Indeterminate cell tumor: a rare dendritic neoplasm.
Indeterminate cell tumor (ICT) is a rare neoplastic dendritic cell disorder that has been poorly defined due to its rarity and poorly understood histogenesis and pathogenesis. It is characterized by a proliferation of dendritic cells, which mimic Langerhans cells immunophenotypically (positive for CD1a and S-100 protein), but lack Birbeck granules characteristic of Langerhans cells. The clinical, morphologic, immunophenotypic, and ultrastructural features of 5 ICT cases are reported in an attempt to further define ICT and to examine the postulated relationship between indeterminate cells and Langerhans cells. Four of 5 patients were females, and 4 of 5 were older than 68 years. Three of 5 patients had cutaneous lesions, whereas 2 presented with cervical lymph node involvement. Two patients had a possible association with lymphoma: first patient had a history of progressive follicular lymphoma that led to patient's demise and the second patient had unexplained systemic lymphadenopathy and died 1 week after the biopsy. All 5 ICT cases expressed CD1a and S-100 protein, but lacked Langerin expression and Birbeck granules ultrastructurally. Interestingly, a t(14;18) was detected by fluorescence in situ hybridization in the ICT cells of the patient with previous follicular lymphoma and a monoclonal kappa light chain gene rearrangement was detected by polymerase chain reaction in the patient with systemic lymphadenopathy. In both cases, there was no morphologic or immunophenotypic evidence of a concurrent B-cell lymphoma. In conclusion, ICT is a rare neoplasm that can occur de novo or in association with a B-cell lymphoma, possibly as a result of B-cell dedifferentiation caused by relatively unknown mechanisms. Finally, Langerin immunostaining may be used as a surrogate marker for the ultrastructural demonstration of Birbeck granules, the absence of which represents a strong diagnostic criterion for ICT.


Meta-analysis and quality of evidence in the economic evaluation of drug trials.
Meta-analysis is an important part of assessing cost-effectiveness in that it may help determine which treatments are indeed effective and estimate the level of effectiveness of each. Meta-analysis uses the data from all the relevant trials and is a powerful tool for detecting effects too small to be picked up by individual trials. The assessment of quality of studies in a meta-analysis is critical, with priority needing to be given to high quality randomised studies. A written protocol, literature retrieval system, evaluation and selection criteria, choice of endpoints and ways to evaluate bias must all be pre-defined. Nevertheless, problems can arise when meta-analysis is used for cost-effectiveness analysis, due to variation in study medication protocols, duration of follow-up, and difficulties in interpreting patient subgroups and compliance. Despite being subject to the design flaws of both the trials analysed and the methods used in the analysis itself, meta-analysis provides a more objective and thorough means of evaluating effectiveness and hence the cost-effectiveness of treatments. Based on the meta-analysis evidence, we recommend that the current QALY league tables be split into an implementation table for clearly effective therapies, and a research priority table where the evidence of treatment effectiveness is less clear and more research is needed.


Role of nerve growth factor in the development of rat sympathetic neurons in vitro. III. Effect on acetylcholine production.
The effect of nerve growth factor (NGF) on the development of cholinergic sympathetic neurons was studied in cultures grown either on monolayers of dissociated rat heart cells or in medium conditioned by them. In the presence of rat heart cells the absolute requirement of neurons for exogenous NGF was partially spared. The ability of heart cells to support neuronal survival was due at least in part to production of a diffusable NGF-like substance into the medium. Although some neurons survived on the heart cell monolayer without added NGF, increased levels of exogenous NGF increased neuronal survival until saturation was achieved at 0.5 microgram/ml 7S NGF. The ability of neurons to produce acetylcholine (ACh) from choline was also dependent on the level of exogenous NGF. In mixed neuron-heart cell cultures, NGF increased both ACh and catecholamine (CA) production per neuron to the same extent; saturation occurred at 1 microgram/ml 7S NGF. As cholinergic neurons developed in culture, they became less dependent on NGF for survival and ACh production, but even in older cultures approximately 40% of the neurons died when NGF was withdrawn. Thus, NGF is as necessary for survival, growth, and differentiation of sympathetic neurons when the neurons express cholinergic functions as when the neurons express adrenergic functions (4, 5).


Preliminary experiments on use of zebrafish as a laboratory model for Giardia duodenalis infection.
Although Giardia duodenalis is considered a parasite of mammals, different genotypes have been identified as infecting several species of freshwater and marine fish in Australia. Establishment of G. duodenalis infection in common laboratory zebrafish (Danio rerio), could provide an excellent tool for a range of studies on Giardia. We conducted preliminary experiments to investigate this possibility. Zebrafish were inoculated with viable G. duodenalis cysts from two different Assemblages (A and D) using a modified oro-gastric tube. Direct microscopy and immunofluorescent antibody test were used to check for Giardia cysts/trophozoites in the intestine, and histology was performed on intestinal mucosa to evaluate possible pathological changes. Giardia cysts were successfully deposited in the zebrafish alimentary tract using a modified oro-gastric tube, and were maintained in the fish gut for at least 8 days. Although a single trophozoite was observed in one fish three days post-exposure, we were unable to demonstrate established, propagative infection under the conditions tested.


Synthetic, structural, and mechanistic aspects of an amine activation process mediated at a zwitterionic Pd(II) center.
A zwitterionic palladium complex [[Ph(2)BP(2)]Pd(THF)(2)][OTf] (1) (where [Ph(2)BP(2)] = [Ph(2)B(CH(2)PPh(2))(2)](-)) reacts with trialkylamines to activate a C-H bond adjacent to the amine N atom, thereby producing iminium adduct complexes [Ph(2)BP(2)]Pd(N,C:eta(2)-NR(2)CHR'). In all cases examined the amine activation process is selective for the secondary C-H bond position adjacent to the N atom. These palladacycles undergo facile beta-hydride elimination/olefin reinsertion processes as evident from deuterium scrambling studies and chemical trap studies. The kinetics of the amine activation process was explored, and beta-hydride elimination appears to be the rate-limiting step. A large kinetic deuterium isotope effect for the amine activation process is evident. The reaction profile in less polar solvents such as benzene and toluene is different at room temperature and leads to dimeric [[Ph(2)BP(2)]Pd](2) (4) as the dominant palladium product. Low-temperature toluene-d(8) experiments proceed more cleanly, and intermediates assigned as [Ph(2)BP(2)]Pd(NEt(3))(OTf) and the iminium hydride species [[Ph(2)BP(2)]Pd(H)(Et(2)N=CHCH(3))][OTf] are directly observed. The complex (Ph(2)SiP(2))Pd(OTf)(2) (14) was also studied for amine activation and generates dimeric [(Ph(2)SiP(2))Pd](2)[OTf](2) (16) as the dominant palladium product. These collective data are discussed with respect to the mechanism of the amine activation and, in particular, the influence that solvent polarity and charge have on the overall reaction profile.


Unexpected hypopotassemia after multiple blood transfusions during an operation.
A series of 226 patients undergoing major surgery was studied to asses the influence of the volume of transfused donor blood on the postoperative serum potassium level. Patients with a low serum potassium and with impaired renal function preoperatively and patients receiving medication capable of reducing the total body potassium were excluded from the study. Laboratory studies included complete blood count, electrolyte value measurements, serum creatinine, BUN, glucose, acid-base balance as well as urinalysis. A direct relationship between the volume of transfused blood and a shift of serum potassium was not found. Hyperkalemia did not occur, however, unexpected hypokalemia occurred in 50 patients. Metabolic acidosis and hyperglycemia were found in 57% and 48% respectively and did not seem to have a distinct influence on the potassium balance. As this hypokalemia can cause complications, its presence has to be anticipated and certain drugs like calcium, insulin, bicarbonate and digitalis have to be used with great caution in this situation.


Supracondylar fractures of the humerus in children. Analysis at maturity of fifty-three patients treated conservatively.
From a pool of 131 supracondylar fractures of the humerus in 131 patients who were treated conservatively, all of which healed in an average time of 4.5 weeks without complications related to the treatment itself, the cases of fifty-three patients were reviewed at maturity. The average age at follow-up was twenty-six years. Nine patients had unimportant limitation of elbow motion, and slight atrophy of the musculature of the arm or forearm, or of both, was present in six patients. Arm-length discrepancy was never observed. The carrying angle remained at about the same value that had been present at the time of fracture-healing in eighteen patients, decreased in twenty-two patients, and increased in thirteen. Malrotation of the distal fragment of the fracture only rarely caused medial tilting of the fragment with consequent cubitus varus. Varus deformity was present in four patients and valgus deformity, in three. None of the patients with valgus deformity had ulnar-nerve palsy. According to our results, varus and valgus deformities of the elbow after supracondylar fractures of the humerus seem to be caused either by growth imbalance of the growth plate of the distal end of the humerus (four patients) or by malreduction of the fracture (three patients). Twelve patients in the entire pool had neurological complications at the time of the fracture. Ten of those patients fully recovered from the deficit, whereas two--one with a radial-nerve deficit and the other with ulnar-nerve involvement--still had neurological impairment at follow-up.


