = 75 PrEP-prescribing physicians and n = 143 men having sex with men (MSM) at risk for HIV completed web-based surveys that directly compared the importance of eight to nine different implant features, respectively. Conjoint analysis determined the importance of these features, relative to each other. Implants presented in the study were well received, with a majority of physicians and MSM indicating that they were likely to recommend or use them. The implant was perceived as unique, reliable, and convenient, as well as able to deliver better compliance. The attributes most critical to the adoption of the implant among physicians and MSM were (1) the chance of becoming infected with HIV while on implant treatment, (2) the length of protection and size of the implant, and (3) the side effect advantages over current PrEP oral pill treatment. Some concerns about the implant included side effects and the product's safety (among MSM) and the cost or insurance coverage level for the implant (both physicians and MSM). There was also some resistance to the implantation procedure itself.


Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake.
The AMP-activated protein kinase (AMPK) is known to increase cardiac insulin sensitivity on glucose uptake. AMPK also inhibits the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) pathway. Once activated by insulin, mTOR/p70S6K phosphorylates insulin receptor substrate-1 (IRS-1) on serine residues, resulting in its inhibition and reduction of insulin signaling. AMPK was postulated to act on insulin by inhibiting this mTOR/p70S6K-mediated negative feedback loop. We tested this hypothesis in cardiomyocytes. The stimulation of glucose uptake by AMPK activators and insulin correlated with AMPK and protein kinase B (PKB/Akt) activation, respectively. Both treatments induced the phosphorylation of Akt substrate 160 (AS160) known to control glucose uptake. Together, insulin and AMPK activators acted synergistically to induce PKB/Akt overactivation, AS160 overphosphorylation, and glucose uptake overstimulation. This correlated with p70S6K inhibition and with a decrease in serine phosphorylation of IRS-1, indicating the inhibition of the negative feedback loop. We used the mTOR inhibitor rapamycin to confirm these results. Mimicking AMPK activators in the presence of insulin, rapamycin inhibited p70S6K and reduced IRS-1 phosphorylation on serine, resulting in the overphosphorylation of PKB/Akt and AS160. However, rapamycin did not enhance the insulin-induced stimulation of glucose uptake. In conclusion, although the insulin-sensitizing effect of AMPK on PKB/Akt is explained by the inhibition of the insulin-induced negative feedback loop, its effect on glucose uptake is independent of this mechanism. This disconnection revealed that the PKB/Akt/AS160 pathway does not seem to be the rate-limiting step in the control of glucose uptake under insulin treatment.


Methyl farnesoate synthesis is necessary for the environmental sex determination in the water flea Daphnia pulex.
Sex-determination systems can be divided into two groups: genotypic sex determination (GSD) and environmental sex determination (ESD). ESD is an adaptive life-history strategy that allows control of sex in response to environmental cues in order to optimize fitness. However, the molecular basis of ESD remains largely unknown. The micro crustacean Daphnia pulex exhibits ESD in response to various external stimuli. Although methyl farnesoate (MF: putative juvenile hormone, JH, in daphnids) has been reported to induce male production in daphnids, the role of MF as a sex-determining factor remains elusive due to the lack of a suitable model system for its study. Here, we establish such a system for ESD studies in D. pulex. The WTN6 strain switches from producing females to producing males in response to the shortened day condition, while the MFP strain only produces females, irrespective of day-length. To clarify whether MF has a novel physiological role as a sex-determining factor in D. pulex, we demonstrate that a MF/JH biosynthesis inhibitor suppressed male production in WTN6 strain reared under the male-inducible condition, shortened day-length. Moreover, we show that juvenile hormone acid O-methyltransferase (JHAMT), a critical enzyme of MF/JH biosynthesis, displays MF-generating activity by catalyzing farnesoic acid. Expression of the JHAMT gene increased significantly just before the MF-sensitive period for male production in the WTN6 strain, but not in the MFP strain, when maintained under male-inducible conditions. These results suggest that MF synthesis regulated by JHAMT is necessary for male offspring production in D. pulex. Our findings provide novel insights into the genetic underpinnings of ESD and they begin to shed light on the physiological function of MF as a male-fate determiner in D. pulex.


The effects of the coverage gap on drug spending: a closer look at Medicare Part D.
We calculated prescription drug usage in two groups of Medicare beneficiaries: employer group with no coverage gap, and individual Part D group with no coverage or some generic drug coverage in the coverage gap. Among those with employer coverage, 40 percent reached the doughnut hole, compared with 25 percent of those without such coverage. Overall, 5 percent went through the doughnut hole to reach the catastrophic coverage level. Those lacking coverage in the doughnut hole reduced their drug use by 14 percent; those with generic coverage reduced their use by 3 percent. Coverage of generic drugs with a $0-$10 copayment in the doughnut hole could be financed by, at most, a six-to-nine-percentage-point increase in initial coinsurance.


Roles of individual EF-hands in the activation of m-calpain by calcium.
m-Calpain is a heterodimeric, cytosolic, thiol protease, which is activated by Ca(2+)-binding to EF-hands in the C-terminal domains of both subunits. There are four potential Ca(2+)-binding EF-hands in each subunit, but their relative affinities for Ca(2+) are not known. In the present study mutations were made in both subunits to reduce the Ca(2+)-binding affinity at one or more EF-hands in one or both subunits. X-ray crystallography of some of the mutated small subunits showed that Ca(2+) did not bind to the mutated EF-hands, but that its binding at other sites was not affected. The structures of the mutant small subunits in the presence of Ca(2+) were otherwise identical to that of the Ca(2+)-bound wild-type small subunit. In the whole enzyme the wild-type macroscopic Ca(2+) requirement (K(d)) was approx. 350 microM. The mutations did not affect the maximum specific activity of the enzyme, but caused increases in K(d), which were characteristic of each site. All the EF-hands could be mutated in various combinations without loss of activity, but preservation of at least one wild-type EF-hand 3 sequence was required to maintain K(d) values lower than 1 mM. The results suggest that all the EF-hands can contribute co-operatively to calpain activation, but that EF-hand 3, in both subunits, has the highest intrinsic affinity for Ca(2+) and provides the major driving force for conformational change.


Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.
Allogeneic bone marrow transplantation (BMT) offers a potential cure for younger patients with myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia (sAML). More than 600 patients from 50 European centers have now been reported to the European Group for Blood and Marrow Transplantation (EBMT). We retrospectively analyzed 131 patients reported to the Chronic Leukemia Working Party of the EBMT who underwent BMT from HLA-identical siblings without prior remission induction chemotherapy. At the time of BMT 46 patients had refractory anemia (RA) or RA with ringed sideroblasts, 67 patients had more advanced MDS subtypes and 18 patients had progressed to sAML. The 5-year disease-free (DFS) and overall survival (OS) for the entire group of patients was 34 and 41%, respectively. Fifty patients died from transplant-related complications, most commonly graft-versus-host disease and/or infections. Relapse occurred in 28 patients between 1 and 33 months after BMT, resulting in an actuarial probability of relapse of 39% at 5 years. DFS and OS were dependent on pretransplant bone marrow blast counts. Patients with RA/RARS, RAEB, RAEB/T and sAML had a 5-year DFS of 52, 34, 19 and 26%, respectively. The 5-year OS for the respective patient groups was 57, 42, 24 and 28%. In a multivariate analysis, younger age, shorter disease duration, and absence of excess of blasts were associated with improved outcome. From these data we conclude that patients with myelodysplasia who have appropriate marrow donors, especially those aged less than 40 years and those with low medullary blast cell count should be treated with BMT as the primary treatment early in the course of their disease. Transplantation early after establishing the diagnosis of MDS may improve prognosis due to a lower treatment-related mortality and a lower relapse risk.


Effect of alcohols and neutral salt on the thermal stability of soluble and precipitated acid-soluble collagen.
The effects of mono- and poly-hydric alcohols in the presence of KCl on the intrinsic stability of collagen molecules in dilute acid solution were compared with corresponding solvent and salt effects on the increased stability of the aggregated molecules in salt-precipitated fibrils. Salt addition decreased solubility and increased the thermal stability of fibrils, but progressively decreased the stability of collagen molecules in solution. In contrast, the alcohols enhanced solubility and decreased fibril stability, the effects increasing with solvent hydrocarbon chain length and with decreasing hydroxyl/methylene-group ratio. Molar destabilization of dissolved collagen by alcohols was lower than for fibrils, and at low salt concentration, both ethylene glycol and glycerol were structural stabilizers. Electron-micrograph studies indicated that salt-precipitated fibrils tended to adopt the native aggregation mode, and qualitatively similar solvent effects were observed in insoluble collagens. Implications of the experimental findings are discussed in terms of a model in which electrostatic and apolar interactions mainly govern the excess of stability in collagen fibrils whereas intrinsic stability of single molecules is a function of polar interactions and polypeptide-chain rigidity.


