Oncologic Effectiveness and Safety of Splenectomy in Total Gastrectomy for Proximal Gastric Carcinoma: Meta-analysis of Randomized Controlled Trials.
The role of splenectomy as an essential component of radical surgery for proximal gastric cancer, from an oncological point of view, is still debated, and no consistent recommendations have been proposed. The aim of this systematic review with meta-analysis was to provide a more robust answer regarding the oncological effectiveness and safety of splenectomy in total gastrectomy for proximal gastric carcinoma. A systematic review and meta-analysis of randomized controlled trials was planned and performed in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement and Cochrane Handbook for Systematic Reviews of Intervention. Patients with a histological diagnosis of gastric adenocarcinoma located in the upper third of the stomach who underwent D2 total gastrectomy with or without splenectomy were selected. The primary outcome was to analyze the influence of splenectomy on the overall survival of patients. Additionally, the mean difference in procedure time, length of hospital stay, number of retrieved lymph nodes, as well as the odds ratio of postoperative complications comparing splenectomy to spleen preservation were investigated in a secondary analysis Results: Overall, four studies with a total of 978 patients met the inclusion criteria. The pooled analysis showed no difference in overall survival rates between those who underwent spleen preservation compared to the splenectomy-treated group (risk ratio=0.92, 95% confidence interval=0.79 to 1.06, p=0.277). Interestingly, all studies reporting overall morbidity data highlighted statistically significant differences in favor of spleen-preservation group (odds ratio=2.11, 95% confidence interval=1.44 to 3.09, p<0.001). In total, gastrectomy for proximal gastric cancer, splenectomy should not be recommended as it increases operative morbidity without improving survival when compared to spleen preservation. Furthermore, our results may help in planning the updated versions of Gastric Cancer Treatment Guidelines. This meta-analysis, however, points to the urgent need for high-quality, well-designed, large-scale, clinical trials, with short-as well as long-term evaluation comparing splenectomy with spleen-preserving procedures, in a controlled randomized manner to help future research and to establish an evidence-based approach to gastric cancer treatment.


Pathological laughing as a manifestation in a clinically isolated brainstem syndrome: a case report.
The prevalence of pathological laughing and crying in multiple sclerosis (MS) is 10%. It has been speculated that the anatomical lesion responsible for the pathological laughing is located in the pontine base, prefrontal cortex, and cerebellum. We report an 18-year-old male patient presenting with pathological laughing and hypomania. In his neurological examination, he had a euphoric effect with ataxic walking and dysarthria speech. He had a bilateral conjugated gaze limitation, with a prominent bilateral horizontal nystagmus on left gaze, dysmetria, dysdiadokokinesia, and remarkable dysfunction in a heel-to-shin test on the left. The IgG index in cerebrospinal fluid was normal with an oligoclonal band was present. In cranial MRI, there was a lesion on central pons which was hypointense in T1 images with contrast enhancement and hyperintense in T2 and flair images. Also another lesion in right brachium pontis which did not contrast enhancement but was hyperintense on T2 and flair images was present. There was an elevation of myoinositol/creatine ratio and choline and a reduction of NAA in proton MR spectroscopy. MR spectroscopic evaluation of the patient demonstrated the demyelination process. There has been no report of patients in whom pathological laughter was the presenting symptom of clinically isolated brainstem syndrome.


Tag retention in and effects of passive integrated transponder tagging on survival and swimming performance of a small-bodied darter.
Fisheries biologists have been hesitant to use passive integrated transponder (PIT) tags in small-bodied fishes (40-200 mm TL) such as darters (Percidae: Etheostomatinae) because of the fishes' size and potential effect on swimming performance. The authors used constant acceleration trials to evaluate the swimming performance of Arkansas darters Etheostoma cragini in control (no incision or tag), sham (incision and suture) or PIT tagged (surgically implanted 8 × 1.4 mm intra-peritoneal PIT tag) treatments. Tag retention and fish survival were monitored for up to 199 days post-tagging. Maximum swimming velocity did not differ between control, sham and PIT tag treatments, nor was maximum swimming velocity affected by the tagging procedure. Tag retention was 100%, and the overall survival of tagged fish was 88% in the swimming study, and 100% in the long-term study, suggesting that small PIT tags are suitable for use in darters. The authors include a brief meta-analysis on the results reported by 20 studies that PIT tagged small-bodied fishes, representing 38 species and nine families of freshwater fish.


Redox-magnetohydrodynamics, flat flow profile-guided enzyme assay detection: toward multiple, parallel analyses.
A proof-of-concept superparamagnetic microbead-enzyme complex was integrated with microfluidics pumped by redox-magneto-hydrodynamics (MHD) to take advantage of the magnet (0.56 T) beneath the chip and the uniform flat flow profile, as a first step toward developing multiple, parallel chemical analyses on a chip without the need for independent channels. The superparamagnetic beads were derivatized with alkaline phosphatase (a common enzyme label for biochemical assays) and magnetically immobilized at three different locations on the chip with one directly on the path to the detector and the other two locations adjacent to, but off the path, by a distance >5 times the detector diameter. Electroactive p-aminophenol, enzymatically generated at the bead-enzyme complex from its electroinactive precursor p-aminophenyl phosphate in a solution containing a redox species [Ru(NH3)6](3+/2+) for pumping and Tris buffer, was transported by redox-MHD and detected with square wave voltammetry at a 312 μm diameter gold microdisk stationed 2 mm downstream from the bead-complex on the flow path. Oppositely biased pumping electrodes, consisting of 2.5 cm long gold bands and separated by 5.6 mm, flanked the active flow region containing the bead-enzyme complex and detection site. The signal from adjacent paths was only 20% of that for the direct path and ≤8% when pumping electrodes were inactive.