In vitro starch digestibility and in vivo glucose response of gluten-free foods and their gluten counterparts.
Recently there has been increasing interest in the production of gluten-free (GF) foods and studies on minor cereals and pseudocereals without celiac activity in order to fulfill the specific needs of people affected by celiac disease. GF bread, pasta, biscuits are usually manufactured using different combinations of thickenings and particular food processing procedures that could affect starch digestibility. Carbohydrates, mainly starch from cereals, play an important part in a balanced diet, and dietary guidelines suggest a diet with low glycemic index foods, that is to say rich in slowly digested carbohydrates. The present study was aimed at evaluating: 1) the importance of some GF food characteristics in relation to their effects on in vitro starch accessibility to digestion, in comparison with traditional gluten products; 2) the in vivo metabolic responses to GF foods. Firstly, starch digestibility of several products was evaluated in vitro. Then, an in vivo study was performed on a group of healthy volunteers. Postprandial glucose and insulin responses were evaluated after administration of three GF foods and traditional bread. Triglycerides and free fatty acids (FFA) were also evaluated. Attempts were also made to explore differences in metabolic responses to GF foods in healthy subjects with respect to celiac subjects. The area under the curve (AUC) of digested starch of GF bread was slightly higher than that of the traditional counterpart. No significant difference was observed in AUCs of digested starch between GF pasta and the traditional pasta. The AUCs of digested starch of quinoa and the two samples of pasta were not statistically different. Significant differences were observed between GF bread and bread-like products. Statistic differences in glucose responses to GF pasta were observed between healthy and celiac subjects. In healthy subjects, the AUCs of glucose response after GF bread were higher than those after bread with gluten. No significant differences were observed between the AUCs of insulin responses to all products tested. Glycemic index (GI) for GF pasta was similar to GI for GF bread while GI for quinoa was slightly lower than that of GF pasta and bread. Two-way ANOVA revealed that quinoa induced lower FFA levels with respect to GF pasta. In addition, triglyceride concentrations were significantly reduced for quinoa with respect to GF bread and bread. Our results indicate that the different formulations and the food processing procedures used in the manufacturing of GF products may affect the rate of starch digestion both in vitro and in vivo. It may be worthwhile improving the formulation of these products. Furthermore, quinoa seems to represent a potential alternative to traditional foods, even if further and larger studies are required to demonstrate its hypoglycemic effects.


Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis.
Peritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to treat clinically due to widespread tumor dissemination in the peritoneal cavity. We developed a clinically relevant, genetically induced, peritoneal carcinomatosis model that recapitulates the histological morphology and immunosuppressive state of the tumor microenvironment of metastatic peritoneal HGSCs by intraperitoneally injecting shp53, AKT, c-Myc, luciferase and sleeping beauty transposase, followed by electroporation (EP) in the peritoneal cavity of immunocompetent mice (intraperitoneal (IP)/EP mice). Similar to the spread of human ovarian cancers, IP/EP mice displayed multiple tumor nodules attached to the surface of the abdomen. Histopathological analysis indicated that these tumors were epithelial in origin. These IP/EP mice also displayed a loss of CD3+ T cell infiltration in tumors, highly expressed inhibitory checkpoint molecules in tumor-infiltrating and global CD4+ and CD8+ T cells, and increased levels of transforming growth factor-β in the ascites, all of which contribute to the promotion of tumor growth. Overall, our tumor model recapitulates clinical peritoneal HGSC metastasis, which makes it ideal for preclinical drug screening, testing of immunotherapy-based therapeutics and studying of the tumor biology of peritoneal carcinomatosis.


Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3.
Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.


Super-Thin and Suprafascial Anterolateral Thigh Perforator Flaps for Extremity Reconstruction.
Background The anterolateral thigh (ALT) flap remains a workhorse for soft tissue reconstruction. However, the traditional ALT flap is often too bulky for resurfacing shallow, distal extremity defects, prohibiting adequate function, or well-fitted orthotics. This study evaluates extremity reconstruction using ALT flaps elevated in the suprafascial or super-thin plane. Methods Retrospective review of ALT free flap reconstruction from October 2014 to July 2016 was performed. Suprafascial and super-thin flaps were those elevated just above the crural fascia and within the superficial scarpal plane, respectively. Adjunct operative procedures, demographics, and complications were recorded. Results A total of 25 patients underwent suprafascial (n = 14) or super-thin (n = 11) ALT flap reconstruction for primarily lower extremity wounds (n = 19), with an average age and body mass index of 53.8 years and 26.3 kg/m2, respectively. Follow-up was 6.3 months. Comorbidities included smoking (n = 7), diabetes (n = 8), peripheral vascular disease (n = 6), and hypertension (n = 8). The presence of hardware (n = 9), trauma (n = 10), and chronic infection (n = 12) were common risk factors. Average flap size was 8.2 × 21.5 cm, with 64% (n = 16) taken on one perforator. Forty-eight percent (n = 12) were end-to-side anastomoses and 62% (n = 13) utilized one venous anastomosis. Mean hospital stay was 7.8 days with a 24% (n = 6) complication rate. There were no partial or complete flap losses. Conclusion The ALT flap, elevated in a suprafascial or super-thin plane, is a safe, effective option for extremity soft tissue reconstruction. The decreased flap volume and bulk provides the improved contour and pliability necessary for appropriate distal extremity function. The potential versatility of super-thin flaps reinforces the importance of continued innovation by reconstructive microsurgeons.


A survey of veterinary radiation facilities in the United States during 2001.
A survey of veterinary radiation therapy facilities in the United States was done in 2001 to determine the type of equipment available, radiation protocols used, case load, tumor types irradiated, as well as other details of the practice of radiation oncology. A total of 42 sites were identified and included 17 (40%) academic institutions, and 25 (60%) private practice external beam radiation facilities. The overall response rate was 79% (33/42 responded). Based on this survey there is substantial variation between facilities in all aspects ranging from equipment and personnel to radiation protocols and caseloads. American College of Veterinary Radiology boarded radiation oncologists direct 76% of the radiation facilities at academic institutions and 60% of the private practice facilities. Three facilities had orthovoltage radiation units only, and 30 facilities had mega-voltage equipment: cobalt 60 or linear accelerator. A total of 18 facilities had linear accelerators with three of these off site at a human radiation facility. Patient load information was available from 31 sites (74% of the radiation facilities in the United States), and based on the responses 2790 dogs and 1081 cats were irradiated in 2001. Canine mast cell tumors were the most frequently irradiated tumor. This represents the first survey of veterinary radiation facilities in the United States and provides information on the specialty of veterinary radiation oncology.


Platinum-based chemotherapy for recurrent CNS tumours in young patients.
Twenty nine patients (median age 12 years) with a CNS tumour, received platinum-based chemotherapy for assessable disease. In 23 patients there was an objective response with improvement lasting for a median duration of 11 months. There was little difference in the response to cisplatinum or carboplatin therapy. The response rates in specific disease groups were: medulloblastoma 8/10, two with a complete response (CR) and six with a partial response (PR); ependymoma 1/5 PR; pineal retinoblastoma 5/5 with three CR and two PR; primitive neurectodermal tumours (PNET) 2/2 PR and pineal germ cell tumours 6/6 with four CR and two PR. It is concluded that platinum-based chemotherapy has a beneficial effect on CNS tumours of the CNS, especially medulloblastoma, ectopic intracranial retino-blastoma and pineal germ cell tumours.


Plasma fluorination of vertically aligned carbon nanotubes: functionalization and thermal stability.
Grafting of fluorine species on carbon nanostructures has attracted interest due to the effective modification of physical and chemical properties of the starting materials. Various techniques have been employed to achieve a controlled fluorination yield; however, the effect of contaminants is rarely discussed, although they are often present. In the present work, the fluorination of vertically aligned multiwalled carbon nanotubes was performed using plasma treatment in a magnetron sputtering chamber with fluorine diluted in an argon atmosphere with an Ar/F2 ratio of 95:5. The effect of heavily diluted fluorine in the precursor gas mixture is investigated by evaluating the modifications in the nanotube structure and the electronic properties upon plasma treatment. The existence of oxygen-based grafted species is associated with background oxygen species present in the plasma chamber in addition to fluorine. The thermal stability and desorption process of the fluorine species grafted on the carbon nanotubes during the fluorine plasma treatment were evaluated by combining different spectroscopic techniques.


Cerebral Microbleeds, Vascular Risk Factors, and Magnetic Resonance Imaging Markers: The Northern Manhattan Study.
Cerebral microbleeds (CMBs) represent intracerebral hemorrhages due to amyloid angiopathy or exposure to modifiable risk factors. Few community-based stroke-free studies including blacks and Hispanics have been done. The Northern Manhattan Study (NOMAS) is a stroke-free, racially and ethnically diverse cohort study. Brain MRI was performed in 1290 participants, 925 of whom had available T2* gradient-recall echo data. We used multivariable logistic regression to examine the association of sociodemographics, vascular risk factors, apolipoprotein E (APOE) genotype, and brain MRI markers with CMB presence and location. The prevalence of CMBs in our cohort was 5%. Of the 46 participants with CMBs, 37% had only deep CMBs, 48% had only lobar CMBs, and 15% had CMBs in both locations. The difference in CMB distribution was not statistically significant across race/ethnic group or APOE genotype. In multivariable analyses, age (OR [95% CI]: 1.09 [1.04, 1.15]) and SBIs (2.58 [1.01, 6.59]) were positively associated with CMB presence, and diabetes medication use was negatively associated (0.25 [0.07, 0.86]). CMBs may represent the severity of vascular disease in this racially and ethnically diverse cohort. Larger studies are needed to elucidate the association between diabetes medication use and CMB presence.


Extracellular volume quantification by cardiac magnetic resonance imaging without hematocrit sampling : Ready for prime time?
Myocardial tissue characterization by cardiovascular magnetic resonance (CMR) T1 mapping currently receives increasing interest as a diagnostic tool in various disease settings. The T1-mapping technique allows non-invasive estimation of myocardial extracellular volume (ECV) using T1-times before and after gadolinium administration; however, for calculation of the myocardial ECV the hematocrit is needed, which limits its utility in routine application. Recently, the alternative use of the blood pool T1-time instead of the hematocrit has been described. The results of CMR T1 mapping data of 513 consecutive patients were analyzed for this study. Blood for hematocrit measurement was drawn when placing the i. v. line for contrast agent administration. Data from the first 200 consecutive patients (derivation cohort) were used to establish a regression formula allowing synthetic hematocrit calculation, which was then validated in the following 313 patients (validation cohort). Synthetic ECV was calculated using synthetic hematocrit, and was compared with conventionally derived ECV. Among the entire cohort of 513 patients (mean age 57.4 ± 17.5 years old, 49.1% female) conventionally measured hematocrit was 39.9 ± 4.7% and native blood pool T1-time was 1570.6 ± 117.8 ms. Hematocrit and relaxivity of blood (R1 = 1/blood pool T1 time) were significantly correlated (r = 0.533, r2 = 0.284, p < 0.001). By linear regression analysis, the following formula was developed from the derivation cohort: synthetic hematocrit = 628.5 × R1 - 0.002. Synthetic and conventional hematocrit as well as ECV showed significant correlation in the validation (r = 0.533, r2 = 0.284, p < 0.001 and r = 0.943, r2 = 0.889, p < 0.001, respectively) as well as the overall cohort (r = 0.552, r2 = 0.305, p < 0.001 and r = 0.957, r2 = 0,916, p < 0.001). By Bland Altman analysis, good agreement between conventional and synthetic ECV was found in the validation cohort (mean difference: 0.007%, limits of agreement: -4.32 and 4.33%, respectively). Synthetic ECV using native blood pool T1-times to calculate the hematocrit, is feasible and leads to almost identical results in comparison with the conventional method. It may allow fully automatic ECV-mapping and thus enable broader use of ECV by CMR T1 mapping in clinical practice.