Changing characteristics of cancer patients during the COVID-19 pandemic.
Cancer patients are more sensitive to infections, and, compared to other patients, may have more serious outcomes. Thus, cancer patients are a high-risk group in the COVID-19 pandemic. The aim of this study was to evaluate how cancer patients are affected by COVID-19 infection; the prevalence, and factors affecting mortality. This single-centre, retrospective study included cancer patients under follow-up treatment at our hospital with a laboratory-confirmed diagnosis of COVID-19. Demographic and clinical data were obtained from electronic medical records. The effects of tumour subtype and patient demographic data on COVID-19 prevalence and mortality were analyzed using univariate and multivariate models. Evaluation was made of 217 cancer patients, comprising140 (64.5%) males and 77 (35.5%) females with a mean age of 62.05 ± 12.95 years. Mortality was seen in 84 (38.7%) patients. Disease grade, chemotherapy within the last 3 months and CT findings were determined to be related to mortality. In logistic regression analysis, the most important factors affecting survival were determined to be severe lung involvement (p < 0.001) and hematological malignancy. It is clear that cancer patients are at greater risk from COVID-19 infection than individuals without a malignant disease. The results showed that cancer patients with different tumour types had different levels of sensitivity to COVID-19. It is clear that with ongoing viral mutations, the duration of the pandemic is unknown. Therefore, the continuation of cancer screening and cancer treatments should not be interrupted.


Mucin- and carbohydrate-stimulated adhesion and subproteome changes of the probiotic bacterium Lactobacillus acidophilus NCFM.
Adhesion to intestinal mucosa is a crucial property for probiotic bacteria. Adhesion is thought to increase host-bacterial interactions, thus potentially enabling health benefits to the host. Molecular events connected with adhesion and surface proteome changes were investigated for the probiotic Lactobacillus acidophilus NCFM cultured with established or emerging prebiotic carbohydrates as carbon source and in the presence of mucin, the glycoprotein of the epithelial mucus layer. Variation in adhesion to HT29-cells and mucin was associated with carbon source and mucin-induced subproteome abundancy differences. Specifically, while growth on fructooligosaccharides (FOS) only stimulated adhesion to intestinal HT-29 cells, cellobiose and polydextrose in addition increased adhesion to mucin. Adhesion to HT-29 cells increased by about 2-fold for bacteria grown on mucin-supplemented glucose. Comparative 2DE-MS surface proteome analysis showed different proteins in energy metabolism appearing on the surface, suggesting they exert moonlighting functions. Mucin-supplemented bacteria had relative abundance of pyruvate kinase and fructose-bisphosphate aldolase increased by about 2-fold while six spots with 3.2-2.1 fold reduced relative abundance comprised elongation factor G, phosphoglycerate kinase, BipAEFTU family GTP-binding protein, ribonucleoside triphosphate reductase, adenylosuccinate synthetase, 30S ribosomal protein S1, and manganese-dependent inorganic pyrophosphatase. Surface proteome of cellobiose- compared to glucose-grown L. acidophilus NCFM had phosphate starvation inducible protein stress-related, thermostable pullulanase, and elongation factor G increasing 4.4-2.4 fold, while GAPDH, elongation factor Ts, and pyruvate kinase were reduced by 2.0-1.5 fold in relative abundance. Addition of recombinant L. acidophilus NCFM elongation factor G and pyruvate kinase to a coated mucin layer significantly suppressed subsequent adhesion of the bacterium. Human diet is important for intestinal health and food components, especially non-digestible carbohydrates can beneficially modify the microbiota. In the present study, effects of emerging and established prebiotic carbohydrates on the probiotic potential of Lactobacillus acidophilus NCFM were investigated by testing adhesion to a mucin layer and intestinal cells, and comparing this with changes in abundancy of surface proteins thought to be important for host interactions. Increased adhesion was observed following culturing of the bacterium with fructooligosaccharides, cellobiose or polydextrose, as well as mucin-supplemented glucose as carbon source. Enhanced adhesion ability can prolong bacterial residence in GIT yielding positive health effects. Higher relative abundance of certain surface proteins under various conditions (i.e. grown on cellobiose or mucin-supplemented glucose) suggested involvement of these proteins in adhesion, as confirmed by competition in case of two recombinantly produced moonlighting proteins. Combination of Lactobacillus acidophilus NCFM with different carbohydrates revealed potential bacterial determinants of synbiotic interactions, including stimulation of adhesion.


Isolation of stage-specific spermatogenic cells by dynamic histone incorporation and removal in spermatogenesis.
Due to the lack of an efficient in vitro spermatogenesis system, studies on mammalian spermatogenesis require the isolation of specific germ cell populations for further analyses. BSA gradient and elutriation have been used for several decades to purify testicular germ cells; more recently, flow cytometric cell sorting has become popular. Although each method has its advantages and disadvantages and is used depending on the purpose of the experiment, reliance on flow cytometric cell sorting is expected to be more prevalent because fewer cells can be managed. However, the currently used flow cytometric cell sorting method for testicular germ cells relies on karyotypic differences via DNA staining. Thus, it remains challenging to separate post-meiotic haploid cells (spermatids) according to their differentiation stage despite significant variations in morphology and chromatin state. In this study, we developed a method for finely separating testicular germ cells using VC mice carrying fluorescently tagged histones. This method enables the separation of spermatogonia, spermatocytes, and spermatids based on the intensity of histone fluorescence and cell size. Combined with a DNA staining dye, this method separates spermatids after elongation according to each spermiogenic stage. Although the necessity for a specific transgenic mouse line is less versatile, this method is expected to be helpful for the isolation of testicular germ cell populations because it is highly reproducible and independent of complex cell sorter settings and staining conditions.


Endosialin expression in relation to clinicopathological and biological variables in rectal cancers with a Swedish clinical trial of preoperative radiotherapy.
The importance of changes in tumour-associated stroma for tumour initiation and progression has been established. Endosialin is expressed in fibroblasts and pericytes of blood vessels in several types of tumours, and is involved in the progression of colorectal cancer. In order to see whether endosialin was related to radiotherapy (RT) response, and clinicopathological and biological variables, we investigated endosialin expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative RT. Endosialin was immunohistochemically examined in normal mucosa, including distant (n = 72) and adjacent (n = 112) normal mucosa, and primary tumours (n = 135). Seventy-three of 135 patients received surgery alone and 62 received additional preoperative RT. Endosialin expression in the stroma increased from normal mucosa to tumour (p < 0.0001) both in RT and non-RT group. In the RT group, endosialin expression in the stroma was positively associated with expression of cyclooxygenase-2 (Cox-2) (p = 0.03), p73 (p = 0.01) and phosphates of regenerating liver (PRL) (p = 0.002). Endosialin expression in the tumour cells of both in the RT group (p = 0.01) and the non-RT group (p = 0.06) was observed more often in tumours with an infiltrative growth pattern than in tumours with an expansive growth pattern. In the RT group, endosialin expression in tumour cells was positively related to PRL expression (p = 0.02), whereas in the non-RT group, endosialin expression in tumour cells was positively related to p73 expression (p = 0.01). Endosialin expression may be involved in the progression of rectal cancers, and was related to Cox-2, p73 and PRL expression. However, a direct relationship between endosialin expression and RT responses in patients was not found.


Ophthalmic disodium cromoglycate.
Disodium cromoglycate has recently been approved for ophthalmic treatment of certain types of conjunctivitis in the United States. This mast cell inhibitor is effective in the treatment of vernal keratoconjunctivitis, allergic conjunctivitis, chronic conjunctivitis, and giant papillary conjunctivitis, especially when a history of atopic disorders or moderately low blood IgE levels are present. This literature review provides a foundation for understanding the balance between the therapeutic efficacy, clinical benefits and side effects in treating IgE-mediated conjunctivitis with disodium cromoglycate.