Efficient gene delivery to pig airway epithelia and submucosal glands using helper-dependent adenoviral vectors.
Airway gene delivery is a promising strategy to treat patients with life-threatening lung diseases such as cystic fibrosis (CF). However, this strategy has to be evaluated in large animal preclinical studies in order to translate it to human applications. Because of anatomic and physiological similarities between the human and pig lungs, we utilized pig as a large animal model to examine the safety and efficiency of airway gene delivery with helper-dependent adenoviral vectors. Helper-dependent vectors carrying human CFTR or reporter gene LacZ were aerosolized intratracheally into pigs under bronchoscopic guidance. We found that the LacZ reporter and hCFTR transgene products were efficiently expressed in lung airway epithelial cells. The transgene vectors with this delivery can also reach to submucosal glands. Moreover, the hCFTR transgene protein localized to the apical membrane of both ciliated and nonciliated epithelial cells, mirroring the location of wild-type CF transmembrane conductance regulator (CFTR). Aerosol delivery procedure was well tolerated by pigs without showing systemic toxicity based on the limited number of pigs tested. These results provide important insights into developing clinical strategies for human CF lung gene therapy.Molecular Therapy-Nucleic Acids (2013) 2, e127; doi:10.1038/mtna.2013.55; published online 8 October 2013.


Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo.
Voltage-gated Na(+) channels (Nav) are essential for myocyte membrane excitability and cardiac function. Nav current (INa) is a large-amplitude, short-duration spike generated by rapid channel activation followed immediately by inactivation. However, even under normal conditions, a small late component of INa (INa,L) persists because of incomplete/failed inactivation of a subpopulation of channels. Notably, INa,L is directly linked with both congenital and acquired disease states. The multifunctional Ca(2+)/calmodulin-dependent kinase II (CaMKII) has been identified as an important activator of INa,L in disease. Several potential CaMKII phosphorylation sites have been discovered, including Ser571 in the Nav1.5 DI-DII linker, but the molecular mechanism underlying CaMKII-dependent regulation of INa,L in vivo remains unknown. To determine the in vivo role of Ser571, 2 Scn5a knock-in mouse models were generated expressing either: (1) Nav1.5 with a phosphomimetic mutation at Ser571 (S571E), or (2) Nav1.5 with the phosphorylation site ablated (S571A). Electrophysiology studies revealed that Ser571 regulates INa,L but not other channel properties previously linked to CaMKII. Ser571-mediated increases in INa,L promote abnormal repolarization and intracellular Ca(2+) handling and increase susceptibility to arrhythmia at the cellular and animal level. Importantly, Ser571 is required for maladaptive remodeling and arrhythmias in response to pressure overload. Our data provide the first in vivo evidence for the molecular mechanism underlying CaMKII activation of the pathogenic INa,L. Relevant for improved rational design of potential therapies, our findings demonstrate that Ser571-dependent regulation of Nav1.5 specifically tunes INa,L without altering critical physiological components of the current.


Maternal performance of Duroc, Hampshire and Landrace backcross gilts fed normal and high fiber diets during postweaning growth.
Duroc (DDDY), Hampshire (HHHY) and Landrace (LLLY) backcross gilts produced from matings of purebred sires and sixth or seventh parity F1 Duroc-Yorkshire, Hampshire-Yorkshire or Landrace-Yorkshire sows were fed and libitum either a high fiber (8.8% crude fiber, 2,910 kcal metabolizable energy (ME/kg) or normal fiber (3.9% crude fiber, 3,428 kcal ME/kg) diet during the postweaning growth period (70 to 170 d of age). A sample of 176 gilts was assigned randomly to one of three groups and exposed to purebred Yorkshire boars. All pregnant gilts were retained and exposed to boars for three additional production cycles. Sows failing to farrow were retained and returned to breeding with their contemporaries. Maternal performance, litter sizes at birth and weaning, pig weights, total litter weights and sow productivity index through four farrowings were not affected by postweaning dietary treatment of gilts. Interactions of nutritional regimen with either backcross type or exposure number were nonsignificant. Performances of the backcross types did differ. The DDDY had larger litter sizes at birth and weaning than HHHY or LLLY (12.0 vs 10.9 and 10.3 at birth and 9.6 vs 8.6 and 8.6 at weaning, respectively). Individual pig weights were similar at weaning among sow backcrosses. Therefore, DDDY females weaned heavier litters due to more pigs per litter and had higher sow productivity indices. Additionally, HHHY had a higher lactational weight loss and greater breeding and gestation weight gains than DDDY or LLLY. Sow feed consumption during lactation did not differ among backcrosses. Backcross type did interact statistically with sow group and exposure for several variables. Most significant interactions were due to differences in relative performance rather than absolute rank.


Life-cycle energy use and greenhouse gas emissions of production of bioethanol from sorghum in the United States.
The availability of feedstock options is a key to meeting the volumetric requirement of 136.3 billion liters of renewable fuels per year beginning in 2022, as required in the US 2007 Energy Independence and Security Act. Life-cycle greenhouse gas (GHG) emissions of sorghum-based ethanol need to be assessed for sorghum to play a role in meeting that requirement. Multiple sorghum-based ethanol production pathways show diverse well-to-wheels (WTW) energy use and GHG emissions due to differences in energy use and fertilizer use intensity associated with sorghum growth and differences in the ethanol conversion processes. All sorghum-based ethanol pathways can achieve significant fossil energy savings. Relative to GHG emissions from conventional gasoline, grain sorghum-based ethanol can reduce WTW GHG emissions by 35% or 23%, respectively, when wet or dried distillers grains with solubles (DGS) is the co-product and fossil natural gas (FNG) is consumed as the process fuel. The reduction increased to 56% or 55%, respectively, for wet or dried DGS co-production when renewable natural gas (RNG) from anaerobic digestion of animal waste is used as the process fuel. These results do not include land-use change (LUC) GHG emissions, which we take as negligible. If LUC GHG emissions for grain sorghum ethanol as estimated by the US Environmental Protection Agency (EPA) are included (26 g CO2e/MJ), these reductions when wet DGS is co-produced decrease to 7% or 29% when FNG or RNG is used as the process fuel. Sweet sorghum-based ethanol can reduce GHG emissions by 71% or 72% without or with use of co-produced vinasse as farm fertilizer, respectively, in ethanol plants using only sugar juice to produce ethanol. If both sugar and cellulosic bagasse were used in the future for ethanol production, an ethanol plant with a combined heat and power (CHP) system that supplies all process energy can achieve a GHG emission reduction of 70% or 72%, respectively, without or with vinasse fertigation. Forage sorghum-based ethanol can achieve a 49% WTW GHG emission reduction when ethanol plants meet process energy demands with CHP. In the case of forage sorghum and an integrated sweet sorghum pathway, the use of a portion of feedstock to fuel CHP systems significantly reduces fossil fuel consumption and GHG emissions. This study provides new insight into life-cycle energy use and GHG emissions of multiple sorghum-based ethanol production pathways in the US. Our results show that adding sorghum feedstocks to the existing options for ethanol production could help in meeting the requirements for volumes of renewable, advanced and cellulosic bioethanol production in the US required by the EPA's Renewable Fuel Standard program.