Contextual cueing of tactile search is coded in an anatomical reference frame.
This work investigates the reference frame(s) underlying tactile context memory, a form of statistical learning in a tactile (finger) search task. In this task, if a searched-for target object is repeatedly encountered within a stable spatial arrangement of task-irrelevant distractors, detecting the target becomes more efficient over time (relative to nonrepeated arrangements), as learned target-distractor spatial associations come to guide tactile search, thus cueing attention to the target location. Since tactile search displays can be represented in several reference frames, including multiple external and an anatomical frame, in Experiment 1 we asked whether repeated search displays are represented in tactile memory with reference to an environment-centered or anatomical reference frame. In Experiment 2, we went on examining a hand-centered versus anatomical reference frame of tactile context memory. Observers performed a tactile search task, divided into a learning and test session. At the transition between the two sessions, we introduced postural manipulations of the hands (crossed ↔ uncrossed in Expt. 1; palm-up ↔ palm-down in Expt. 2) to determine the reference frame of tactile contextual cueing. In both experiments, target-distractor associations acquired during learning transferred to the test session when the placement of the target and distractors was held constant in anatomical, but not external, coordinates. In the latter, RTs were even slower for repeated displays. We conclude that tactile contextual learning is coded in an anatomical reference frame. (PsycINFO Database Record


Botulinum toxin in writer's cramp: objective response evaluation in 31 patients.
To quantify the treatment effect of local botulinum toxin injections in writer's cramp a newly developed rating scale of writing performance and a computer assisted analysis of writing speed were used in 31 patients undergoing botulinum toxin therapy. Baseline data of the writer's cramp rating scale (WCRS, see appendix) and computer based writing speed analysis were compared with those obtained at the time of subjective best response as recorded during follow up visits. The mean dose injected per session was 133.2 units Dysport divided between two forearm muscles. Of all 124 injection sessions during mean follow up of one year 76% produced a good improvement. The most common side effect was weakness (72% of the follow up visits). The WCRS scores as assessed by a blinded videotape review by four independent raters showed good reliability between raters and a significant improvement after treatment (P < 0.001). The speed of pen movements showed a significant (P < 0.05) increase after treatment at subjective best effect recordings and a significant correlation with WCRS subscores, documenting the validity of the scale. The present study is the first to show significant effects of botulinum toxin treatment in patients with writer's cramp on the basis of a quantifiable scale for writing performance which correlates significantly with writing speed measurements. The WCRS as employed in this study might therefore prove a useful rating instrument in other studies assessing severity and treatment response in patients with writer's cramp.


Enzymatic biodegradation of hydrogels for protein delivery targeted to the small intestine.
Multiresponsive poly(methacrylic acid-co-N-vinylpyrrolidone) hydrogels were synthesized with biodegradable oligopeptide crosslinks. The oligopeptide crosslinks were incorporated using EDC-NHS zero-length links between the carboxylic acid groups of the polymer and free primary amines on the peptide. The reaction of the peptide was confirmed by primary amine assay and IR spectroscopy. The microgels exhibited pH-responsive swelling as well as enzyme-catalyzed degradation targeted by trypsin present in the small intestine, as demonstrated upon incubation with gastrointestinal fluids from rats. Relative turbidity was used to evaluate enzyme-catalyzed degradation as a function of time, and initial trypsin concentration controlled both the degradation mechanism as well as the extent of degradation. Trypsin activity was effectively extinguished by incubation at 70 °C, and both the microgels and degradation products posed no cytotoxic effect toward two different cell lines. The microgels demonstrated pH-dependent loading of the protein insulin for oral delivery to the small intestine.


Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios.
Glucuronidation is a listed clearance mechanism for 1 in 10 of the top 200 prescribed drugs. The objective of this article is to encourage those studying ligand interactions with UDP-glucuronosyltransferases (UGTs) to adequately consider the potential consequences of in vitro UGT inhibition in humans. Spurred on by interest in developing potent and selective inhibitors for improved confidence around UGT reaction phenotyping, and the increased availability of recombinant forms of human UGTs, several recent studies have reported in vitro inhibition of UGT enzymes. In some cases, the observed potency of UGT inhibitors in vitro has been interpreted as having potential relevance in humans via pharmacokinetic drug-drug interactions. Although there are reported examples of clinically relevant drug-drug interactions for UGT substrates, exposure increases of the aglycone are rarely greater than 100% in the presence of an inhibitor relative to its absence (i.e., AUCi/AUC < or = 2). This small magnitude in change is in contrast to drugs primarily cleared by cytochrome P450 enzymes, where exposures have been reported to increase as much as 35-fold on coadministration with an inhibitor (e.g., ketoconazole inhibition of CYP3A4-catalyzed terfenadine metabolism). In this article the evidence for purported clinical relevance of potent in vitro inhibition of UGT enzymes will be assessed, taking the following into account: in vitro data on the enzymology of glucuronide formation from aglycone, pharmacokinetic principles based on empirical data for inhibition of metabolism, and clinical data on the pharmacokinetic drug-drug interactions of drugs primarily cleared by glucuronidation.


Audiovisual integration during speech comprehension: an fMRI study comparing ROI-based and whole brain analyses.
Visual information (lip movements) significantly contributes to speech comprehension raising the question for the neural implementation of audiovisual (AV) integration during speech processing. To replicate and extend earlier neuroimaging findings, we compared two different analysis approaches in a slow event-related fMRI study of healthy native speakers of German who were exposed to AV speech stimuli (disyllabic nouns) with audio and visual signals being either congruent or incongruent. First, data was subjected to whole brain general linear model analysis after transformation of all individual data sets into standard space. Second, a region of interest (ROI) approach based on individual anatomy was used with ROI defined in areas identified previously as being important for AV processing. Standard space analysis revealed a widespread cortical network including the posterior part of the left superior temporal sulcus, Broca's region and its right hemispheric counterpart showing increased activity for incongruent stimuli. The ROI approach allowed to identify differences in activity between Brodmann areas 44 and 45, within Broca's area for incongruent stimulation, and also allowed to study activity of subdivisions of superior temporal regions. The complementary strengths and weaknesses of the two analysis approaches are discussed.


Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells.
Pancreatic cancer (PanC) is one of the most lethal malignancies, and resistance towards gemcitabine, the front-line chemotherapy, is the main cause for dismal rate of survival in PanC patients; overcoming this resistance remains a major challenge to treat this deadly malignancy. Whereas several molecular mechanisms are known for gemcitabine resistance in PanC cells, altered metabolism and bioenergetics are not yet studied. Here, we compared metabolic and bioenergetic functions between gemcitabine-resistant (GR) and gemcitabine-sensitive (GS) PanC cells and underlying molecular mechanisms, together with efficacy of a natural agent bitter melon juice (BMJ). GR PanC cells showed distinct morphological features including spindle-shaped morphology and a decrease in E-cadherin expression. GR cells also showed higher ATP production with an increase in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Molecular studies showed higher expression of glucose transporters (GLUT1 and 4) suggesting an increase in glucose uptake by GR cells. Importantly, GR cells showed a significant increase in Akt and ERK1/2 phosphorylation and their inhibition decreased cell viability, suggesting their role in survival and drug resistance of these cells. Recently, we reported strong efficacy of BMJ against a panel of GS cells in culture and nude mice, which we expanded here and found that BMJ was also effective in decreasing both Akt and ERK1/2 phosphorylation and viability of GR PanC cells. Overall, we have identified novel mechanisms of gemcitabine resistance in PanC cells which are targeted by BMJ. Considering the short survival in PanC patients, our findings could have high translational potential in controlling this deadly malignancy.


Modeling of alternative testing strategies to demonstrate freedom from Mycobacterium avium ssp. paratuberculosis infection in test-negative dairy herds in the Republic of Ireland.
In light of the various adverse effects of Johne's disease on animal productivity and the debate on the role of its causative organism, Mycobacterium avium ssp. paratuberculosis, in the etiology of Crohn's disease, major dairy-producing countries around the world have implemented national control programs aimed at reducing the prevalence of this infection in cattle. A pilot control program was initiated in Ireland in 2013, with a key objective to provide farmers with test-negative dairy herds with tools and knowledge to increase their confidence of freedom over time. The aim of this study was to estimate the confidence of freedom obtained in test-negative Irish dairy herds over time with various sampling scenarios and to evaluate the cost-effectiveness of alternative scenarios for achieving an acceptable level of confidence of freedom in herds with no evidence of infection. A stochastic model was developed to simulate repeated annual testing of individual animals using ELISA and confirmatory assays over a period of 20 yr. Two scenarios modeled the current herd-screening options, whereas 14 alternative scenarios explored the effect of varying parameters from the current testing strategies, such as the frequency of testing, the eligibility criteria for selecting animals, the type of assay, the probability of introduction, and the assay sensitivity. Results showed that the current testing strategy with milk twice a year or serum once a year in all animals over 2 yr old provided the highest annual herd sensitivity, with a median value of 55%. Although the median confidence of freedom increased over time for all scenarios, the time required to reach 90 and 95% confidence of freedom was highly variable between scenarios. Under the testing scenario where serum tests were used once a year, the confidence of freedom reached 90% after 4 yr and 95% after 7 yr of testing. Some of the alternative scenarios achieved an acceptable level of confidence of freedom in a reasonable timeframe and at lesser cost than the current testing strategies. The results of this work are used to provide recommendations for the next phases of the program.