Inferring the physical connectivity of complex networks from their functional dynamics.
Biological networks, such as protein-protein interactions, metabolic, signalling, transcription-regulatory networks and neural synapses, are representations of large-scale dynamic systems. The relationship between the network structure and functions remains one of the central problems in current multidisciplinary research. Significant progress has been made toward understanding the implication of topological features for the network dynamics and functions, especially in biological networks. Given observations of a network system's behaviours or measurements of its functional dynamics, what can we conclude of the details of physical connectivity of the underlying structure? We modelled the network system by employing a scale-free network of coupled phase oscillators. Pairwise phase coherence (PPC) was calculated for all the pairs of oscillators to present functional dynamics induced by the system. At the regime of global incoherence, we observed a Significant pairwise synchronization only between two nodes that are physically connected. Right after the onset of global synchronization, disconnected nodes begin to oscillate in a correlated fashion and the PPC of two nodes, either connected or disconnected, depends on their degrees.Based on the observation of PPCs, we built a weighted network of synchronization (WNS), an all-to-all functionally connected network where each link is weighted by the PPC of two oscillators at the ends of the link. In the regime of strong coupling, we observed a Significant similarity in the organization of WNSs induced by systems sharing the same substrate network but different configurations of initial phases and intrinsic frequencies of oscillators.We reconstruct physical network from the WNS by choosing the links whose weights are higher than a given threshold. We observed an optimal reconstruction just before the onset of global synchronization.Finally, we correlated the topology of the background network to the observed change of the functional activities in the system. The results presented in this study indicate a strong relationship between the structure and dynamics of complex network systems. As coupling strength increases, synchronization emerges among hub nodes and recruits small-degree nodes. The results show that the onset of global synchronization in the system hinders the reconstruction of an underlying complex structure. Our analysis helps to clarify how the synchronization is achieved in systems of different network topologies.


Protective effect of liraglutide on experimental testicular ischaemia reperfusion in rats.
This study was performed to evaluate the effect of liraglutide on experimental testicular ischaemia reperfusion in rats in terms of biochemistry, histopathology and immunohistochemistry. A total of 28 male Wistar-Albino rats were divided randomly into 4 groups: control (7), sham (7), ischaemia-reperfusion (7) and ischaemia-reperfusion + liraglutide (7). Biochemically, Nitric Oxide, Malondialdehyde, Superoxide dismutase, Glutathione peroxidase and Catalase levels were measured in the testis. Apoptosis protease activating factor-1 and inducible nitric oxide synthase activity were evaluated immunohistochemically as well. Statistical analyses were made via the Kruskal-Wallis and Mann-Whitney U tests. In the reperfusion group, CAT and SOD values were increased (p > .05), NO and MDA values were decreased (p < .05) after administration of liraglutide. In addition, GPx values were significantly increased in ischaemia reperfusion + liraglutide administered group compared to reperfusion group (p < .05). Apaf-1 and iNOS activity were significantly decreased with the addition of liraglutide treatment to the ischaemia-reperfusion group (p < .05). First of all, we would like to say that liraglutide treatment is moderately preventive against I/R injury in testicular torsion. The anti-inflammatory, antioxidant and antiapoptotic properties of liraglutide are create a moderately protective effect as we show in this study.


Chemotherapy and Immune Checkpoint Blockade for Gastric and Gastroesophageal Junction Adenocarcinoma.
Combining immune checkpoint blockade (ICB) with chemotherapy improves outcomes in patients with metastatic gastric and gastroesophageal junction (G/GEJ) adenocarcinoma; however, whether this combination has activity in the perioperative setting remains unknown. To evaluate the safety and preliminary activity of perioperative chemotherapy and ICB followed by maintenance ICB in resectable G/GEJ adenocarcinoma. This investigator-initiated, multicenter, open-label, single-stage, phase 2 nonrandomized controlled trial screened 49 patients and enrolled 36 patients with resectable G/GEJ adenocarcinoma from February 10, 2017, to June 17, 2021, with a median (range) follow-up of 35.2 (17.4-73.0) months. Thirty-four patients were deemed evaluable for efficacy analysis, with 28 (82.4%) undergoing curative resection. This study was performed at 4 referral institutions in the US. Patients received 3 cycles of capecitabine, 625 mg/m2, orally twice daily for 21 days; oxaliplatin, 130 mg/m2, intravenously and pembrolizumab, 200 mg, intravenously with optional epirubicin, 50 mg/m2, every 3 weeks before and after surgery with an additional cycle of pembrolizumab before surgery. Patients received 14 additional doses of maintenance pembrolizumab. The primary end point was pathologic complete response (pCR) rate. Secondary end points included overall response rate, disease-free survival (DFS), overall survival (OS), and safety. A total of 34 patients (median [range] age, 65.5 [25-90] years; 23 [67.6%] male) were evaluable for efficacy. Of these patients, 28 (82.4%) underwent curative resection, 7 (20.6%; 95% CI, 10.1%-100%) achieved pCR, and 6 (17.6%) achieved a pathologic near-complete response. Of the 28 patients who underwent resection, 4 (14.3%) experienced disease recurrence. The median DFS and OS were not reached. The 2-year DFS was 67.8% (95% CI, 0.53%-0.87%) and the OS was 80.6% (95% CI, 0.68%-0.96%). Treatment-related grade 3 or higher adverse events for evaluable patients occurred in 20 patients (57.1%), and 12 (34.3%) experienced immune-related grade 3 or higher adverse events. In this trial of unselected patients with resectable G/GEJ adenocarcinoma, capecitabine, oxaliplatin, and pembrolizumab resulted in a pCR rate of 20.6% and was well tolerated. This trial met its primary end point and supports the development of checkpoint inhibition in combination with perioperative chemotherapy in locally advanced G/GEJ adenocarcinoma. ClinicalTrials.gov Identifier: NCT02918162.


[Globalization and infectious diseases in Mexico's indigenous population].
This paper discusses the health status of indigenous populations in Mexico. The first section characterizes the concept of globalization and its links to the population's health. Based on available statistical data, the second section documents the current indigenous populations' health status in the country. The article then argues that the presupposition of equity, crucial to globalization theory, does not apply to this case. Using the Mexican National Health Survey (2000), the third section further analyzes the health status of indigenous populations and identifies important inconsistencies in the data. The discussion section contends that these inconsistencies derive from the fact that such health surveys fail to contemplate the cultural specificities of indigenous peoples, thus leading to erroneous interpretations of the data. The article concludes that statistics on indigenous peoples' health must be interpreted with extreme caution and always with the support of social science theories and research methods.


Typical and atypical pathology in primary progressive aphasia variants.
To characterize in vivo signatures of pathological diagnosis in a large cohort of patients with primary progressive aphasia (PPA) variants defined by current diagnostic classification. Extensive clinical, cognitive, neuroimaging, and neuropathological data were collected from 69 patients with sporadic PPA, divided into 29 semantic (svPPA), 25 nonfluent (nfvPPA), 11 logopenic (lvPPA), and 4 mixed PPA. Patterns of gray matter (GM) and white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support vector machine (SVM) algorithms. A clinical diagnosis of PPA was associated with frontotemporal lobar degeneration (FTLD) with transactive response DNA-binding protein (TDP) inclusions in 40.5%, FTLD-tau in 40.5%, and Alzheimer disease (AD) pathology in 19% of cases. Each variant was associated with 1 typical pathology; 24 of 29 (83%) svPPA showed FTLD-TDP type C, 22 of 25 (88%) nfvPPA showed FTLD-tau, and all 11 lvPPA had AD. Within FTLD-tau, 4R-tau pathology was commonly associated with nfvPPA, whereas Pick disease was observed in a minority of subjects across all variants except for lvPPA. Compared with pathologically typical cases, svPPA-tau showed significant extrapyramidal signs, greater executive impairment, and severe striatal and frontal GM and WM atrophy. nfvPPA-TDP patients lacked general motor symptoms or significant WM atrophy. Combining GM and WM volumes, SVM analysis showed 92.7% accuracy to distinguish FTLD-tau and FTLD-TDP pathologies across variants. Each PPA clinical variant is associated with a typical and most frequent cognitive, neuroimaging, and neuropathological profile. Specific clinical and early anatomical features may suggest rare and atypical pathological diagnosis in vivo. Ann Neurol 2017;81:430-443.