Effect of cleaning, milling, and baking on deoxynivalenol in wheat.
Samples of wheat naturally infected by Fusarium graminearum Schwabe were obtained from mills in Oklahoma, Missouri, Kansas, and Minnesota and fields in Nebraska and Kansas in 1982; they were analyzed for deoxynivalenol (DON). The wheat was milled, and DON was found throughout all the milling fractions (bran, shorts, reduction flour, and break flour). The DON recoveries for each mill run ranged from 90 to 98%. These samples, regardless of DON concentration, also gave similar fractional distributions of DON. The greatest (21 ppm [21 micrograms/g]) concentration of DON was found in the bran, and the smallest (1 ppm) was found in the break flour. Cleaning and milling were not effective in removing DON; DON was not destroyed in the bread baked from the naturally contaminated whole wheat flour, but the effect on its concentration in the samples analyzed varied, the reduction ranging from 19 to 69%. The percent reduction found in the cleaned wheat ranged from 6 to 19%. DON concentrations in the following commercially made breads, caraway rye, seedless rye, and pumpernickel, were 45 ppb (ng/g), 39 ppb, and 0 ppb, respectively. The limits of detection by gas chromatography-mass spectrometry and high-pressure liquid chromatography for DON were 0.5 and 10 ng, respectively.


Associations of β-Amyloid and Vascular Burden With Rates of Neurodegeneration in Cognitively Normal Members of the 1946 British Birth Cohort.
The goals of this work were to quantify the independent and interactive associations of β-amyloid (Aβ) and white matter hyperintensity volume (WMHV), a marker of presumed cerebrovascular disease (CVD), with rates of neurodegeneration and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British Birth Cohort. Participants underwent brain MRI and florbetapir-Aβ PET as part of Insight 46, an observational population-based study. Changes in whole-brain, ventricular, and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI with the boundary shift integral. Linear regression was used to test associations with baseline Aβ deposition, baseline WMHV, APOE ε4, and office-based Framingham Heart Study Cardiovascular Risk Score (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53, and 69 years. Three hundred forty-six cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time points (mean [SD] scan interval 2.4 [0.2] years). Being Aβ positive at baseline was associated with 0.87-mL/y faster whole-brain atrophy (95% CI 0.03, 1.72), 0.39-mL/y greater ventricular expansion (95% CI 0.16, 0.64), and 0.016-mL/y faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10-mL additional WMHV at baseline was associated with 1.07-mL/y faster whole-brain atrophy (95% CI 0.47, 1.67), 0.31-mL/y greater ventricular expansion (95% CI 0.13, 0.60), and 0.014-mL/y faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent, and there was no evidence that Aβ and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjustment for Aβ status and WMHV, no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, and no evidence that FHS-CVS or systolic BP acted synergistically with Aβ. Aβ and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways.


Characterization of hemoglobin lepore variants by advanced mass-spectrometric procedures.
We describe an analytical protocol for characterizing the molecular structure of hemoglobin (Hb) Lepore variants by using two different mass-spectrometric approaches. The first method consists of direct examination of the chromatographically separated hybrid globins by electro-spray mass spectrometry; the variant Lepore globin is identified through the accurate determination of its molecular mass. Alternatively, the anomalous globins are digested with trypsin and their structures are determined by fast atom bombardment mass-spectrometric analysis of the peptide mixture. The application of this procedure to the identification of Hb Lepore Boston and Hb Lepore Baltimore is described.


The oceanic microcosm of particles.
Analyses of suspended particulate matter larger than 1 micrometer, filtered from thousands of liters of surface and deep waters during GEOSECS expeditions to the Atlantic and Pacific oceans, have provided new information on the nature and time scales of chemical processes associated with the particles. Trace element and radionuclide data show that particles scavenge trace elements such as Th, Pu, Fe, Pb, and Cu from the ocean column, thereby controlling their concentrations. For other elements, however, particles are a source: carbon and silicon, for example, are introduced at depths as sinking particles dissolve. Studies of both particulate concentrations by filtration of seawater and particulate fluxes by using sediment traps seem necessary to delineate the intricate nature of chemical processes in the oceans.


The non-monophyletic origin of the tRNA molecule.
The hypothesis that the tRNA molecule may have originated from the assembly of two similar RNA hairpin structures is utilised to understand the evolutionary period in which this molecule originated. Consistent with the exon theory of genes is the observation that the introns in tRNA genes are found almost exclusively in the anticodon loop and "stitched together" the two halves of the molecule, which originally may have been simply two hairpin structures and which can still be observed in the three-dimensional structure of tRNAs. This theory therefore considers these hairpin structures as minigenes on which complex protein synthesis may have been achieved. This in turn leads to the belief that the organisation of the genetic code may have been determined by use of the hairpin structures but not the complete tRNA molecule. In view of this, it can be conjectured that tRNA molecules might have been assembled only after the establishment of the main phyletic lines. If this is all true, then the origin of the tRNA molecule might have been non-monophyletic, i.e. a tRNA specific for a certain amino acid might have been assembled in different phyletic lines with a second and different hairpin structure. This leads to the belief that tRNAs specific for different amino acids but belonging to the same phyletic line might have been more similar to one another than to tRNAs specific for the same amino acid but belonging to different phyletic lines. This prediction seems to be supported by phylogenetic analysis making major use of the bootstrap technique performed on the tRNA sequences and by analysis already existing in the literature which supports the non-monophyletic origin of the tRNA molecule. The main conclusion of this paper is that if the tRNA molecule was assembled in the main phyletic lines this would imply a still rapidly evolving translation apparatus which, in turn, seems to imply that the last universal common ancestor was a progenote.