Toward strengthening active case finding for ending tuberculosis in India.
Active case finding (ACF) is critical for the timely detection and treatment of diseases like tuberculosis (TB). ACF is crucial in India, where health-seeking behaviour across various populations is low and non-reporting is a barrier to breaking disease transmission cycles and eliminating the disease. As an integral part of India's national TB control programs, there is further scope for improvement in its design. This paper outlines a roadmap for ACF for TB in the country. It is based on current national strategic plans for public health monitoring and TB case identification. It suggests that ACF should be strengthened by developing it as a learning surveillance system involving a change from a siloed public health approach to a more comprehensive surveillance exercise. It defines operational requirements for establishing predictive capabilities and introducing feedback and learning in the system as a precondition. It highlights the importance of establishing proper processes, as well as extending and expanding on existing infrastructural and human resource, and inter-programmatic coordination and collaboration in the health sector.


Challenges in robotic distal pancreatectomy: systematic review of current practice.
Over the last decade, robotics has gained popularity and is increasingly employed to accomplish several abdominal surgical procedures. Nevertheless, pancreatectomies are regarded as demanding procedures for which the application of minimally-invasive surgery is still limited and its effectiveness has not been conclusively established. We aimed to investigate the current role of robot-assisted surgery to perform distal pancreatectomy. A systematic review of the English-language literature was conducted for articles dealing with robotic-assisted distal pancreatectomies. All relevant papers were evaluated on surgical and oncological outcomes. A total of 10 articles reporting on robotic distal pancreatectomies were finally considered in the analysis, including 259 patients. Mean operative time was 271 minutes (range 181-398); mean blood loss was 210 mL (range 104-361), in 11.6% of cases conversion to laparotomy occurred, spleen preservation was accomplished in 51.4% of procedures, mean time of postoperative hospital stay was 7 days. Overall, postoperative mortality and morbidity were 0% and 23.4% respectively, the mean number of lymph nodes harvested was 12.7. In all included series, no case of R1 resection was reported. Despite its relatively recent introduction in clinical practice, robotic-assisted surgery has been widely employed to perform distal pancreatectomy worldwide and it should be considered a safe and effective procedure. Both surgical and pathologic data support its application in the management of pancreatic lesions of the body and tail.


CTLA4 gene polymorphisms are associated with, and linked to, insulin-dependent diabetes mellitus in a Russian population.
The association between the human cytotoxic T lymphocyte-associated antigen-4 (CTLA4) gene and insulin-dependent diabetes mellitus (IDDM) is unclear in populations. We therefore investigated whether the gene conferred susceptibility to IDDM in a Russian population. We studied two polymorphic regions of the CTLA4 gene, the codon 17 dimorphism and the (AT)n microsatellite marker in the 3' untranslated region in 56 discordant sibling pairs and in 33 identical by descent (IBD) affected sibships. The Alal7 allele of the CTLA4 gene was preferentially transmitted from parents to diabetic offspring (p<0.0001) as shown by the combined transmission/disequlibrium test (TDT) and sib TDT (S-TDT) analysis. A significant difference between diabetic and non-diabetic offspring was also observed for the transmission of alleles 17, 20, and 26 of the dinucleotide microsatellite. Allele 17 was transmitted significantly more frequently to affected offspring than to other children (p=0.0112) whereas alleles 20 and 26 were transmitted preferentially to non-diabetic sibs (p=0.045 and 0.00068 respectively). A nonrandom excess of the Ala17 CTLA4 molecular variant (maximum logarithm of odds score (MLS) of 3.26) and allele 17 of the dinucleotide marker (MLS=3.14) was observed in IBD-affected sibling pairs. The CTLA4 gene is strongly associated with, and linked to IDDM in a Russian population.


A hierarchical Ni-Co-O@Ni-Co-S nanoarray as an advanced oxygen evolution reaction electrode.
Developing an efficient electro-catalyst for water oxidation is essential for improving the performance, which holds the key for a number of energy conversion and storage devices. Here we report an effective method for fabricating a Ni-Co-O@Ni-Co-S hierarchical nanoarray, which showed a significantly improved activity relative to Ni-Co-O nanowire arrays for oxygen evolution reactions. The enhanced performance was attributed to the secondary formed Ni-Co-S nanoplatelets which not only acted as efficient electrocatalysts, but also facilitated the electrolyte penetration and increased the surface area.


[Clinical pathomorphology of the liver and gastric mucosa in peptic ulcer complications].
Tests of the functional state of the liver and indices of the immuno-biological reactivity were studied in 193 patients with complicated forms of the ulcerous disease. The intravital morphological investigation of the liver and gastric mucosa tissues was performed. The correlative relations between the character of changes in the stomach and liver and processes of autoallergy were detected. The comparison of different parameters enabled most informative indices to be revealed.


Classification of Inflammation of Unknown Origin patients based on RNA-seq and SomaScan data.
A preliminary analysis was conducted on data acquired from RNA sequencing and SomaScan platforms, for the classification of patients with Inflammation of Unknown Origin. To this end, a multimodal data integration approach was designed, by combining the two platforms, in order to assess the potentiality of learning estimators, using the differentially expressed features from the independent profiling experiments of both platforms. The classification framing was the differentiation of Inflammation of Unknown Origin patients against a multitude of Systemic Autoinflammatory disease patients. Separate false discovery rate analyses were performed on each dataset to extract statistically significant features between the two designated sample groups. Genomic analysis managed higher overall classification metrics compared to proteomic analysis, averaging an ~19% increase overall metrics and classifiers, with a ~0.07% increase in standard error. The multimodal data integration approach achieved similar results to the individual platforms' analyses. More specifically, it managed the same classification accuracy, sensitivity, and specificity scores as the best individual analysis, with the simple Logistic Regression estimator.Clinical Relevance- This study highlights the advantage of exploiting RNA sequencing data to identify potential Inflammation of Unknown Origin disease specific biomarkers, even against other Systemic Autoinflammatory diseases. These findings are further emphasized given the non-apparent clinical discrepancy between Inflammation of Unknown Origin and other Systemic Autoinflammatory diseases.


Molecular characterization and expression of the Trichoplusia ni granulovirus helicase gene.
A putative DNA helicase gene from the granulovirus of Trichoplusia ni (TnGV) was cloned, sequenced, and compared with the corresponding gene of several multinucleocapsid nucleopolyhedroviruses (MNPVs) including those from Autographa californica (AcMNPV), Orgyia pseudotsugata (OpMNPV), Bombyx mori (BmNPV), and Spodoptera exigua (SeMNPV). The TnGV helicase gene (p137) encoded a helicase of 1158 amino acids with a predicted mass of 137 kDa. Comparison of p137 with AcMNPV p143 revealed 44.5% identity at the nucleotide level, and, respectively, 28.6% identity and 53.0% similarity at the amino acid level. Similar levels of identity and similarity were obtained when TnGV p137 was compared with the corresponding helicase genes of BmNPV, OpMNPV and SeMNPV. Using an antisense probe made from an internal 1.6 kb region of p137, a major transcript of approximately 3600 nt was detected by Northern blot analysis in fat body tissue from TnGV-infected larvae of T. ni. As both TnGV and AcMNPV replicate efficiently in larvae of T. ni, these results demonstrate that baculovirus putative DNA helicases which have diverged markedly can function efficiently in the same host. Three genes flanking TnGV p137, designated ORF68, ORF219 and ORF157, corresponded in order and orientation with AcMNPV ORFs 93, 94 and 96. However, the amino acid similarity between corresponding genes ranged from only 50.4 to 62.5%, providing further evidence that related baculovirus proteins which have diverged markedly can function efficiently in the same host.


Monovalent sulfur oxoanions enable millimeter-long single-crystalline h-WO3 nanowire synthesis.
Here, we discuss a misunderstanding regarding chemical capping, which has intrinsically hindered the extension of the length of hexagonal (h)-WO3 nanowires in previous studies. Although divalent sulfate ions (SO42-) have been strongly believed to be efficient capping ions for directing anisotropic h-WO3 nanowire growth, we have found that the presence of SO42- is highly detrimental to the anisotropic crystal growth of the h-WO3 nanowires, and a monovalent sulfur oxoanion (HSO4-) rather than SO42- only substantially promotes the anisotropic h-WO3 nanowire growth. Ab initio electronic structure simulations revealed that the monovalent sulfur oxoanions were preferentially able to cap the sidewall plane (100) of the h-WO3 nanowires due to the lower hydration energy when compared with SO42-. Based on this capping strategy, using the monovalent sulfur oxoanion (CH3SO3-), which cannot generate divalent sulfur oxoanions, we have successfully fabricated ultra-long h-WO3 nanowires up to the millimeter range (1.2 mm) for a wider range of precursor concentrations. We have demonstrated the feasibility of these millimeter-long h-WO3 nanowires for the electrical sensing of molecules (lung cancer biomarker: nonanal) on flexible substrates, which can be operated at room temperature with mechanical flexibility with bending cycles up to 104 times due to the enhanced textile effect.


Poor outcomes in a cohort of HIV-infected adolescents undergoing treatment for multidrug-resistant tuberculosis in Mumbai, India.
Little is known about the treatment of multidrug-resistant tuberculosis (MDR-TB) in HIV-co-infected adolescents. This study aimed to present the intermediate outcomes of HIV-infected adolescents aged 10-19 years receiving second-line anti-TB treatment in a Médecins Sans Frontières (MSF) project in Mumbai, India. A retrospective review of medical records of 11 adolescents enrolled between July 2007 and January 2013 was undertaken. Patients were initiated on either empirical or individualized second-line ambulatory anti-TB treatment under direct observation. The median age was 16 (IQR 14-18) years and 54% were female. Five (46%) adolescents had pulmonary TB (PTB), two (18%) extrapulmonary disease (EPTB) and four (36%) had both. Median CD4 count at the time of MDR-TB diagnosis was 162.7 cells/µl (IQR: 84.8-250.5). By January 2013, eight patients had final and 3 had interim outcomes. Favourable results were seen in four (36.5%) patients: one was cured and three were still on treatment with negative culture results. Seven patients (64%) had poor outcomes: four (36.5%) died and three (27%) defaulted. Three of the patients who died never started on antiretroviral and/or TB treatment and one died 16 days after treatment initiation. Two of the defaulted died soon after default. All patients (100%) on-treatment experienced adverse events (AEs): two required permanent discontinuation of the culprit drug and two were hospitalized due to AEs. No patient required permanent discontinuation of the entire second-line TB or antiretroviral regimens. Early mortality and mortality after default were the most common reasons for poor outcomes in this study. Early mortality suggests the need for rapid diagnosis and prompt treatment initiation, and adolescents might benefit from active contact-tracing and immediate referral. Default occurred at different times, suggesting the need for continuous, intensified and individualized psychosocial support for co-infected adolescents. Operational research among co-infected adolescents will be especially important in designing effective interventions for this vulnerable group.