The functional consequences of cross-talk between the vitamin D receptor and ERK signaling pathways are cell-specific.
The actions of the active metabolite of 1,25-(OH)2D3 (1,25-D) are mediated primarily by the vitamin D receptor (VDR), a member of the nuclear receptor family of ligand-activated transcription factors. Although their ligands cause transcriptional activation, many of the ligands also rapidly activate cellular signaling pathways through mechanisms that have not been fully elucidated. We find that 1,25-D causes a rapid, but sustained activation of ERK (extracellular signal-regulated kinase) in bone cell lines. However, the effect of ERK activation on VDR transcriptional activity was cell line-specific. Inhibition of ERK activation by the MEK inhibitor, U0126, stimulated VDR activity in MC3T3-E1 cells, but inhibited the activity in MG-63 cells as well as in HeLa cells. VDR is not a known target of ERK. We found that the ERK target responsible for reduced VDR activity in MC3T3-E1 cells is RXRalpha. MC3T3-E1 cells express lower levels of RXRbeta and RXRgamma than either HeLa or MG-63 cells. Although overexpression of RXRalpha in MC3T3-E1 cells increased VDR activity, U0126 further enhanced the activity. In contrast, overexpression of RXRgamma stimulated VDR activity but abrogated the stimulation by U0126. Thus, although 1,25-D treatment activates ERK in many cell types, subsequently inducing changes independent of VDR, the effects of treatment with 1,25-D on the transcriptional activity of VDR are RXR isoform-specific. In cells in which RXRalpha is the VDR partner, the transcriptional activation of VDR by 1,25-D is attenuated by the concomitant activation of ERK. In cells utilizing RXRgamma, ERK activation enhances VDR transcriptional activity.


Attenuating the mortality risk of high serum uric acid: the role of physical activity underused.
High serum uric acid (sUA) has been associated with increased mortality risks, but its clinical treatment varied with potential side effects. The role of physical activity has received limited attention. A cohort, consisting of 467 976 adults, who went through a standard health screening programme, with questionnaire and fasting blood samples, was successively recruited between 1996 and 2008. High sUA is defined as uric acid above 7.0 mg/dL. Leisure time physical activity level was self-reported, with fully active defined as those with 30 min per day for at least 5 days a week. National death file identified 12 228 deaths with a median follow-up of 8.5 years. Cox proportional model was used to analyse HRs, and 12 variables were controlled, including medical history, life style and risk factors. High sUA constituted one quarter of the cohort (25.6%). Their all-cause mortality was significantly increased [HR: 1.22 (1.15-1.29)], with much of the increase contributed to by the inactive (HR: 1.27 (1.17-1.37)), relative to the reference group with sUA level of 5-6 mg/dL. When they were fully active, mortality risks did not increase, but decreased by 11% (HR: 0.89 (0.82-0.97)), reflecting the benefits of being active was able to overcome the adverse effects of high sUA. Given the same high sUA, a 4-6 years difference in life expectancy was found between the active and the inactive. Physical activity is a valuable alternative to pharmacotherapy in its ability to reduce the increases in mortality risks from high sUA. By being fully active, exercise can extend life span by 4-6 years, a level greater than the 1-4 years of life-shortening effect from high sUA.


Prevalence and Determinants of Self-reported Morbidity among Pregnant Women in Rural Areas of Pakistan.
The maternal mortality ratio (MMR) in Pakistan is estimated at 400 maternal deaths per 100,000 live births. Prevalence of minor and major illnesses related with pregnancy and childbirth is much higher. However, most births in the rural areas take place at home, conducted by untrained traditional birth attendants. Data on the prevalence of maternal morbidity is, therefore, limited. Self-reporting of illnesses related with pregnancy and childbirth is generally considered as unreliable, as women's perception of the seriousness of the health problems is inadequate. The data were collected in a baseline survey that was conducted for an operations research project of the Ministry of Health, Government of Pakistan. The baseline survey comprised interviews with the ever-married women in the reproductive ages (15-49 years). For the selection of eligible women for the interview, a two-staged cluster random sampling procedure was applied. The response rate was 94.4% and interviews with 9,118 of the identified 9,655 females were successfully completed. The interviews were conducted by female interviewers having graduate degree or above. Completed questionnaires were edited and coded by a team of professional data editors. The prevalence of maternal morbidity in this study was 20%, which is considered to be high, although can be expected in this population. Nearly half of the women reported some kind of illness during pregnancy, which is also expected. This study also estimated that the unmet obstetric need among rural women was very high; this finding has policy implication, as the need for alternative and more operational indicators of maternal health is increasingly felt. It is recommended that population-based studies and national surveys routinely incorporate well designed questions to elicit information on self-reported maternal morbidity; the same studies can also be used to identify the determinants of common obstetric problems and to estimate the unmet need of obstetric care.


Insights into the assembly and regulation of the bacterial divisome.
The ability to split one cell into two is fundamental to all life, and many bacteria can accomplish this feat several times per hour with high accuracy. Most bacteria call on an ancient homologue of tubulin, called FtsZ, to localize and organize the cell division machinery, the divisome, into a ring-like structure at the cell midpoint. The divisome includes numerous other proteins, often including an actin homologue (FtsA), that interact with each other at the cytoplasmic membrane. Once assembled, the protein complexes that comprise the dynamic divisome coordinate membrane constriction with synthesis of a division septum, but only after overcoming checkpoints mediated by specialized protein-protein interactions. In this Review, we summarize the most recent evidence showing how the divisome proteins of Escherichia coli assemble at the cell midpoint, interact with each other and regulate activation of septum synthesis. We also briefly discuss the potential of divisome proteins as novel antibiotic targets.


Interaction of positronium with dissolved oxygen in liquids.
The interaction of positronium (Ps) with molecular oxygen dissolved in liquids is experimentally investigated. Computer software has been developed for fitting the positron annihilation lifetime spectra in liquids using parameters with clear physical meaning: rate constants of the Ps chemical reactions, annihilation rate constants of the different positron states, probability of Ps formation in a quasi-free state, typical formation time of a Ps nanobubble. Such processing of the spectra allowed identification of the dominant interaction of the Ps atom with dissolved oxygen. It turns out to be mainly ortho-para-conversion (Ps → 1/4 p-Ps + 3/4 o-Ps), but not oxidation (Ps + O2→ e+ + O2-). Values of the reaction rate constants are obtained.


Simultaneous four-wave mixing and cross-gain modulation for implementing an all-optical XNOR logic gate using a single SOA.
We report on an all-optical XNOR-gate using simultaneous Four-Wave Mixing (FWM) and Cross-Gain Modulation (XGM) in a semiconductor optical amplifier (SOA). FWM generates the bitwise AND output corresponding to the two input data streams while XGM is used to generate the NOR output. These two outputs are combined using a coupler to obtain the final XNOR output. Error-free operation for RZ data with <2dB power-penalty is reported.


A new ketogenic formulation improves functional outcome and reduces tissue loss following traumatic brain injury in adult mice.
Rationale: Traumatic brain injury (TBI) leads to neurological impairment, with no satisfactory treatments available. Classical ketogenic diets (KD), which reduce reliance on carbohydrates and provide ketones as fuel, have neuroprotective potential, but their high fat content reduces compliance, and experimental evidence suggests they protect juvenile brain against TBI, but not adult brain, which would strongly limit their applicability in TBI. Methods: We designed a new-KD with a fat to carbohydrate plus protein ratio of 2:1, containing medium chain triglycerides (MCT), docosahexaenoic acid (DHA), low glycaemic index carbohydrates, fibres and the ketogenic amino acid leucine, and evaluated its neuroprotective potential in adult TBI. Adult male C57BL6 mice were injured by controlled cortical impact (CCI) and assessed for 70 days, during which they received a control diet or the new-KD. Results: The new-KD, that markedly increased plasma Beta-hydroxybutyrate (β-HB), significantly attenuated sensorimotor deficits and corrected spatial memory deficit. The lesion size, perilesional inflammation and oxidation were markedly reduced. Oligodendrocyte loss appeared to be significantly reduced. TBI activated the mTOR pathway and the new-KD enhanced this increase and increased histone acetylation and methylation. Conclusion: The behavioural improvement and tissue protection provide proof of principle that this new formulation has therapeutic potential in adult TBI.