Medication overuse headache: self-perceived and actual knowledge among pharmacy staff.
The aim of this study was to investigate knowledge about medication overuse headache (MOH) among pharmacy staff. MOH is a public health problem both in Sweden and in many other countries. Persons with MOH have limited contact with health care, and medications used are to large extent over-the-counter (OTC) medications. Therefore, pharmacists have an important role in, eg, advising these individuals about their medication use. Little is, however, known about the actual level of knowledge about MOH among pharmacy staff, which determines the quality of their advice to MOH sufferers. A total of 326 questionnaires were distributed to 44 pharmacies in Gothenburg, Sweden. The questionnaire included background questions, questions about advice on headache treatment, source of knowledge about MOH, and questions on self-perceived and actual knowledge on MOH. The response rate was 70%. A majority of the pharmacy staff (90.6%) considered themselves to have knowledge about MOH to some or a greater extent. Almost half had learned about MOH through their university/vocational education. Only 8.6% knew that all 5 headache medications listed in the questionnaire can cause development of MOH, but 40% responded correctly on which treatment advice one can give a person with MOH. Actual knowledge on treatment advice differed significantly between groups of self-perceived knowledge. The knowledge on MOH is insufficient among pharmacy staff, but with the proper knowledge, pharmacy staff is well positioned to effect both primary and secondary prevention of MOH. We suggest not only increasing educational efforts about MOH within pharmacy programs but also continuing education at the pharmacies for all staff. Further, it is also important to increase knowledge among pharmacy customers.


[Trophic disorders in ganglionitis of the superior cervical sympathetic ganglion under experimental and clinical conditions].
The paper is concerned with a clinical study of 9 patients where ganglionitis of the upper cervical sympathic node proceeded with an atrophy of the soft tissues in the form of facial hemiatrophy. Besides in experiments on 18 guinea pigs the authors either removed or irritated the upper cervical sympathic node and then after a certain period during 30 days performed histological and histochemical studies of the soft tissues of the animal muzzle. It was possible to mark a prevalent lesion of the skin and subcutaneous fatty tissue. In the early periods of the experiment there was a more expressed change in the metabolic reactions and less-structural disorders which developed eventually and had a secondary character due to disorders of metabolic processes. These data permit to consider that such changes take place in the faces of patients with ganglionitis of the upper cervical sympathic node.


Signaling from Akt to FRAP/TOR targets both 4E-BP and S6K in Drosophila melanogaster.
The eIF4E-binding proteins (4E-BPs) interact with translation initiation factor 4E to inhibit translation. Their binding to eIF4E is reversed by phosphorylation of several key Ser/Thr residues. In Drosophila, S6 kinase (dS6K) and a single 4E-BP (d4E-BP) are phosphorylated via the insulin and target of rapamycin (TOR) signaling pathways. Although S6K phosphorylation is independent of phosphoinositide 3-OH kinase (PI3K) and serine/threonine protein kinase Akt, that of 4E-BP is dependent on PI3K and Akt. This difference prompted us to examine the regulation of d4E-BP in greater detail. Analysis of d4E-BP phosphorylation using site-directed mutagenesis and isoelectric focusing-sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that the regulatory interplay between Thr37 and Thr46 of d4E-BP is conserved in flies and that phosphorylation of Thr46 is the major phosphorylation event that regulates d4E-BP activity. We used RNA interference (RNAi) to target components of the PI3K, Akt, and TOR pathways. RNAi experiments directed at components of the insulin and TOR signaling cascades show that d4E-BP is phosphorylated in a PI3K- and Akt-dependent manner. Surprisingly, RNAi of dAkt also affected insulin-stimulated phosphorylation of dS6K, indicating that dAkt may also play a role in dS6K phosphorylation.


Trim-cyclophilin A fusion proteins can restrict human immunodeficiency virus type 1 infection at two distinct phases in the viral life cycle.
The Trim5alpha protein from several primates restricts retroviruses in a capsid (CA)-dependent manner. In owl monkeys, the B30.2 domain of Trim5 has been replaced by cyclophilin A (CypA) following a retrotransposition. Restriction of human immunodeficiency virus type 1 (HIV-1) by the resulting Trim5-CypA fusion protein depends on CA binding to CypA, suggesting both that the B30.2 domain might be involved in CA binding and that the tripartite RING motif, B-BOX, and coiled coil (RBCC) motif domain can function independently of the B30.2 domain in restriction. To investigate the potential of RBCCs from other Trims to participate in restricting HIV-1, CypA was fused to the RBCC of Trim1, Trim18, and Trim19 and tested for restriction. Despite low identity within the RBCC domain, all fusion proteins were found to restrict HIV-1 but not the nonbinding G89V mutant, indicating that the overall structure of RBCC and not its primary sequence was important for the restriction function. The critical interaction between CA and Trim-CypA appears to take place soon after viral entry. Quantitative PCR analysis of viral reverse transcriptase products revealed that the different fusion proteins block HIV-1 at two distinct stages of its life cycle, either prior to reverse transcription or just before integration. With Trim1 and Trim18, this timing is dependent on the length of the Trim component of the fusion protein. These observations suggest that restriction factor binding can have different mechanistic consequences.