Effects of composite beta- and kappa-casein genotypes on milk coagulation, quality, and yield traits in Italian Holstein cows.
The aim of the study was to estimate the effect of the composite CSN2 and CSN3 genotypes on milk coagulation, quality, and yield traits in Italian Holstein cows. A total of 1,042 multiparous Holstein cows reared on 34 commercial dairy herds were sampled once, concurrently with monthly herd milk recording. The data included the following traits: milk coagulation time; curd firmness; pH and titratable acidity; fat, protein, and casein contents; somatic cell score; and daily milk, fat, and protein yields. A single-trait animal model was assumed with fixed effects of herd, days in milk, parity, composite casein genotype of CSN2 and CSN3 (CSN2-CSN3), and random additive genetic effect of an animal. The composite genotype of CSN2-CSN3 showed a strong effect on both milk coagulation traits and milk and protein yields, but not on fat and protein contents and other milk quality traits. For coagulation time, the best CSN2-CSN3 genotypes were those with at least one B allele in both the CSN2 and CSN3 loci. The CSN3 locus was associated more strongly with milk coagulation traits, whereas the CSN2 locus was associated more with milk and protein yields. However, because of the tight linkage between the 2 loci, the composite genotypes, or haplotypes, are more appropriate than the single-locus genotypes if they were considered for use in selection.


Attosecond single-cycle undulator light: a review.
Research at modern light sources continues to improve our knowledge of the natural world, from the subtle workings of life to matter under extreme conditions. Free-electron lasers, for instance, have enabled the characterization of biomolecular structures with sub-ångström spatial resolution, and paved the way to controlling the molecular functions. On the other hand, attosecond temporal resolution is necessary to broaden our scope of the ultrafast world. Here we discuss attosecond pulse generation beyond present capabilities. Furthermore, we review three recently proposed methods of generating attosecond x-ray pulses. These novel methods exploit the coherent radiation of microbunched electrons in undulators and the tailoring of the emitted wavefronts. The computed pulse energy outperforms pre-existing technologies by three orders of magnitude. Specifically, our simulations of the proposed Soft X-ray Laser at MAX IV (Lund, Sweden) show that a pulse duration of 50-100 as and a pulse energy up to 5 [Formula: see text]J is feasible with the novel methods. In addition, the methods feature pulse shape control, enable the incorporation of orbital angular momentum, and can be used in combination with modern compact free-electron laser setups.


Immunoregulatory T-lymphocyte functions in patients with small cell lung cancer.
The present study was performed to elucidate the differences in immune status between patients with small cell lung cancer (SCLC) and those with non-small cell lung cancer. The study group consisted of 18 patients with SCLC and 15 with non-SCLC. Two healthy volunteers and 13 patients with benign disease were also included in the present study as the non-cancer control. In the non-SCLC group, although not statistically significant, the percentages of both OKT3+ and OKT4+ T-lymphocytes in the peripheral blood lymphocytes (PBL) were slightly decreased, associated with a slight increase in the percentage of OKT8+ T-cells, and a slight decrease in the OKT4+ to OKT8+ T-cell ratio. In contrast, the PBL of the SCLC patients showed significantly lower proliferative responses to phytohemagglutinin and human recombinant interleukin 2 than did the PBL of both the SCLC patients and the noncancer control group. The ability of PBL to produce lymphokines (interleukin 2 and macrophage activating factor) was significantly impaired in the SCLC group but not in the non-SCLC group. These results suggest that suppression of helper T-cell functions and/or potentiation of suppressor T-cell functions should occur in patients with SCLC.


Time-domain Features of Angular-velocity Signals for Camera-based Respiratory RoI detection: A Clinical Study in NICU.
Camera-based measurement of respiratory rate (RR) is emerging for preterm infants monitoring in Neonatal Intensive Care Units (NICU). Accurate detection of respiratory region of interest (Resp-RoI), e.g. thorax and abdomen of infants, is essential for achieving a fully-automatic solution and for high-quality RR estimation. However, the application of fast Fourier transform (FFT) for detecting Resp-RoI in premature infants may not be appropriate due to their irregular breathing patterns. This study proposes a new method for detecting Resp-RoIs in premature infants that uses time-domain features of angular-velocity of respiration. By fusing respiratory motion on orthogonal directions, the proposed method is more robust to variations of infant posture in the incubator.. In addition, using inter-beat interval (IBI) features in the time domain helps to distinguish between Resp-RoI and background. The proposed method was validated on 20 preterm infants in NICU. It obtains a clear improvement on Resp-RoI detection (RoI correspondence = 0.74) and RR estimation (MAE = 3.62 bpm) against the benchmarked approaches (maxFFT: RoI correspondence = 0.45, MAE = 5.61 bpm).


Hereditary Spherocytosis: Can Next-Generation Sequencing of the Five Most Frequently Affected Genes Replace Time-Consuming Functional Investigations?
Congenital defects of the erythrocyte membrane are common in northern Europe and all over the world. The resulting diseases, for example, hereditary spherocytosis (HS), are often underdiagnosed, partly due to their sometimes mild and asymptomatic courses. In addition to a broad clinical spectrum, this is also due to the occasionally complex diagnostics that are not available to every patient. To test whether next-generation sequencing (NGS) could replace time-consuming spherocytosis-specific functional tests, 22 consecutive patients with suspected red cell membranopathy underwent functional blood tests. We were able to identify the causative genetic defect in all patients with suspected HS who underwent genetic testing (n = 17). The sensitivity of the NGS approach, which tests five genes (ANK1 (gene product: ankyrin1), EPB42 (erythrocyte membrane protein band4.2), SLC4A1 (band3), SPTA1 (α-spectrin), and SPTB (β-spectrin)), was 100% (95% confidence interval: 81.5-100.0%). The major advantage of genetic testing in the paediatric setting is the small amount of blood required (<200 µL), and compared to functional assays, sample stability is not an issue. The combination of medical history, basic laboratory parameters, and an NGS panel with five genes is sufficient for diagnosis in most cases. Only in rare cases, a more comprehensive functional screening is required.


Russian Translation.
This discussion has described the status of the large United States program for translation from the Russian. A partial description of what is being done or planned, and by whom, has been provided as a guide for those who wish to follow the subject further. The urge to pass on useful information has necessarily restricted the space which might also have been profitably devoted to the philosophic aspects of the problem. Although it is not said with any sense of pride in achievement-because much more remains to be done than has been done-it would seem fair to describe the current national translation activity, including all contributions to it, as a phenomenon. Phenomena in scientific communication are not common: a full appreciation of their significance requires more analysis than results from a simple listing of their outward characteristics. But a few observations might be made in conclusion. Most United States scientists probably feel that, as a nation, we are and should be world leaders in science, even though this feeling is neither nurtured nor expressed in a spirit of violent competition. If this assumption is allowed, the point which seems to remain is that the United States will not retain its position casually. Our scientists expect to maintain an awareness of the scientific achievements and failures of the other nations of the world. But we must especially become more aware of the advances of Soviet science, both qualitatively and quantitatively. The evidence points toward this last conclusion, regardless of whether one is concerned with the production of ideas or things, increase in man's knowledge of himself and his environment, conflict between idealisms, or simply the national security.


Cadherin-11 as a therapeutic target in chronic, inflammatory rheumatic diseases.
Cadherin-11 has been identified as a key regulator of synovial architecture mediating contact between Fibroblast-like Synoviocytes and organization in the lining layer. A central role for cadherin-11 has also been suggested in the formation of the rheumatoid pannus. Therapeutic targeting of cadherin-11 results in amelioration of autoimmune experimental arthritis, as well as of experimental fibrosis. In addition, cadherin-11 expression is upregulated in the synovium of patients with chronic inflammatory arthritis, whereas detection of cadherin-11 mRNA transcripts in the peripheral blood has been associated with more severe disease phenotypes in two prototypic conditions of chronic joint inflammation and fibrosis, namely, rheumatoid arthritis and systemic sclerosis, respectively. Currently, a monoclonal antibody against cadherin-11 is in early phases of clinical trials in patients with rheumatoid arthritis. Herein, we review the current knowledge regarding the potential role of cadherin-11 in pathogenesis, as well as a biomarker and therapeutic target in chronic inflammatory rheumatic diseases.


COVID-19 #StayAtHome Restrictions and Deep Vein Thrombosis: Case Report.
The COVID-19 pandemic triggered countermeasures like #StayAtHome initiatives, which have changed the whole world. Despite the success of such initiatives in limiting the spread of COVID-19 to #FlattenTheCurve, physicians are now confronted with the adverse effects of the current restrictive pandemic management strategies and social distancing measures. We aim to draw attention to the particular importance and magnitude of what may be the adverse effects of COVID-19-related policies. We herein report a case of an otherwise healthy 84-year-old woman with deep vein thrombosis (DVT) due to COVID-19-related directives. #StayAtHome policies and consequential social isolation have diminished our patient's social life and reduced her healthy movement behaviors. The patient spent long hours in a seated position while focusing on the intensive flow of media information regarding the pandemic. Reduced mobility due to preventive social isolation during the COVID-19 pandemic was the only identified cause of the DVT. While evaluating the effect of the COVID-19 pandemic and governmentally implemented containment measures, including social isolation and mobility reduction, adverse events should be considered. Digital approaches might play a crucial role in supporting public health.