Afatinib in first-line setting for NSCLC harbouring common EGFR mutations: new light after the preliminary results of LUX-Lung 7?
The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) changed dramatically the history of non-small cell lung cancer (NSCLC) harboring EGFR sensitive mutations. Several randomized prospective trials confirmed the superiority of these target agents about survival and response rate when comparing with platinum-based chemotherapy. Knowledge about EGFR mutations increased gradually during the development of target agents and different clinical trials. EGFR mutations cannot be considered all equal, but different entities should be considered in our clinical practice: exon 19 deletions, exon 21 mutation (L858R) and uncommon mutation (exon 20, exon 18 and double mutation). Nowadays, we dispose of three different EGFR TKIs (afatinib, erlotinib and gefitinib) approved for the treatment for first-line treatment of patients di NSCLC carrying EGFR, that was compared only by indirect analysis, producing data not always clear and convincing. This research highlight is an overview of data about EGFR TKIs in first-line setting, focusing on differences about exon 19 deletions and L585R mutation in patients treated with different TKIs. In addition, we report the preliminary results of the first head-to-head randomized clinical trial between two different EGFR TKIs, the LUX-Lung 7 (LL7) that compared afatinib and gefitinib showing interesting results.


Clinical Application and the Free Posterior Thigh Perforator Flap.
The posterior thigh region has been neglected as a donor site for free perforator flaps, likely due to difficulties in positioning the patient during surgery. This study describes the clinical application of the posterior thigh perforator flap based on the third perforating artery of the profunda femoris artery (PFA). The free posterior thigh perforator flap based on the third perforating artery of the PFA was used for reconstruction of soft tissue defects in nine patients between February 2010 and May 2014. Flap sizes ranged from 12 × 7 cm to 20 × 13 cm. The length of the vascular pedicle averaged 10.28 cm, and the mean diameters of the third perforating artery and venae comitantes were 1.68 and 1.14 mm, respectively. All of the perforators originated from the PFA. Of the 9 free flaps used in 9 patients, 7 flaps survived completely. There were no early complications in these flaps. During the follow-up period, no patient experienced cold intolerance, scar contracture, or scar pain. There were no functional impairments at the donor or recipient sites. The posterior thigh flap based on the third perforating artery of the PFA is an excellent option for reconstructing soft tissue defects. The anatomical location of the third perforating artery is relatively consistent. The vascular pedicle is relatively longer and has large caliber vessels. The scar at the donor site can be well concealed with low morbidity. The skin color and texture of this flap show satisfactory results.


The modes of action of ion-channel-targeting neurotoxic insecticides: lessons from structural biology.
Insecticides are indispensable tools for plant protection in modern agriculture. Despite having highly heterogeneous structures, many neurotoxic insecticides use similar principles to inhibit or deregulate neuronal ion channels. Insecticides targeting pentameric ligand-gated channels are structural mimetics of neurotransmitters or manipulate and deregulate the proteins. Those binding to (pseudo-)tetrameric voltage-gated(-like) channels, on the other hand, are natural or synthetic compounds that directly block the ion-conducting pore or prevent conformational changes in the transmembrane domain necessary for opening and closing the pore. The use of a limited number of inhibition mechanisms can be problematic when resistances arise and become more widespread. Therefore, there is a rising interest in the development of insecticides with novel mechanisms that evade resistance and are pest-insect-specific. During the last decade, most known insecticide targets, many with bound compounds, have been structurally characterized, bringing the rational design of novel classes of agrochemicals within closer reach than ever before.


[The postcholecystectomy syndrome and its prevention].
61 patients had a surgery because of postcholecystectomy syndrome (PCS). In 29 patients PCS was caused by bile tract diseases, in 15 patients--liver and pancreas diseases, in 12 cases disease of other organs. There was no mortality in restorative operations. The mortality rate in reconstructive operations was 5%. The full clinical and instrumental examination of extrahepatic bile ducts is the best way to prevent PCS. PCS was most frequently observed in patients, operated on urgently. The results of 79 cases of reconstructive and restorative operations in patients operated on urgently are analysed.


Novel use of laparoscopic-guided TAP block in total laparoscopic hysterectomy.
Transverse abdominis plane (TAP) block is a peripheral nerve block designed to anaesthetise the nerves supplying the anterolateral abdominal wall (T6 to L1). We introduced laparoscopic TAP block at Ninewells Hospital in 2014 and present a retrospective study assessing its efficacy. To our knowledge, there is limited study done on laparoscopic-guided TAP block whilst there are abundant literatures available on ultrasound-guided TAP block. To evaluate the efficacy of laparoscopic-guided TAP block as postoperative analgesia following total laparoscopic hysterectomy (TLH). A retrospective study was done between November 2014 to October 2016 (24 months) comparing patients who had TLH with TAP block (Group 1; n = 45) and patients who had TLH without TAP block (Group 2; n = 31) in our gynaecology unit. Patients were identified from theatre database. Data was collected from clinical portal and medical notes. The data included demographic information, BMI, METS score, intra-operative opiates use, post-operative pain scores, opiate requirements and use of patient-controlled analgesia (PCA), total dose of opiates used and day of discharge. The outcomes were analysed using means, odds ratios (OR), Mann-Whitney U-test and Fisher's exact or Chi-square test with 95% confidence interval (CI). Patients in Group 1 were older (mean age of 64.4, range 38-87) when compared to Group 2 (mean age of 49.3, range 37-81). Group 1 and 2 had comparable mean BMI (30.34 vs. 30.02) and METS score (6.77 vs. 7.76). Mean post-operative pain scores were lower in Group 1 within 4 hours, in periods of 4-12 hours, 12-24 hours and 24-48 hours post-op. Smaller proportion of patients in Group 1 required opiates post-operatively in all periods as compared to Group 2. This was statistically significant in the periods of 12-24 hours post-op (OR 0.31, 95% CI 0.11-0.82; p = .01). PCA use was significantly lower in Group 1 (OR 0.02, 95% CI 0.0014-0.46; p = .01). Group 1 had lower mean total dose of opiates used (27.182 mg, range 0-102 mg) than Group 2 (59.452 mg, range 0-240 mg), which was statistically significant (p < .0001). Average post-op hospital stay was 1.3 and 1.8 days in Group 1 and 2, respectively. Laparoscopic-guided TAP block delivered as post-operative analgesia following TLH results in reduced opiate requirement at post-operative period 12-24 hours, reduced PCA use and lower total dose of opiates used.


First Report of Resistance to Ivermectin in Parascaris univalens in Iceland.
Horses in Iceland have been isolated for more than 1,000 yr but still harbor a similar range of gastrointestinal parasites as do horses across the world. The long isolation of the horses and their parasites presumably means that no resistance genes have been introduced into the Parascaris spp. population. It is therefore of particular interest to investigate the efficacy of ivermectin on Parascaris spp. infecting Icelandic foals. Potential treatment failure of ivermectin in Iceland will add substantial new information on how resistance can arise independently. This study aimed to determine the efficacy of subcutaneous injection of ivermectin for the treatment of Parascaris spp. infection in foals and to identify the Parascaris species present in the west and north of Iceland. A fecal egg count reduction (FECR) test (FECRT) was performed on 50 foals from 8 farms, including an untreated control group of 6 foals, from September to November 2019. The foals were between 3 and 5 mo of age at the start of the study and had not previously been treated with anthelmintic drugs. Each foal was treated subcutaneously with off-label use of Ivomec® injection 10 mg/ml or Noromectin® 1% at a dose of 0.2 mg/kg. The FECR for each farm was calculated in 2 ways, by the eggCounts package in R and by the Presidente formula (FECRT). Both calculation methods resulted in efficacy levels between 0% and 80.78%, indicating ivermectin resistance on all farms. We also confirmed, by karyotyping, that the species of equine ascarid present in the west and north of Iceland is Parascaris univalens. This study provides evidence for treatment failure of ivermectin against P. univalens infection in foals. Since Icelandic horses have been isolated on the island for more than 1,000 yr, this implies that resistance alleles have developed independently in the Icelandic Parascaris population. The actual clinical impact of ivermectin resistance is unknown but another drug of choice should be considered to treat Parascaris infection in foals in Iceland.


Retrograde fenestration of endoluminal grafts from target vessels: feasibility, technique, and potential usage.
To report initial experiments involving a new method for percutaneous intraprocedural stent-graft fenestration from the target vessel. In bench and canine models, the fabric of an implanted Zenith endograft was punctured easily using the stiff end of a coronary 0.014-inch guidewire delivered through the target vessel (e.g., renal or iliac artery). A 20-G cutting needle was passed over the coronary wire to enlarge the puncture site, followed by a cutting balloon to create a fenestration that was of sufficient size to allow deployment of a stent. In vivo endograft fenestration of a Zenith endograft is feasible. In addition to providing a percutaneous means of intentionally fenestrating a stent-graft from the artery to be perfused, the technique has potential application as a bailout maneuver after inadvertent side branch occlusion. Although the time to achieve successful fenestration in the experimental model was long, refinement may achieve performance times adequate to maintain viability of the end organ.