Human plasma-derived FVIII/VWD concentrate (Biostate): a review of experimental and clinical pharmacokinetic, efficacy and safety data.
Human plasma-derived factor VIII/von Willebrand factor complex concentrates are used to control bleeding in patients with von Willebrand disease (VWD) or haemophilia A (HA). The properties of these haemostatic factor concentrates vary widely, which can have significant clinical implications. This review provides an extensive overview of the molecular properties, in addition to pharmacokinetic, efficacy and safety data, and case studies of clinical experience of one such concentrate, Biostate. These data are discussed in the context of various therapeutic applications and compared with other factor concentrate products. Data are presented from data on file from the manufacturer; product information and published experimental and clinical pharmacokinetic, safety and efficacy study data; and example case studies of clinical experience. The data discussed herein demonstrate that Biostate has well-established efficacy profiles in the treatment of patients with VWD or HA, with the control of bleeding rated as 'excellent', 'good' or 'moderate' in >90% of patients. In an immune-tolerance induction setting, 73% of patients achieved a complete response following treatment with Biostate. Biostate was generally well tolerated in patients with HA or VWD, with infrequent minor adverse events reported and no reported cases of clinically relevant thrombosis.


Cardiac rehabilitation goal attainment after myocardial infarction with versus without diabetes: A nationwide registry study.
Patients with first-time myocardial infarction (MI) and diabetes mellitus (DM) constitute a vulnerable subgroup of cardiovascular (CV) patients for which secondary prevention is particularly important. We investigated if patients with versus without DM differ in attaining four main lifestyle-related cardiac rehabilitation (CR) targets, one-year post-MI. This national cohort study (2006-2015) identified individuals with and without DM at hospital admission in the Swedish cardiac registry, SWEDEHEART. CR goal attainment was assessed one year later. The study population included 47,907 unique patients with first-time MI <75 years at baseline (61.8 mean age, 26.7% women, 14.6% with DM). After imputation, propensity score matching was performed. Analyses were conducted with logistic regression. In the matched population, having DM was associated (OR [95% CI]) with lower odds of attaining the one-year post-MI CR goal for both smoking cessation (0.90 [0.81, 0.99]) and attendance in exercise training (0.88 [0.83, 0.95]), yet with higher odds of the <1.8 mmol LDL-C target (1.28 [1.19, 1.36]), and similar odds for the <140 mm Hg systolic blood pressure target (0.97 [0.91, 1.04]). In addition, women with DM were particularly unlikely to attend exercise training. Patients with first-time MI and DM are less likely to attain two of four selected CR goals compared to those without DM. The particularly low exercise training attendance by women with DM is of concern. Possibilities for tailored interventions targeting behavioural change for this high-risk group, including focused efforts to increase exercise training attendance in women with DM, should be investigated.


Covariation of sex differences in mental rotation with body size.
Sex difference in mental rotation ability was reconsidered. The Vandenberg-Kuse figures were administered to 120 male and 76 female students from the Medical School of BlackSea Technical University in Trabzon, Turkey to assess the mental rotation ability. Students' height and weight were measured. As expected, men outperformed women on this test and had greater height and weight. Number correct on mental rotation test significantly correlated with height and weight for the total sample and for men, but only with weight for women. Using weight as covariate, the sex difference was no longer significant. The mean mental rotation score was significantly higher for heavy women than for light men. There was a positive correlation between weight and mental rotation test scores for heavy women, but height and weight were negatively correlated with mental rotation test scores for light men. These results suggest that there is no sex difference in mental rotation ability as measured.


Pregnancy and Birth Outcomes among Women with Idiopathic Thrombocytopenic Purpura.
To examine pregnancy and birth outcomes among women with idiopathic thrombocytopenic purpura (ITP) or chronic ITP (cITP) diagnosed before or during pregnancy. A linkage of mothers and babies within a large U.S. health insurance database that combines enrollment data, pharmacy claims, and medical claims was carried out to identify pregnancies in women with ITP or cITP. Outcomes included preterm birth, elective and spontaneous loss, and major congenital anomalies. Results suggest that women diagnosed with ITP or cITP prior to their estimated date of conception may be at higher risk for stillbirth, fetal loss, and premature delivery. Among 446 pregnancies in women with ITP, 346 resulted in live births. Women with cITP experienced more adverse outcomes than those with a pregnancy-related diagnosis of ITP. Although 7.8% of all live births had major congenital anomalies, the majority were isolated heart defects. Among deliveries in women with cITP, 15.2% of live births were preterm. The results of this study provide further evidence that cause and duration of maternal ITP are important determinants of the outcomes of pregnancy.


Self-assembly of triazatriangulenium-based functional adlayers on Au(111) surfaces.
Detailed scanning tunneling microscopy studies of the attachment of freestanding molecular functions to Au(111) surfaces via self-assembly of functional molecules based on triazatriangulenium platforms are presented. As shown for molecules with side chains of different length and phenyl, azobenzyl, or azobenzyl derivatives with different terminal groups (iodo, cyano, or dimethyl) as functional units, this approach allows the preparation of very stable, hexagonally ordered adlayers. The intermolecular spacings in these adlayers are independent of the attached functions with the latter being orientated perpendicular to the Au surface. Due to their open structure, adlayers of platforms with attached functional groups exhibit a tendency towards bilayer formation, which can be suppressed by derivatization with appropriate terminal groups.


Physical activity recommendations for patients with heart failure based on sex: A qualitative interview study.
Physical activity is an essential part of managing heart failure. However, adherence to activity recommendations is low, especially in female patients. The aim of this study was to investigate the perceptions of healthcare providers regarding sex differences in physical activity, motivation, barriers, and whether adaptations in care based on sex might be meaningful. This is a qualitative study; data were collected in semi-structured interviews with healthcare providers. The data were analysed using qualitative content analysis. The major overarching theme was that healthcare providers feel that "Men and women are equal, but different". This theme was explained in terms of 7 sub-themes with associated categories, as follows: "Men and women prefer and perform different physical activity regardless of health status", "Male and female heart failure patients have different motivations for, and barriers to, being active", "Factors related to differences in physical activity and physical capacity between male and female heart failure patients", "Heart failure has more impact on physical activity and physical capacity than patient's sex", and "Tailoring activity advice for heart failure patients based on sex." Healthcare providers had clear opinions regarding the existence of sex differences that might affect patients' care. Several differences were identified in male and female heart failure patients in terms of physical activity. There seems to be a conflict between fear of discriminating and the value of personalizing care.