Thoracic metastasectomy for thyroid malignancies.
To better define early and long-term outcomes of patients undergoing thoracic metastasectomy for thyroid cancer. We identified, reviewed, and analyzed the medical records of all patients who underwent thoracic metastasectomy for thyroid cancer in our institution from 1971 to 2006. There were 48 patients (25 men, 23 women). A complete resection (R0) of all known disease was performed in 33 (69%) patients, while 15 (31%) underwent incomplete resection (R1 or R2). By histology, the majority were papillary 31 (65%), follicular 8 (17%), medullary 5 (10%), and Hürthle cell 4 (8%). Ninety percent were confined to a single side of the chest, with 10% presenting with bilateral metastases. Thoracotomy was performed in 28 (58%), sternotomy in 12 (25%), and thoracoscopy was used in 8 (17%). Operative mortality was zero and postoperative complications occurred in 8 patients (17%). There are currently 18 surviving patients from the cohort (37%) with a median follow-up of 10 years (range, 1 month to 17 years). The overall 5-year survival after thoracic metastasectomy was 60%. Based on histology, 5-year survival for papillary cancer was 64% compared to 37% for follicular and Hürthle cell neoplasms (p=0.03). All five medullary thyroid cancer patients were alive at 5 years. Five-year survival was also improved for patients less than 45 years old at the time of diagnosis of their initial thyroid malignancy (94% vs 49%; p=0.03). Disease-free interval of >3 years between initial thyroid malignancy diagnosis and thoracic metastasectomy demonstrated improved 5-year survival (67% vs 52%; p=0.01). Pulmonary resection for thyroid metastasis is safe with low morbidity and mortality. Retrospective analysis demonstrates improved long-term survival in patients with papillary histology, longer disease-free interval (>3 years) and younger age at diagnosis of initial thyroid malignancy. Excellent long-term survival was also achievable in selected patients with medullary thyroid metastasis.


A comparative study indicates both positive and purifying selection within ryanodine receptor (RyR) genes, as well as correlated evolution.
Ryanodine receptors are Ca(2+) ion channels that allow Ca(2+) to flow into the cytosol, from an internal store, in the form of transients. RyRs form a small gene family and vertebrates have three major isoforms, RyR1, RyR2, and RyR3, which are mixed and matched in different combinations in different tissues resulting in different Ca(2+) transients for each tissue. In this study, we characterized the interspecies evolution of RyRs within vertebrates. First, we compared the nucleotide divergence of key gene regions including divergent regions (DRs), which are believed to be responsible for the functional divergence between RyRs, and mutation hot-spot regions, which are responsible for RyR-related pathologies. We found evidence that DRs undergo positive selection and mutation hot-spot regions undergo purifying selection. Second, we estimated the extent of purifying selection for RyR1, RyR2, and RyR3 by estimating dN/dS ratios. We found all three genes to be under strong purifying selection, overall. This is consistent with RyRs being used in a diverse set of physiological contexts and therefore under potentially high pleiotropic constraint. Third, we tested for the correlated evolution of dN/dS ratios between RyR genes. We found that RyR2 and RyR3, and RyR3 and a skeletal form of dihydropyridine receptor (DHPR) have correlated rates of evolution. We propose that compensatory effects may explain their correlated evolution. We tested for compensatory function by simulating mutations via a physiological model of RyR function, but did not find evidence for compensation, which indicates that the correlation is likely a result of another process.


Differential production of IL-12, IFN-alpha, and IFN-gamma by mouse dendritic cell subsets.
Dendritic cells (DC) not only stimulate T cells effectively but are also producers of cytokines that have important immune regulatory functions. In this study we have extended information on the functional differences between DC subpopulations to include differences in the production of the major immune-directing cytokines IL-12, IFN-alpha, and IFN-gamma. Splenic CD4(-)8(+) DC were identified as the major IL-12 producers in response to microbiological or T cell stimuli when compared with splenic CD4(-)8(-) or CD4(+)8(-) DC; however, all three subsets of DC showed similar IL-12 regulation and responded with increased IL-12 p70 production if IL-4 was present during stimulation. High level CD8 expression also correlated with extent of IL-12 production for DC isolated from thymus and lymph nodes. By using gene knockout mice we ruled out any role for CD8alpha itself, or of priming by T cells, on the superior IL-12-producing capacity of the CD8(+) DC. Additionally, CD8(+) DC were identified as the major producers of IFN-alpha compared with the two CD8(-) DC subsets, a finding that suggests similarity to the human plasmacytoid DC lineage. In contrast, the CD4(-)8(-) DC produced much more IFN-gamma than the CD4(-)8(+) or the CD4(+)8(-) DC under all conditions tested.


Relationship Between Circulating Metabolic Hormones and Their Central Receptors During Ovariectomy-Induced Weight Gain in Rats.
Although increasing research focuses on the phenomenon of body weight gain in women after menopause, the complexity of body weight regulation and the array of models used to investigate it has proven to be challenging. Here, we used ovariectomized (OVX) rats, which rapidly gain weight, to determine if receptors for ghrelin, insulin, or leptin in the dorsal vagal complex (DVC), arcuate nucleus (ARC), or paraventricular nucleus (PVN) change during post-ovariectomy weight gain. Female Sprague-Dawley rats with ad libitum access to standard laboratory chow were bilaterally OVX or sham OVX. Subgroups were weighed and then terminated on day 5, 33, or 54 post-operatively; blood and brains were collected. ELISA kits were used to measure receptors for ghrelin, insulin, and leptin in the DVC, ARC, and PVN, as well as plasma ghrelin, insulin, and leptin. As expected, body weight increased rapidly after ovariectomy. However, ghrelin receptors did not change in any of the areas for either group, nor did circulating ghrelin. Thus, the receptor:hormone ratio indicated comparable ghrelin signaling in these CNS areas for both groups. Insulin receptors in the DVC and PVN decreased in the OVX group over time, increased in the PVN of the Sham group, and were unchanged in the ARC. These changes were accompanied by elevated circulating insulin in the OVX group. Thus, the receptor:hormone ratio indicated reduced insulin signaling in the DVC and PVN of OVX rats. Leptin receptors were unchanged in the DVC and ARC, but increased over time in the PVN of the Sham group. These changes were accompanied by elevated circulating leptin in both groups that was more pronounced in the OVX group. Thus, the receptor:hormone ratio indicated reduced leptin signaling in the DVC and PVN of both groups, but only in the OVX group for the ARC. Together, these data suggest that weight gain that occurs after removal of ovarian hormones by ovariectomy is associated with selective changes in metabolic hormone signaling in the CNS. While these changes may reflect behavioral or physiological alterations, it remains to be determined whether they cause post-ovariectomy weight gain or result from it.


The potential of CBC-derived ratios (monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte) to predict or diagnose incident TB infection in Tanzanian adolescents.
Ratios of different immune cell populations (i.e., monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte ratios) have been studied as a means of predicting future tuberculosis (TB) disease risk or to assist in the diagnosis of incident TB disease. No studies to-date, however, have evaluated the potential of these ratios to predict or assist in the diagnosis of incident TB infection - the first step in the natural history of TB disease. In this prospective study, we evaluated the complete blood count (CBC)-derived metrics of monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) as predictors of future TB infection risk or aids in the diagnosis of TB infection among 145 Tanzanian adolescents enrolled in the DAR-901 vaccine trial, using paired CBCs and interferon-gamma release assays (IGRAs) obtained at 0, 60 and 720 days after study enrollment. At baseline, there were no significant differences between study participants who remained persistently IGRA negative throughout the study period and those who subsequently converted to IGRA positive with respect to MLR (0.18 vs 0.17, p = 0.10), NLR (0.88 vs 1.02, p = 0.08), or PLR (115 vs 120, p = 0.28). Similarly, no significant differences were noted with respect to MLR, NLR, and PLR between IGRA converters and time-matched negative controls at the time of IGRA conversion. With respect to other blood cell measures, however, there were modest but significant differences between IGRA negatives and IGRA converters with respect to red blood cell count (4.8 vs 4.6 × 106 cells/mcL, p = 0.008), hemoglobin (12.6 vs 12.3 g/dL, p = 0.01), and hematocrit (38.8 vs 37.8%, p = 0.005). In contrast to prior studies that have suggested that the ratios of different immune cell populations are associated with development of TB disease, our present findings do not demonstrate an association between these ratios and the development of TB infection. However, decreased red blood cell measures were associated with the subsequent development of TB infection, suggesting either that dysregulation of iron metabolism may play a role in TB pathogenesis or that following TB infection, iron dysregulation may precede IGRA positivity. Clinicaltrials.gov NCT02712424 . Date of registration: March 14, 2016.


[Ambulance transportation and prehospital treatment in connection with admission for suspected acute myocardial infarction].
The aim was to describe ambulance transportation and pre-hospital treatment in connection with admission for suspected acute myocardial infarction. For all patients with suspected acute coronary syndrome who were urgently admitted to the Cardiological Department, Odense University Hospital between 3 August 1998 and 6 December 1998, information about ambulance transportation and pre-hospital treatment was collected through interviews with the patients and study of ambulance records, admission notes, and hospital medical records. In addition, details of the regarding response times were obtained from Falck's emergency service and from nurses' papers. Altogether 279 patients (83%) were transported by ambulance. Half the ambulances arrived at the hospital after 34 minutes (range 11-140 minutes), but every third ambulance took more than 40 minutes to reach the hospital. The pre-hospital treatment of all the patients was: oxygen 69%, nitroglycerin sublingually 46%, nitrous oxide 2%, defibrillation 1.4%, acetylsalicylic acid 9%, morphine injection 8%, and ECG monitoring 57%. The study showed that there were quality problems, as every third ambulance took more than 40 minutes to reach the hospital. It also showed that acetylsalicylic acid and morphine were used only to a limited extent in a pre-hospital situation.