The deposition of strontium-substituted hydroxyapatite coatings.
Strontium substituted hydroxyapatite (SrHA) coatings have received a lot of interest recently as strontium (Sr) has been shown to have the dual benefit of promoting bone formation and reducing bone resorption, in vivo. In this work, SrHA coatings were deposited onto polycrystalline titanium surfaces using radio frequency (RF) magnetron co-sputtering and compared to those deposited from HA alone. In particular, the influence of different levels of Sr-substitution of the sputtering targets (5 and 13% Sr-substituted HA targets) on the properties of the deposited coatings produced at a low discharge power level (150 W) were investigated using FTIR, XPS, XRD, ToFSIMS and AFM techniques (both before and after annealing at 500 °C). The results show that Sr could be successfully incorporated into the HA lattice to form SrHA coatings and that they contained no other impurities. However, the coating produced from the 13% Sr-substituted target had a higher Ca+Sr/P ratio (1.95±0.14) and Sr content when compared to the coating produced from the 5% Sr-substituted target (1.58±0.20). The deposition rate also decreased with increasing Sr content of the sputtering targets. Furthermore, as the Sr content of the coatings increased, so did the preferred 002 orientation of the coating along with increased surface roughness and heterogeneity of the surface features. Therefore, this study has shown that RF magnetron sputtering offers a means to control attendant properties of Sr-substituted HA, such as the crystallinity, stoichiometry, phase purity and surface topography.


A randomized, controlled trial of oxycodone versus placebo in patients with postherpetic neuralgia and painful diabetic neuropathy treated with pregabalin.
The aim of this randomized double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of pregabalin in combination with oxycodone or placebo, in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). After a 7-day washout period, 62 patients were randomized to receive either oxycodone mixture 10 mg/day or placebo mixture for 1 week. Patients were then started on open-label pregabalin (75, 150, 300 and 600 mg/day) according to a forced titration dosing regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks. The primary efficacy measure was a decrease in the pain-intensity score of at least 2cm and a pain score <4cm measured using a 10-cm visual analogue scale (VAS) following pregabalin dosage escalation and treatment for 4 weeks. Secondary efficacy measures included sleep interference and the Neuropathic Pain Scale. There were similar levels of overall efficacy between pregabalin/oxycodone and pregabalin/placebo groups in relieving PHN and PDN related pain. Peripheral neuropathic pain presents commonly in clinical practice, and 2 of its most prevalent types are PHN and PDN. Currently available treatments provide some degree of pain relief in approximately 40-60% of patients, leaving the remainder with unremitting pain. Although this study supports the effectiveness of pregabalin in the treatment of PHN or PDN, it also shows that the addition of a low dose of oxycodone at 10mg/day does not enhance the pain-relieving effects of pregabalin.


The tetraspanin protein CD9 modulates infection with human herpesvirus 6A and 6B in a CD46-dependent manner.
Tetraspanins are four-span transmembrane proteins that organize the membrane by forming tetraspanin-enriched microdomains. These have been shown to be important for virus entry. The human herpesvirus (HHV)-6A receptor CD46 is known to form complexes with the tetraspanin CD9 and β1-integrins, however the significance of this for HHV-6A infection remains unexplored. Using a genetic approach, we demonstrate that knock out of CD46 abolishes binding to and infection of SupT1 cells by both HHV-6A and HHV-6B, establishing CD46 as a necessary receptor for productive infection of these cells. Knock out of CD9 in SupT1 cells had no effect on binding of either virus to the cell surface, but it reduced expression of immediate early transcripts to between 25-60% compared with the wild type cells. Although HHV-6B required CD46 for infection of SupT1, infection of Molt3 cells was independent of CD46 expression. Conversely, the absence of CD9 expression promoted infection of Molt3 cells with HHV-6B, indicating a negative role of CD9 for CD46-independent infection. Taken together, these data demonstrate that CD9 modulates infection with HHV-6A/B by promoting CD46-dependent infection and impairing CD46-independent infection. This also suggests that HHV-6A is strictly dependent on CD46 for entry, although other proteins, like CD9, may enhance the infection, whereas HHV-6B is more promiscuous and may use CD134, as demonstrated by others, CD46 in SupT1, and a novel yet unidentified receptor in Molt3 cells.Importance The mechanisms of entry of human herpesvirus (HHV)-6A and HHV-6B into host cells are of significance in order to develop novel drugs that may inhibit infection. To elucidate the contribution of the membrane proteins CD9 and CD46, we employed a genetic approach that eliminated these molecules from the host cell. This demonstrated that CD46 is critical for infection by HHV-6A, whereas infection by HHV-6B appeared to be more promiscuous. The infection of a T-cell line in the absence of CD46 and CD134 strongly suggest that an additional receptor for HHV-6B entry exists. Moreover, elimination of CD9 and subsequent reconstitution experiments demonstrated that CD9 promoted infection with HHV-6A and HHV-6B mediated by CD46, but inhibited infection with HHV-6B that occurred independent of CD46. Together, this demonstrated a CD46-dependent role of CD9 during infection with HHV-6A and HHV-6B and emphasized that HHV-6B may employ different entry mechanisms in various cells.


A molecular characterization of the agonist binding site of a nematode cys-loop GABA receptor.
Cys-loop GABA receptors represent important targets for human chemotherapeutics and insecticides and are potential targets for novel anthelmintics (nematicides). However, compared with insect and mammalian receptors, little is known regarding the pharmacological characteristics of nematode Cys-loop GABA receptors. Here we have investigated the agonist binding site of the Cys-loop GABA receptor UNC-49 (Hco-UNC-49) from the parasitic nematode Haemonchus contortus. We used two-electrode voltage-clamp electrophysiology to measure channel activation by classical GABA receptor agonists on Hco-UNC-49 expressed in Xenopus laevis oocytes, along with site-directed mutagenesis and in silico homology modelling. The sulphonated molecules P4S and taurine had no effect on Hco-UNC-49. Other classical Cys-loop GABAA receptor agonists tested on the Hco-UNC-49B/C heteromeric channel had a rank order efficacy of GABA > trans-4-aminocrotonic acid > isoguvacine > imidazole-4-acetic acid (IMA) > (R)-(-)-4-amino-3-hydroxybutyric acid [R(-)-GABOB] > (S)-(+)-4-amino-3-hydroxybutyric acid [S(+)-GABOB] > guanidinoacetic acid > isonipecotic acid > 5-aminovaleric acid (DAVA) (partial agonist) > β-alanine (partial agonist). In silico ligand docking revealed some variation in binding between agonists. Mutagenesis of a key serine residue in binding loop C to threonine had minimal effects on GABA and IMA but significantly increased the maximal response to DAVA and decreased twofold the EC50 for R(-)- and S(+)-GABOB. The pharmacological profile of Hco-UNC-49 differed from that of vertebrate Cys-loop GABA receptors and insect resistance to dieldrin receptors, suggesting differences in the agonist binding pocket. These findings could be exploited to develop new drugs that specifically target GABA receptors of parasitic nematodes.


Adolescent female sex workers: invisibility, violence and HIV.
A large number of female sex workers are children. Multiple studies demonstrate that up to 40% of women in prostitution started this work prior to age 18. In studies across India, Nepal, Thailand and Canada, young age at entry to sex work has been found to heighten vulnerability to physical and sexual violence victimisation in the context of prostitution, and relates to a two to fourfold increase in HIV infection. Although HIV risk reduction among adult female sex workers has been a major focus of HIV prevention efforts across the globe, no public health interventions, to date, have addressed the increased hazards and HIV risk faced by adolescent female sex workers. Beyond the structural barriers that limit access to this vulnerable group, historical tensions between HIV prevention and child protection agencies must be overcome in order to develop effective strategies to address this large scale yet little recognised human rights and HIV-related crisis.


Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration.
Angiotensin-converting enzyme 2 (ACE2) is a terminal carboxypeptidase with important functions in the renin-angiotensin system and plays a critical role in inflammatory lung diseases. ACE2 cleaves single-terminal residues from several bioactive peptides such as angiotensin II. However, few of its substrates in the respiratory tract have been identified, and the mechanism underlying the role of ACE2 in inflammatory lung disease has not been fully characterized. In an effort to identify biological targets of ACE2 in the lung, we tested its effects on des-Arg9 bradykinin (DABK) in airway epithelial cells on the basis of the hypothesis that DABK is a biological substrate of ACE2 in the lung and ACE2 plays an important role in the pathogenesis of acute lung inflammation partly through modulating DABK/bradykinin receptor B1 (BKB1R) axis signaling. We found that loss of ACE2 function in mouse lung in the setting of endotoxin inhalation led to activation of the DABK/BKB1R axis, release of proinflammatory chemokines such as C-X-C motif chemokine 5 (CXCL5), macrophage inflammatory protein-2 (MIP2), C-X-C motif chemokine 1 (KC), and TNF-α from airway epithelia, increased neutrophil infiltration, and exaggerated lung inflammation and injury. These results indicate that a reduction in pulmonary ACE2 activity contributes to the pathogenesis of lung inflammation, in part because of an impaired ability to inhibit DABK/BKB1R axis-mediated signaling, resulting in more prompt onset of neutrophil infiltration and more severe inflammation in the lung. Our study identifies a biological substrate of ACE2 within the airways, as well as a potential new therapeutic target for inflammatory diseases.


Antioxidant and Genotoxic Effects of Aqueous and Methanol Extracts from Two Edible Mushrooms from Turkey in Human Peripheral Lymphocytes.
This study reported the genetic and oxidative effects of aqueous and methanol extracts from two edible mushrooms, Lepista nuda (Bull.) Cooke and Pleurotus ostreatus (Jacq.) P. Kummer, in cultured human lymphocytes. Chromosome aberration (CA) and micronucleus (MN) assays were used for genotoxic influences estimation. In addition, the changes of total antioxidant capacity (TAC) and total oxidative stress (TOS) in the cells were monitored. The fungal extracts at all applied concentrations did not indicate significant differences (p > 0.05) in CA and MN analyses. Furthermore, while the treatments with maximum concentration of aqueous extract of L. nuda statistically (p < 0.05) increased TAC especially, TOS levels in the cells were reduced by them in comparison with negative control. Based on TAC analysis, low IC50 values belonging to aqueous (5.43 mg/L) and methanol (10.88 mg/L) extracts of L. nuda were remarkable. Our data demonstrated that the extracts obtained from P. ostreatus and especially L. nuda can be a new resource for therapeutics with their nonmutagenic and antioxidant features.


Eplerenone improves carotid intima-media thickness (IMT) in patients with primary aldosteronism.
Primary aldosteronism (PA) is associated with a higher rate of cardiovascular events than essential hypertension. Although adrenalectomy has been reported to reduce carotid intima-media thickness (IMT) in patients with PA, the effects of the selective aldosterone blocker, eplerenone, on vascular damage in these patients remains unclear. To evaluate the effects of eplerenone on vascular status in PA patients, we sequentially measured carotid IMT (using computer software to calculate an average IMT for accurate and reproducible evaluation) in 22 patients including 8 patients treated by unilateral adrenalectomy and 14 patients treated with eplerenone for 12 months. Patients who underwent adrenalectomy showed significant reductions in aldosterone concentration (from 345 ± 176 pg/mL to 67 ± 34 pg/mL; P<0.01) and IMT (from 0.67 ± 0.07 mm to 0.63 ± 0.09 mm; P<0.05) 6 months after surgery. Patients treated with eplerenone showed significant reductions in IMT from baseline (0.75 ± 0.10 mm) to 6 (0.71 ± 0.11 mm; P<0.05) and 12 (0.65 ± 0.09 mm; P<0.01) months, although plasma aldosterone level increased significantly, from 141 ± 105 pg/mL to 207 ± 98 pg/mL (P<0.05). Eplerenone treatment of patients with PA reduces blood pressure, increases serum potassium level, and improves vascular status. Carotid IMT may be a useful marker for evaluating the effectiveness of eplerenone in patients with PA.


[Norwegian tourists' use of medical services abroad].
Previous studies have shown that one in three holidaymakers experienced illness on their trip abroad. We wanted to find out what happens to Norwegian tourists. We have collected data from the Association of Norwegian Tour/Operators on travel patterns, and from a travel insurance company on illness and expenses. Between 1.5% and 5% of travellers get so ill that they need medical assistance. The number of consultations that results in hospitalisation vary from less than 5% in one country to more than 30% in neighbouring territories. Average cost of hospitalisation differ considerably from one country to another. It appears that cultural differences, differing treatment facilities, and varying required rates of return are decisive for whether or not a patient is referred to hospital.


PROSPECT guideline for rotator cuff repair surgery: systematic review and procedure-specific postoperative pain management recommendations.
Rotator cuff repair can be associated with significant and difficult to treat postoperative pain. We aimed to evaluate the available literature and develop recommendations for optimal pain management after rotator cuff repair. A systematic review using procedure-specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials published in English from 1 January 2006 to 15 April 2019 assessing postoperative pain after rotator cuff repair using analgesic, anaesthetic or surgical interventions were identified from MEDLINE, Embase and Cochrane Databases. Out of 322 eligible studies identified, 59 randomised controlled trials and one systematic review met the inclusion criteria. Pre-operative and intra-operative interventions that improved postoperative pain were paracetamol, cyclo-oxygenase-2 inhibitors, intravenous dexamethasone, regional analgesia techniques including interscalene block or suprascapular nerve block (with or without axillary nerve block) and arthroscopic surgical technique. Limited evidence was found for pre-operative gabapentin, perineural adjuncts (opioids, glucocorticoids, or α-2-adrenoceptor agonists added to the local anaesthetic solution) or postoperative transcutaneous electrical nerve stimulation. Inconsistent evidence was found for subacromial/intra-articular injection, and for surgical technique-linked interventions, such as platelet-rich plasma. No evidence was found for stellate ganglion block, cervical epidural block, specific postoperative rehabilitation protocols or postoperative compressive cryotherapy. The analgesic regimen for rotator cuff repair should include an arthroscopic approach, paracetamol, non-steroidal anti-inflammatory drugs, dexamethasone and a regional analgesic technique (either interscalene block or suprascapular nerve block with or without axillary nerve block), with opioids as rescue analgesics. Further randomised controlled trials are required to confirm the influence of the recommended analgesic regimen on postoperative pain relief.


Poverty or income inequality as predictor of mortality: longitudinal cohort study.
To determine the effect of inequality in income between communities independent of household income on individual all cause mortality in the United States. Longitudinal cohort study. A nationally representative sample of 14,407 people aged 25-74 years in the United States from the first national health and nutrition examination survey. Subjects were followed from initial interview in 1971-5 until 1987. Complete follow up information was available for 92.2% of the sample. Relation between both household income and income inequality in community of residence and individual all cause mortality at follow up was examined with Cox proportional hazards survival analysis. Community income inequality showed a significant association with subsequent community mortality, and with individual mortality after adjustment for age, sex, and mean income in the community of residence. After adjustment for individual household income, however, the association with mortality was lost. In this nationally representative American sample, family income, but not community income inequality, independently predicts mortality. Previously reported ecological associations between income inequality and mortality may reflect confounding between individual family income and mortality.


The choice of test in phase II cancer trials assessing continuous tumour shrinkage when complete responses are expected.
Traditionally, phase II cancer trials test a binary endpoint formed from a dichotomisation of the continuous change in tumour size. Directly testing the continuous endpoint provides considerable gains in power, although also results in several statistical issues. One such issue is when complete responses, i.e. complete tumour removal, are observed in multiple patients; this is a problem when normality is assumed. Using simulated data and a recently published phase II trial, we investigate how the choice of test affects the operating characteristics of the trial. We propose using parametric tests based on the censored normal distribution, comparing them to the t-test and Wilcoxon non-parametric test. The censored normal distribution fits the real dataset well, but simulations indicate its type-I error rate is inflated, and its power is only slightly higher than the t-test. The Wilcoxon test has deflated type I error. For two-arm designs, the differences are much smaller. We conclude that the t-test is suitable for use when complete responses are present, although positively skewed data can result in the non-parametric test having higher power.


Development of the lymphoedema genito-urinary cancer questionnaire.
The aim of this study was to develop a patient self-report tool to detect symptoms of genital and lower limb lymphoedema in male survivors of genitourinary cancer. The study incorporated the views of patients and subject specialists (lymphoedema and urology) in the design of a patient questionnaire based on the literature. Views on comprehensiveness, relevance of content, ease of understanding and perceived acceptability to patients were collated. The findings informed the development of the next iteration of the questionnaire. The overall view of participants was that the development and application of such a tool was of great clinical value and the Lymphoedema Genito-Urinary Cancer Questionnaire (LGUCQ) has significant potential for further development as a research tool to inform prevalence of this under-reported condition.