Nanoscale Drug Delivery Systems: From Medicine to Agriculture.
The main challenges in drug delivery systems are to protect, transport and release biologically active compounds at the right time in a safe and reproducible manner, usually at a specific target site. In the past, drug nano-carriers have contributed to the development of precision medicine and to a lesser extent have focused on its inroads in agriculture. The concept of engineered nano-carriers may be a promising route to address confounding challenges in agriculture that could perhaps lead to an increase in crop production while reducing the environmental impact associated with crop protection and food production. The main objective of this review is to contrast the advantages and disadvantages of different types of nanoparticles and nano-carriers currently used in the biomedical field along with their fabrication methods to discuss the potential use of these technologies at a larger scale in agriculture. Here we explain what is the problem that nano-delivery systems intent to solve as a technological platform and describe the benefits this technology has brought to medicine. Also here we highlight the potential drawbacks that this technology may face during its translation to agricultural applications, based on the lessons learned so far from its use for biomedical purposes. We discuss not only the characteristics of an ideal nano-delivery system, but also the potential constraints regarding the fabrication including technical, environmental, and legal aspects. A key motivation is to evaluate the potential use of these systems in agriculture, especially in the area of plant breeding, growth promotion, disease control, and post-harvest quality control. Further, we highlight the importance of a rational design of nano-carriers and identify current research gaps to enable scale-up relevant to applications in the treatment of plant diseases, controlled release of fertilizers, and plant breeding.


Effective treatment with Gilteritinib-based regimens for FLT3-mutant extramedullary relapse in acute promyelocytic leukemia.
Extramedullary relapse (EMR) is rare in acute promyelocytic leukemia (APL) and, there is a lack of information on its management. Current practices for EMR in APL are always to adopt strategies from other subtypes of Acute lymphoblastic leukemia (ALL) and Acute myeloid leukemia (AML). Gilteritinib, a highly selective FLT3 inhibitor, has demonstrated a remarkable effect on EMR in FLT3-mutant AML. Therefore, it is worthwhile exploring if FLT3 mutation can be a therapeutic target and assessing the efficacy of Gilteritinib on FLT3-mutant EMR in APL. We described three cases of FLT3-mutant EMR in APL, comprising two isolated EMR cases and one systemic relapse. The patients underwent treatment with Gilteritinib-based regimens based on FLT3 mutation. All three patients achieved complete regression of EMR, and no signs of tumor lysis syndrome during Gilteritinib-based therapy, only patient 1 showed mild granulocytopenia. They all maintained molecular complete remission (mCR) during the follow-up period. The Gilteritinib-based regimen shows a high and sustained therapeutic effect with minimal adverse effects, and provides a valuable experience for further evaluation in EMR APL patients.


Alcohol-containing protein transduction domain mimics.
The application and design of protein transduction domains (PTDs) and protein transduction domain mimics (PTDMs) have revolutionized the field of biomacromolecule delivery. Our group has previously synthesized block copolymer PTDMs with well-defined hydrophobic and cationic blocks via ring-opening metathesis polymerization (ROMP). We have optimized the balance of hydrophobicity and cationic density to intracellularly deliver model proteins, active proteins, and antibodies. Despite the presence of serine, threonine, and tyrosine in naturally occurring PTDs, synthetic analogs have yet to be studied in PTDMs. In our present work, we introduce different alcohol groups to our PTDM structures as a new design parameter. A library of nine novel PTDMs were synthesized to incorporate alcohol groups of varying structures and evaluated based on their ability to intracellularly deliver fluorescently labeled antibodies. One PTDM in this novel library, named PTDM4, incorporates alcohol groups in both the hydrophobic and cationic blocks and was found to be the best performing PTDM with almost twice the median fluorescence intensity of the delivered antibody and half the cationic density compared to our positive control, a PTDM thoroughly studied by our group. PTDM4 was further studied by intracellularly delivering the active enzyme, TAT-Cre Recombinase. The activity of TAT-Cre Recombinase delivered by PTDM4 was comparable to that of the positive control, again with half the cationic density. This study is one of the first to examine the effects of alcohol groups on intracellular antibody and active enzyme delivery.


Diagnostic criteria for apathy in clinical practice.
Apathy is an important and distressing behavioural symptom in Alzheimer's disease and in various neuropsychiatric disorders. Recently, diagnostic criteria for apathy have been proposed. In groups of patients suffering from different neuropsychiatric diseases, (i) to estimate the prevalence of patients meeting the proposed diagnostic criteria; (ii) to estimate the concurrent validity of the criteria with the neuropsychiatric inventory (NPI) apathy item; (iii) to identify the most frequently met criteria or sub-criteria in each specific neuropsychiatric disease and (iv) to estimate the inter-observer reliability of the diagnostic criteria for apathy. This cross-sectional, multicentric, observational study was performed on 306 patients. Each of the participating centres had to check the presence of apathy according to the diagnostic criteria for apathy in consecutive patients belonging to the following diagnoses list: Alzheimer disease (AD), mixed dementia, mild cognitive impairment (MCI), Parkinson's disease (PD), Schizophrenia (DSM-IV) and major depressive episode. In addition to the clinical interview, the assessment included the Mini Mental Score Examination (MMSE) and the NPI. At the end of the visit, clinicians were required to check the diagnostic criteria for apathy. Using the diagnostic criteria for apathy, the frequency of apathy was of 53% in the whole population, 55% in AD, 70% in mixed dementia, 43% in MCI, 27% in PD, 53% in schizophrenia and 94% in major depressive episode. In AD, mixed dementia, MCI and PD, the NPI apathy score was significantly higher for patient fulfilling the apathy criteria. Goal-directed cognitive activity (criteria B2-Cognition) was the most frequently observed domain followed by goal-directed behaviour (criteria B1-Behaviour) and emotion (criteria B3), respectively. Inter-rater reliability was high for the overall diagnostic (κ coefficient = 0.93; p = 0.0001) and for each criteria. This study is the first one to test the diagnostic criteria for apathy in clinical practice. Results make the diagnostic criteria useful for clinical practice and research.