An amino acid substitution-selection model adjusts residue fitness to improve phylogenetic estimation.
Standard protein phylogenetic models use fixed rate matrices of amino acid interchange derived from analyses of large databases. Differences between the stationary amino acid frequencies of these rate matrices from those of a data set of interest are typically adjusted for by matrix multiplication that converts the empirical rate matrix to an exchangeability matrix which is then postmultiplied by the amino acid frequencies in the alignment. The result is a time-reversible rate matrix with stationary amino acid frequencies equal to the data set frequencies. On the basis of population genetics principles, we develop an amino acid substitution-selection model that parameterizes the fitness of an amino acid as the logarithm of the ratio of the frequency of the amino acid to the frequency of the same amino acid under no selection. The model gives rise to a different sequence of matrix multiplications to convert an empirical rate matrix to one that has stationary amino acid frequencies equal to the data set frequencies. We incorporated the substitution-selection model with an improved amino acid class frequency mixture (cF) model to partially take into account site-specific amino acid frequencies in the phylogenetic models. We show that 1) the selection models fit data significantly better than corresponding models without selection for most of the 21 test data sets; 2) both cF and cF selection models favored the phylogenetic trees that were inferred under current sophisticated models and methods for three difficult phylogenetic problems (the positions of microsporidia and breviates in eukaryote phylogeny and the position of the root of the angiosperm tree); and 3) for data simulated under site-specific residue frequencies, the cF selection models estimated trees closer to the generating trees than a standard Г model or cF without selection. We also explored several ways of estimating amino acid frequencies under neutral evolution that are required for these selection models. By better modeling the amino acid substitution process, the cF selection models will be valuable for phylogenetic inference and evolutionary studies.


A single exposure to immobilization causes long-lasting pituitary-adrenal and behavioral sensitization to mild stressors.
We have previously reported that a single exposure to immobilization (IMO) in rats causes a long-term desensitization of the hypothalamic-pituitary-adrenal (HPA) response to the same (homotypic) stressor. Since there are reports showing that a single exposure to other stressors causes sensitization of the HPA response to heterotypic stressors and increases anxiety-like behavior, we studied in the present work the long-term effects of IMO on behavioral and HPA response to mild superimposed stressors. In Experiments 1 and 2, adult male Sprague-Dawley rats were subjected to 2 h of IMO and then exposed for 5 min to the elevated plus-maze (EPM) at 1, 3 or 7 days after IMO. Blood samples were taken at 15 min after initial exposure to the EPM. Increases in anxiety-like behavior and HPA responsiveness to the EPM were found at all times post-IMO. Changes in the resting levels of HPA hormones did not explain the enhanced HPA responsiveness to the EPM (Experiment 3). In Experiments 4 and 5, we studied the effects of a single exposure to a shorter session of IMO (1 h) on behavioral and HPA responses to a brief and mild session of foot-shocks done 10 days after IMO. Neither previous IMO nor exposure to shocks in control rats modified behavior in the EPM. However, a brief session of shocks in previously IMO-exposed rats dramatically increased anxiety in the EPM. HPA and freezing responses to shocks were similar in control and previous IMO groups. Therefore, a single exposure to IMO appears to induce long-lasting HPA and behavioral sensitization to mild superimposed stressors, although the two responses are likely to be at least partially independent. Long-term effects of IMO on the susceptibility to stress-induced endocrine and emotional disturbances may be relevant to the characterization of animal models of post-traumatic stress.


MiRBooking simulates the stoichiometric mode of action of microRNAs.
In eucaryotes, gene expression is regulated by microRNAs (miRNAs) which bind to messenger RNAs (mRNAs) and interfere with their translation into proteins, either by promoting their degradation or inducing their repression. We study the effect of miRNA interference on each gene using experimental methods, such as microarrays and RNA-seq at the mRNA level, or luciferase reporter assays and variations of SILAC at the protein level. Alternatively, computational predictions would provide clear benefits. However, no algorithm toward this task has ever been proposed. Here, we introduce a new algorithm to predict genome-wide expression data from initial transcriptome abundance. The algorithm simulates the miRNA and mRNA hybridization competition that occurs in given cellular conditions, and derives the whole set of miRNA::mRNA interactions at equilibrium (microtargetome). Interestingly, solving the competition improves the accuracy of miRNA target predictions. Furthermore, this model implements a previously reported and fundamental property of the microtargetome: the binding between a miRNA and a mRNA depends on their sequence complementarity, but also on the abundance of all RNAs expressed in the cell, i.e. the stoichiometry of all the miRNA sites and all the miRNAs given their respective abundance. This model generalizes the miRNA-induced synchronistic silencing previously observed, and described as sponges and competitive endogenous RNAs.


Mode couplings and resonance instabilities in finite dust chains.
Employing a numerical simulation, the normal modes are investigated for finite, one-dimensional horizontal dust chains in complex plasma. Mode couplings induced by the ion flow within the sheath are identified in the mode spectra and the coupling rules are determined. Two types of resonance-induced instabilities are observed, one bidirectional and one unidirectional. Bidirectional instability is found to cause melting of the chain with the melting proceeding via a two-step process which obeys the Lindemann criterion. The relationship between the normal mode spectra observed in finite systems and the wave dispersion relations seen in larger systems was also examined using a dust chain model. For this case, the dispersion relation was obtained through multiplication of the mode spectra matrix by a transition matrix. The resulting dispersion relations exhibit both the general features observed in larger crystals as well as several characteristics unique to finite systems, such as discontinuities and strong energy-density fluctuations.


Differential functional significance of AP-1 binding sites in the promoter of the gene encoding mouse tissue inhibitor of metalloproteinases-3.
Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular-matrix-associated protein that suppresses tumorigenicity or invasion in several model systems. We have identified, by in vitro footprinting, six AP-1 (activator protein-1) or AP-1-like binding sites in the mouse TIMP-3 promoter that bind purified c-Jun homodimers. Electrophoretic mobility shift assays revealed that the non-consensus fifth AP-1 binding site (AP-720; nt -720 to -714) had the strongest binding activity for recombinant c-Jun protein, and that the fourth binding site (AP-763; nt -763 to -754) and AP-720 showed strong binding activity for cellular nuclear proteins. Antibody supershift and blocking experiments suggest that AP-720, but not AP-763, binds authentic AP-1 components. Transient transfection reporter assays of deletion constructs showed that the region spanning AP-720 has the highest transcriptional activity, and that sequences 5' to this region (nt -2846 to -747) may contain negative regulatory elements. The deletion construct containing about 500 nt 5' to the transcriptional start, but no AP-1 sites, showed lower but significant activity, suggesting both AP-1-dependent and -independent regulation of the mouse TIMP-3 promoter. Mutational inactivation of AP-720 abolished the activity increment that distinguished the reporter construct containing both AP-720 and sixth AP-1 binding site (AP-617; nt -617 to -611) from that containing only AP-617. In summary, we report here that both AP-1 and non-AP-1 elements contribute to activity, with the non-consensus AP-1 site at -720 showing the greatest functional significance among the AP-1 sites.


Experiences of racial discrimination and adverse gene expression among black individuals in a level 1 trauma center sample.
Up to 40 % of individuals who sustain traumatic injuries are at risk for posttraumatic stress disorder (PTSD) and the conditional risk for developing PTSD is even higher for Black individuals. Exposure to racial discrimination, including at both interpersonal and structural levels, helps explain this health inequity. Yet, the relationship between racial discrimination and biological processes in the context of traumatic injury has yet to be fully explored. The current study examined whether racial discrimination is associated with a cumulative measure of biological stress, the gene expression profile conserved transcriptional response to adversity (CTRA), in Black trauma survivors. Two-weeks (T1) and six-months (T2) post-injury, Black participants (N = 94) provided a blood specimen and completed assessments of lifetime racial discrimination and PTSD symptoms. Mixed effect linear models evaluated the relationship between change in CTRA gene expression and racial discrimination while adjusting for age, gender, body mass index (BMI), smoking history, heavy alcohol use history, and trauma-related variables (mechanism of injury, lifetime trauma). Results revealed that for individuals exposed to higher levels of lifetime racial discrimination, CTRA significantly increased between T1 and T2. Conversely, CTRA did not increase significantly over time in individuals exposed to lower levels of lifetime racial discrimination. Thus, racial discrimination appeared to lead to a more sensitized biological profile which was further amplified by the effects of a recent traumatic injury. These findings replicate and extend previous research elucidating the processes by which racial discrimination targets biological systems.


The evolutionary history of cytochrome P450 genes in four filamentous Ascomycetes.
The Cytochrome P450 system is important in fungal evolution for adapting to novel ecological niches. To elucidate the evolutionary process of cytochrome P450 genes in fungi with different life styles, we studied the patterns of gene gains and losses in the genomes of four filamentous Ascomycetes, including two saprotrophs (Aspergillus nidulans (AN) and Neurospora crassa (NC)) and two plant pathogens (Fusarium graminearum (FG) and Magnaporthe grisea (MG)). A total of 376 P450 genes were assigned to 168 families according to standard nomenclature. On average, only 1 to 2 genes per family were in each genome. To resolve conflicting results between different clustering analyses and standard family designation, a higher order relationship was formulated. 376 genes were clustered into 115 clans. Subsequently a novel approach based on parsimony was developed to build the evolutionary models. Based on these analyses, a core of 30 distinct clans of P450s was defined. The core clans experienced contraction in all four fungal lineages while new clans expanded in all with exception of NC. MG experienced more genes and clans gains compared to the other fungi. Parsimonious analyses unanimously supported one species topology for the four fungi. The four studied fungi exhibit unprecedented diversity in their P450omes in terms of coding sequence, intron-exon structures and genome locations, suggesting a complicated evolutionary history of P450s in filamentous Ascomycetes. Clan classification and a novel strategy were developed to study evolutionary history. Contraction of core clans and expansion of novel clans were identified. The exception was the NC lineage, which exhibited pure P450 gene loss.


The C-CAP Process: A Comprehensive Approach to Community Resource Mapping.
Place-based systems change approaches are gaining popularity to address the complex problems associated with locational disadvantage. An important stage of place-based systems change involves understanding the context that surrounds (re)produces a target problem. Community resource mapping can be used to establish the context and identify the strengths of a community that might be leveraged through systems change efforts. Approaches to community resource mapping draw on a range of philosophical assumptions and methodological frameworks. However, comprehensive, practical guidance for researchers and practitioners to conduct community resource mapping is scarce. Drawing on the learnings from a literature review, scoping workshops, and reflective practice sessions, we developed a flexible, methodologically robust process called the Contextualize, Collect, Analyze, and Present (C-CAP) process: a four-phase approach to preparing for, conducting, and reporting on community resource mapping. The C-CAP process was co-developed by researchers and practitioners and was tested and refined in two different communities. The C-CAP process provides robust guidance for conducting and reporting on a community resource mapping project. The C-CAP process can be applied by public health practitioners and researchers and adapted for use across different communities, problems, and target groups. We encourage others guided by differing theoretical perspectives to apply C-CAP and share the learnings. Application of the C-CAP process has the potential to improve the comparability and comprehensiveness of findings from community resource mapping projects and avoids duplication of effort by reducing the need to design new processes for each new community resource mapping activity.