Regulation of Cl/HCO3 exchange in gastric parietal cells.
Microspectrofluorimetry of the fluorescent indicators 2',7'-bis-(2-carboxyethyl)-5(and-6)carboxyfluorescein and 6-methoxy-N-(3-sulfopropyl)-quinolinium was used to measure intracellular pH (pHi), intracellular Cl (Cli), and transmembrane fluxes of HCO3 and Cl in single parietal cells (PC) in isolated rabbit gastric glands incubated in HCO3/CO2-buffered solutions. Steady-state pHi was 7.2 in both resting (50 microM cimetidine) and stimulated (100 microM histamine) PCs. Transmembrane anion (HCO3 or Cl) flux rates during Cl removal from or readdition to the perfusate were the same in resting and stimulated PCs. These rates increased at alkaline pHi, though this pHi dependence was small in the physiological range. Maximum velocity (Vmax) for Cl influx or HCO3 efflux was 80-110 mM/min at pHi 7.6-7.8, and the Km for extracellular concentrations of Cl (Clo) was 25 mM; in the physiological range (pHi 7.1-7.3), Vmax for anion fluxes was approximately 50 mM/min. Steady-state Cli in the unstimulated PC was 62 +/- 5 mM, but on histamine stimulation, Cli decreased rapidly to 25 mM and then increased back to a steady-state level of 44 mM. HCO3 fluxes due to Cl removal or readdition were completely blocked by 0.5 mM 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonic acid (H2DIDS), but Cl fluxes were only inhibited by 80%. H2DIDS did not inhibit the decrease in Cli that occurred with histamine treatment. Diphenylamine carboxylate (0.5 mM) inhibited Cl flux by only 50% and caused no additional inhibition of Cl flux when used in conjunction with H2DIDS. Transmembrane anion fluxes during solution Cl removal or readdition occurred 80% through the anion exchanger at the basal membrane and 20% through other pathway(s), presumably the Cl channel in the apical membrane. We conclude that the increase in transport activity via the Cl/HCO3 exchanger that occurs during histamine-induced increases in HCl secretion is due mostly to the decrease in Cli. In the resting cell with Cli = 62 mM, Clo = 120 mM, pHi = 7.2, and extracellular pH = 7.4, the anion exchanger is poised near its thermodynamic equilibrium. During histamine stimulation Cli drops from 62 mM to 44 mM, the thermodynamic equilibrium of the anion exchanger at the basolateral membrane is disturbed, and the anion exchanger then exchanges cellular HCO3 for extracellular Cl. Cli serves a crucial regulatory role in stimulus-secretion coupling in the PC.


Stable, efficient, and all-solution-processed quantum dot light-emitting diodes with double-sided metal oxide nanoparticle charge transport layers.
An efficient and stable quantum dot light-emitting diode (QLED) with double-sided metal oxide (MO) nanoparticle (NP) charge transport layers is fabricated by utilizing the solution-processed tungsten oxide (WO3) and zinc oxide (ZnO) NPs as the hole and electron transport layers, respectively. Except for the electrodes, all other layers are deposited by a simple spin-coating method. The resulting MO NP-based QLEDs show excellent device performance, with a peak luminance of 21300 cd/m(2) at the emission wavelength of 516 nm, a maximal current efficiency of 4.4 cd/A, and a low turn-on voltage of 3 V. More importantly, with the efficient design of the device architecture, these devices exhibit a significant improvement in device stability and the operational lifetime of 95 h measured at room temperature can be almost 20-fold longer than that of the standard device.


Approaching psoriasis differently: patient-physician relationships, patient education and choosing the right topical vehicle.
Psoriasis is a common, frustrating problem for dermatologists and patients. Long-held notions about the need to use thick, greasy corticosteroid ointments for psoriasis contributed to frustration for many patients. Fortunately, the general approach to managing psoriasis is changing. The purpose of this article is to describe key components of psoriasis management with a focus on the changing paradigm for treating the disease. In addition to making the right diagnosis and prescribing the right treatment, key elements of psoriasis management include establishing a strong physician-patient relationship, educating patients about the disease and recognizing the importance of adherence to topical treatment. In light of the tendency toward poor adherence, use of a fast-acting agent in a vehicle that patients are willing to use is critically important for successful disease management.


How to Map Noise.
Noise mapping is a method of presenting complex noise information in a clear and simple way either on a physical map or in a database. This mapping information can be either calculated or measured using a variety of techniques and methods. Furthermore, the results of such exercises can be presented in many different ways and used for a number of different purposes. This paper attempts to examine these issues in the light of the "mapping requirements" outlined in the recently proposed Directive of the European Parliament and of the Council, relating to the Assessment and Management of Environmental Noise (Comm (2000) 468 final). This proposed Directive was laid before the Parliament and Council in the autumn of 2000. The First Reading of the proposal was successfully negotiated just before Christmas 2000. The Second Reading is likely to commence shortly.


Erythroderma: A clinicopathological study of 47 cases from 2018 to 2020.
Erythroderma, or exfoliative dermatitis, is an inflammatory disorder characterized by erythema and scaling, affecting most of the skin surface. It may be a result of many different causes such as previous dermatoses (psoriasis, eczema, atopic dermatitis [AD], pityriasis rubra pilaris, and pemphigus foliaceous), drug reactions, malignancies (mycosis fungoides [MF], Sézary syndrome, adult T cell leukemia/lymphoma), infections, and idiopathic disorders. Regardless of the etiology, the clinical appearance of erythroderma is similar in all patients. The most prominent physical examination findings in almost all patients are diffuse erythema and scaling. In a 2-year period, 47 patients who were hospitalized and treated in our department were included in the study. We classified patients into seven subgroups: psoriasis, AD, drug-induced erythroderma, MF, pityriasis rubra pilaris, bullous pemphigoid, and polymorphous light eruption. All patients had a biopsy during the acute stage and diagnoses were histopathologically confirmed. Some patients had multiple biopsies for histopathological confirmation. In our study, the majority of the patients were men over the age of 54. The most common etiological cause of erythroderma is psoriasis. We aim to analyze clinical, laboratory, and histopathological findings of erythrodermic inpatients prospectively in Istanbul University-Cerrahpasa Cerrahpasa Medical Faculty between January 2018 and 2020.


Soma-to-germline interactions during Drosophila oogenesis are influenced by dose-sensitive interactions between cut and the genes cappuccino, ovarian tumor and agnostic.
The cut gene of Drosophila melanogaster encodes a homeodomain protein that regulates a soma-to-germline signaling pathway required for proper morphology of germline cells during oogenesis. cut is required solely in somatic follicle cells, and when cut function is disrupted, membranes separating adjacent nurse cells break down and the structural integrity of the actin cytoskeleton is compromised. To understand the mechanism by which cut expression influences germline cell morphology, we determined whether binucleate cells form by defective cytokinesis or by fusion of adjacent cells. Egg chambers produced by cut, cappuccino, and chickadee mutants contained binucleate cells in which ring canal remnants stained with antibodies against Hu-li tai shao and Kelch, two proteins that are added to ring canals after cytokinesis is complete. In addition, defects in egg chamber morphology were observed only in middle to late stages of oogenesis, suggesting that germline cell cytokineses were normal in these mutants. cut exhibited dose-sensitive genetic interactions with cappuccino but not with chickadee or other genes that regulate cytoskeletal function, including armadillo, spaghetti squash, quail, spire, Src64B, and Tec29A. Genomic regions containing genes that cooperate with cut were identified by performing a second-site noncomplementing screen using a collection of chromosomal deficiencies. Sixteen regions that interact with cut during oogenesis and eight regions that interact during the development of other tissues were identified. Genetic interactions between cut and the ovarian tumor gene were identified as a result of the screen. In addition, the gene agnostic was found to be required during oogenesis, and genetic interactions between cut and agnostic were revealed. These results demonstrate that a signaling pathway regulating the morphology of germline cells is sensitive to genetic doses of cut and the genes cappuccino, ovarian tumor, and agnostic. Since these genes regulate cytoskeletal function and cAMP metabolism, the cut-mediated pathway functionally links these elements to preserve the cytoarchitecture of the germline cells.