Historical decline in coral reef growth after the Panama Canal.
The Panama Canal is near its vessel size and tonnage handling capacity, and Panamanians have decided to expand it. The expansion of the Canal may consider the historical long-lasting impacts on marine coastal habitats particularly on sensitive coral reefs. These potential impacts were discussed during the national referendum as were other equally important issues, such as its effects on forests, watersheds, and water supply. Coral growth rates provide a direct measure of coral fitness and past environmental conditions comparable to analyses of tree rings. We examined stable isotopes, metal geochemical tracers, and growth rates on a century-long (1880-1989) chronology based on 77 cores of the dominant reef-building coral Siderastrea siderea collected near the Caribbean entrance to the canal. Our results showed a gradual decline in coral growth unrelated to changes in sea surface temperature but linked to runoff and sedimentation to coastal areas resulting from the construction and operation of the Panama Canal.


Differences in cortico-striatal-cerebellar activation during working memory in syndromal and nonsyndromal children with prenatal alcohol exposure.
Although children with heavy prenatal alcohol exposure may exhibit the distinctive facial dysmorphology seen in full or partial fetal alcohol syndrome (FAS/PFAS), many lack that dysmorphology. This study examined the functional organization of working memory in the brain in three groups of children-those meeting diagnostic criteria for FAS or PFAS, heavily exposed (HE) nonsyndromal children, and healthy controls. A verbal n-back task (1-back and 0-back) was administered to 47 children (17 with FAS/PFAS, 13 HE, and 17 controls) during fMRI. Intra-group one-sample t-tests were used to identify activity regions of interest central to verbal working memory including the dorsal prefrontal cortex (dPFC), inferior frontal gyrus, caudate/putamen, parietal cortex, and cerebellar Crus I/lobule VI and lobule VIIB-IX. Whereas groups did not differ in task sensitivity, fMRI analyses suggested different patterns of sub-network recruitment across groups. Controls primarily recruited left inferior frontal gyrus (Broca's area). By contrast, HE primarily recruited an extensive set of fronto-striatal regions, including left dPFC and left caudate, and the FAS/PFAS group relied primarily on two cerebellar subregions and parietal cortex. This study is, to our knowledge, the first to demonstrate differential recruitment of critical brain regions that subserve basic function in children with different fetal alcohol spectrum disorders compared to controls. The distinct activation patterns seen in the two exposed groups may be related to substantial differences in alcohol dose/occasion to which these groups were exposed in utero.


Influence of maternal angiogenic factors during pregnancy on microvascular structure in school-age children.
Reduced placental growth factor (PlGF) levels and higher soluble fms-like tyrosine kinase (sFlt-1) levels in mothers during pregnancy may have persistent effects on vascular structures in their offspring. We examined whether angiogenic factors during pregnancy also affect childhood retinal microvasculature in a population-based prospective cohort study among 3505 mothers and their children. We measured maternal PlGF and sFlt-1 in the first and second trimester of pregnancy. At the age of 6, we measured childhood retinal arteriolar and venular calibers from digitized retinal photographs. We performed multiple linear regression models, taking maternal and childhood sociodemographic and lifestyle-related characteristics, birth characteristics, and childhood current body mass index and blood pressure into account. We observed that first trimester maternal PlGF and sFlt-1 levels were not associated with childhood retinal arteriolar caliber. Lower second trimester maternal PlGF levels, but not sFlt-1 levels, were associated with narrower childhood retinal arteriolar caliber (difference: -0.09 SD score [95% confidence interval, -0.16 to 0.01], per SD score decrease in PlGF). This association was not explained by maternal and childhood sociodemographic and lifestyle-related characteristics, birth characteristics, or childhood current body mass index and blood pressure. Maternal PlGF and sFlt-1 levels in the first or second trimester were not associated with childhood retinal venular caliber. Our results suggest that lower maternal second trimester PlGF levels affect the microvascular development in the offspring, leading to narrower retinal arteriolar caliber in childhood. Further studies are needed to confirm these findings and to explore the underlying mechanisms and long-term cardiovascular consequences.


Laboratory studies for the detection of carcinoma of the prostate.
Acid phosphatase and prostate-specific antigen are extremely useful markers for the management of patients with prostatic carcinoma. Prostatic acid phosphatase, because of its relatively low sensitivity and specificity, as well as analyte instability and diurnal variability, is unsuitable for prostate cancer screening. Improved performance characteristics, stability, the lesser diurnal variation, and the association of elevated prostate-specific antigen with prostatic intraepithelial neoplasia make prostate-specific antigen possibly a better candidate for early detection of this common malignancy. Further investigations in this area are clearly indicated before we can recommend screening with prostate-specific antigen.


Solvent fluctuations around solvophobic, solvophilic, and patchy nanostructures and the accompanying solvent mediated interactions.
Using classical density functional theory(DFT), we calculate the density profile ρ(𝐫) and local compressibility χ(𝐫) of a simple liquidsolvent in which a pair of blocks with (microscopic) rectangular cross section are immersed. We consider blocks that are solvophobic, solvophilic and also ones that have both solvophobic and solvophilic patches. Large values of χ(𝐫) correspond to regions in space where the liquid density is fluctuating most strongly. We seek to elucidate how enhanced density fluctuations correlate with the solvent mediated force between the blocks, as the distance between the blocks and the chemical potential of the liquid reservoir vary. For sufficiently solvophobic blocks, at small block separations and small deviations from bulk gas-liquid coexistence, we observe a strongly attractive (near constant) force, stemming from capillary evaporation to form a low density gas-like intrusion between the blocks. The accompanying χ(𝐫) exhibits a structure which reflects the incipient gas-liquid interfaces that develop. We argue that our model system provides a means to understanding the basic physics of solvent mediated interactions between nanostructures, and between objects such as proteins in water that possess hydrophobic and hydrophilic patches.


Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease.
In Alzheimer's disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal components. In Drosophila, pan-neuronal Tau expression triggers reductions in multiple core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss of function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle burden. Our results implicate spliceosome disruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD.