Two novel deletion mutations in β-globin gene cause β-thalassemia trait in two Chinese families.
β-Thalassemia is mainly caused by point mutations in the β-globin gene cluster. With the rapid development of sequencing technic, more and more variants are being discovered. In this study, we found two novel deletion mutations in two unrelated families, HBB: c.180delG (termed βCD59) and HBB: c.382_402delCAGGCTGCCTATCAGAAAGTG (termed βCD128-134) in family A and B, respectively. Both the two novel mutations lead to β-thalassemia trait. However, when compounded with other β0-thalassemia, it may behave with β-thalassemia intermedia or β-thalassemia major. Our study broadens the variants spectral of β-thalassemia in Chinese population and provides theoretical guidance for the prenatal diagnosis.


[Measurement of free silica concentration in the dust by small X-ray diffractometer].
X-ray diffraction method was applied to measure free silica concentration in the dust and the procedure of analysis have been established. The filter used was the polyvinyl chloride filter. Good linear relationship was shown to exist between the amount of silica and the intensity of its diffracted rays (r = 0.99). The standard deviation of repeated tests was 3.199%. The coefficient of variation was 4.43. An amount of 0.015 mg silica collected on the filter (d = 9 mm) can be detected. This method is suitable for monitoring and investigating silica contents in labour hygiene studies.


Randomized, prospective, observational simulation study comparing residents' needle-guided vs free-hand ultrasound techniques for central venous catheter access.
Short-axis ultrasound-guided placement of central venous catheters (CVCs) is widely accepted as safe practice. However, utilizing the long-axis approach could further improve safety, as it allows for better visualization of the needle as it is advanced to the target vessel. However, the long-axis approach has not widely been used due to the technical difficulty. Recently, a new needle guidance device has become available to aid in the long-axis approach. We hypothesized that the use of a needle guide paired with the long-axis approach would facilitate puncture of the target vessel in a simulation model more effectively than similar free-hand techniques. A prospective observational study of anaesthesia residents using a CVC partial-task training device was conducted. Each resident performed needle puncture of the target vessel with three different techniques, assigned in random order: short-axis free hand (S-FH), long-axis free hand (L-FH), and long-axis needle guide (NG). To prove the effectiveness of the needle guide, the fraction of time the needle tip remained in view of the ultrasound was recorded and compared. Time required for completing the task and the number of needle sticks and needle re-directions were compared. Thirty-three residents participated in the study. The fraction of time the needle tip remained in view of the ultrasound was significantly higher for the residents using NG [0.90 (0.10)] compared with residents using the other techniques [L-FH: 0.36 (0.20), S-FH: 0.18 (0.10)] (P<0.001). For each resident, the use of the needle guide in the long-axis approach increased visualization by 352 (276)% compared with that of L-FH and by 1028 (1804) % compared with that of S-FH. There was no significant difference in time required to puncture the target between NG [23.7 (14.6) s] and L-FH [30.3 (36.5) s] (P=0.21); however, both were significantly longer than S-FH [17.0 (13.3) s] (P=0.012). The numbers of needle sticks and of needle re-directions did not differ among the groups. The needle guide device used in the long-axis approach improved the needle visualization compared with free-hand techniques. The needle guide used in the long-axis technique, however, did not facilitate puncture of the target vessel in this simulation model when compared with free-hand techniques.


Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy?
The benefits of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) should outweigh surgical morbidity. Even when the generally agreed upon selection criteria for CN are met, some patients do poorly after surgery. The objective of this study was to identify preoperative factors that were prognostic of outcome in patients who were being considered for CN. The authors conducted a retrospective study to investigate the overall survival (OS) of patients who underwent CN using the OS of patients with mRCC who did not undergo CN as a referent group. Patients who underwent CN were divided into 2 groups based on when their OS diverged from that of nonsurgical patients. Chi-square analysis was used to identify variables that differed between the 2 surgical groups. Multivariate Cox proportional hazards regression was used to analyze those variables for the entire CN cohort. Risk factors were defined as preoperative variables that remained significant on multivariate analysis. The median OS and the overall risk of death were calculated based on the number of risk factors. From 1991 to 2007, 566 patients who were eligible for or received systemic therapy underwent CN, and 110 patients received medical therapy alone. On multivariate analysis, independent preoperative predictors of inferior OS in surgical patients included a lactate dehydrogenase level greater than the upper limit of normal, an albumin level less than the lower limit of normal, symptoms at presentation caused by a metastatic site, liver metastasis, retroperitoneal adenopathy, supradiaphragmatic adenopathy, and clinical tumor classification>or=T3. Inferior OS and an increased risk of death were correlated positively with the number of risk factors. Surgical patients who had >or=4 risk factors did not appear to benefit from CN. The authors of this report identified 7 preoperative variables that permitted them to identify patients who were unlikely to benefit from CN.


Impact of pre-operative body mass index in head and neck cancer patients undergoing microvascular reconstruction.
To analyse the relationship of pre-operative body mass index with surgical complications and oncological outcomes in patients undergoing microvascular reconstruction for head and neck squamous cell cancer. A retrospective review was conducted of 259 patients who underwent microvascular free flap reconstruction after head and neck ablative surgery. Mean body mass index was 22.48 kg/m2. There were no correlations between body mass index and: flap failure (p = 0.739), flap ischaemia (p = 0.644), pharyngocutaneous fistula (p = 0.141) or wound infection (p = 0.224). The five-year disease-specific survival rate was 63 per cent. On univariate analysis, the five-year disease-specific survival rate was significantly correlated with pre-operative body mass index, based on Kaplan-Meier survival curves (p = 0.028). The five-year disease-specific survival rates in underweight, normal weight, overweight and obese groups were 47 per cent, 55 per cent, 65 per cent and 80 per cent, respectively. Pre-operative body mass index was a useful predictor for recurrence and survival in patients who underwent microvascular reconstruction for head and neck squamous cell cancer.


Phase diagram of Mg insertion into Chevrel phases, MgxMo6T8 (T = S, Se). 3. The crystal structure of triclinic Mg2Mo6Se8.
This series of papers is devoted to unique cathode materials for Mg batteries, MgxMo6T8 (T = S, Se, x = 1 and 2) Chevrel phases (CPs). In this part, a combination of neutron and high-resolution synchrotron X-ray diffractions was used to study the crystal structure of Mg2Mo6Se8, which is triclinic at room temperature (space group P1, a = 6.868 A, b = 6.921 A, c = 6.880 A, alpha = 93.00 degrees , beta = 94.40 degrees , gamma = 96.22 degrees ). In contrast to other members of the MgxMo6T8 family, this compound does not follow the classic scheme of successive cation insertion into so-called inner and outer sites: Both the Mg(2+) ions per formula are located in the tetrahedral sites of the outer ring. This surprising cation location, predicted previously for Mg-containing CPs by ab initio calculations, provides the uniform distribution of the cation charge in the triclinic structure, which is similar to that of rhombohedral CPs. A mapping of the cation sites was widely used to demonstrate the variety of cation arrangement in CPs and the factors affecting this arrangement, as well as to clarify the origin of the exceptionally high mobility of the Mg(2+) ions in Mg2Mo6Se8.


[The value of radioimmunoassay of urinary hCG in an in vitro fertilization program].
Radio-immuno-assay estimations of urinary hCG were carried out with pharmacia Kit beta hCG Riact on 36 women who had received embryo transfers. The analysis was carried in order to try and find how and at what moment in time it is possible to diagnose very early a developing pregnancy after embryo transfer. In this work we have found that the mean level of urinary hCG was significantly higher (P less than 0.001) in women who became pregnant (group B) than in those who did not become pregnant (group A). The difference in mean hormone levels in these two groups became more marked in the following days. The time doubling of the hCG level varied between 1.21 and 3.24 days in group B. By the eighth day the level of urinary hCG was less in group B than in group A, probably due to rapid renal breakdown of hCG. In summary these results show that the level of urinary hCG estimated from the 11th day onwards after an embryo transfer repeated two or three days later makes it possible to detect early pregnancies.


Progressive multifocal leukoencephalopathy in HIV-infected patients in the era of HAART: radiological features at diagnosis and follow-up and correlation with clinical variables.
The magnetic resonance (MR) imaging patterns of HIV-infected patients affected by progressive multifocal leukoencephalopathy (PML) in the HAART era have not been extensively documented. The aim of the present study is to describe the MR features of PML in HIV-infected patients at diagnosis, and the evolution during follow-up, evaluating the impact of HAART on imaging, and to correlate the MR pattern with the virological and immunological levels and with survival. We retrospectively reviewed MR imaging at baseline and at the last available follow-up within 6 months of diagnosis (median 4 months, range 1-6) of 31 HIV-positive patients affected by PML. A closer follow-up [median interval from diagnosis 39 days (range 20-139)] was also reported. At the onset of neurological disorder, 19 patients were naive for antiretroviral therapy, 7 patients were on HAART, and 5 patients were experienced but were not taking antiretroviral therapy. Upon PML diagnosis no significant differences at imaging were observed between naive and experienced patients and HAART-treated or non-HAART-treated patients. MR findings were not related to immunological status, either at baseline or at follow-up. A radiological improvement within 6 months was associated with a higher probability of a more favorable clinical evolution [OR 14.0 (2.2-87.2), p = 0.003]. The overall probability of survival at 6 months was 61.5%. A better survival was observed in patients with stable or improved MR imaging findings within 6 months [HR 4.55 (95%CI 1.36-15.19, p = 0.009]. Although HAART prolonged the survival of HIV-positive patients affected by PML, it did not seem to influence the PML MR pattern of presentation and the imaging evolution. Only the radiological outcome was predictive of clinical outcome.