The use of one- versus two-tailed tests to evaluate prevention programs.
Investigators have used both one- and two-tailed tests to determine the significance of findings yielded by program evaluations. While the literature that addresses the appropriate use of each type of significance test should be used is historically inconsistent, almost all authorities now agree that one-tailed tests are rarely (if ever) appropriate. A review of 85 published evaluations of school-based drug prevention curricula specified on the National Registry of Effective Programs and Practices revealed that 20% employed one-tailed tests and, within this subgroup, an additional 4% also employed two-tailed tests. The majority of publications either did not specify the type of statistical test employed or used some other criterion such as effect sizes or confidence intervals. Evaluators reported that they used one-tailed tests either because they stipulated the direction of expected findings in advance, or because prior evaluations of similar programs had yielded no negative results. The authors conclude that one-tailed tests should never be used because they introduce greater potential for Type I errors and create an uneven playing field when outcomes are compared across programs. The authors also conclude that the traditional threshold of significance that places α at .05 is arbitrary and obsolete, and that evaluators should consistently report the exact p values they find.


Transposon Tn10-dependent expression of the lamB gene in Escherichia coli.
Among Tn10 insertions isolated in or near the malB region of Escherichia coli, one (zjb-729::Tn10) mapped between malK and lamB or late in malK and allowed MalT-independent expression of lamB. Tn10-dependent expression of a lamB-lacZ protein fusion was 25% of the expression of the fusion from the malK-lamB operon promoter in malTc constitutive strains. The maltoporin content of a strain carrying this Tn10 was about 20% that of a malTc malB+ strain. Transport of maltose at concentrations of below 10(-6) M was reduced about threefold. When maltoporin was present at about 50% of the level of malTc malB+ strains, maltose transport was largely restored. We conclude that maltoporin is not rate limiting for maltose transport in wild-type cells but becomes rate limiting when the ratio of maltoporin to other maltose transport components is reduced more than twofold.


FeON-FeOFF: the Helicobacter pylori Fur regulator commutates iron-responsive transcription by discriminative readout of opposed DNA grooves.
Most transcriptional regulators bind nucleotide motifs in the major groove, although some are able to recognize molecular determinants conferred by the minor groove of DNA. Here we report a transcriptional commutator switch that exploits the alternative readout of grooves to mediate opposite output regulation for the same input signal. This mechanism accounts for the ability of the Helicobacter pylori Fur regulator to repress the expression of both iron-inducible and iron-repressible genes. When iron is scarce, Fur binds to DNA as a dimer, through the readout of thymine pairs in the major groove, repressing iron-inducible transcription (FeON). Conversely, on iron-repressible elements the metal ion acts as corepressor, inducing Fur multimerization with consequent minor groove readout of AT-rich inverted repeats (FeOFF). Our results provide first evidence for a novel regulatory paradigm, in which the discriminative readout of DNA grooves enables to toggle between the repression of genes in a mutually exclusive manner.


Variant angina pectoris. Pain and arrhythmias controlled after postoperative myocardial infarction.
A 30-year-old man with variant angina pectoris and ventricular arrhythmias had an angiographically demonstrable 60% obstructive lesion of the proximal left anterior descending coronary artery that was observed to progress to 100% during spasm. Control of pain and arrhythmia by pharmacologic means was unsuccessful. Aortocoronary saphenous vein-internal mammary coronary bypass was associated with an anteroseptal wall myocardial infarction and relief from both angina pectoris and arrhythmias. It is suggested that infarction of the ischemic myocardium played a role in the successful management of this case.


Metabolomic and Lipidomic Signature of Skeletal Muscle with Constitutively Active Mechanistic Target of Rapamycin Complex 1.
Regulation of mechanistic target of rapamycin complex 1 (mTORC1) plays an important role in aging and nutrition. For example, caloric restriction reduces mTORC1 signaling and extends lifespan, whereas nutrient abundance and obesity increase mTORC1 signaling and reduce lifespan. Skeletal muscle-specific knockout (KO) of DEP domain-containing 5 protein (DEPDC5) results in constitutively active mTORC1 signaling, muscle hypertrophy and an increase in mitochondrial respiratory capacity. The metabolic profile of skeletal muscle, in the setting of hyperactive mTORC1 signaling, is not well known. To determine the metabolomic and lipidomic signature in skeletal muscle from female and male wild-type (WT) and DEPDC5 KO mice. Tibialis anterior (TA) muscles from WT and transgenic (conditional skeletal muscle-specific DEPDC5 KO) were obtained from female and male adult mice. Polar metabolites and lipids were extracted using a Bligh-Dyer extraction from 5 samples per group and identified and quantified by LC-MS/MS. Resulting analyte peak areas were analyzed with t-test, analysis of variance, and Volcano plots for group comparisons (e.g., WT compared with KO) and multivariate statistical analysis for genotype and sex comparisons. A total of 162 polar metabolites (organic acids, amino acids, and amines and acyl carnitines) and 1141 lipid metabolites were detected in TA samples by LC-MS/MS. Few polar metabolites showed significant differences in KO muscles compared with WT within the same sex group. P-aminobenzoic acid, β-alanine, and dopamine were significantly higher in KO male muscle whereas erythrose-4-phosphate and oxoglutaric acid were significantly reduced in KO females. The lipidomic profile of the KO groups revealed an increase of muscle phospholipids and reduced triacylglycerol and diacylglycerol compared with the WT groups. Sex differences were detected in polar metabolome and lipids were dependent on genotype. The metabolomic profile of mice with hyperactive skeletal muscle mTORC1 is consistent with an upregulation of mitochondrial function and amino acid utilization for protein synthesis.


Describing and Predicting Preprocedural Anxiety in Patients Scheduled for Advanced Gastrointestinal Endoscopy During the COVID-19 Pandemic.
Advanced gastrointestinal endoscopy includes a group of specialized procedures and interventions that are being performed more frequently, with little attention given to a patient's preprocedural anxiety issues. Compounding this concern, in 2020 the COVID-19 pandemic resulted in the delay of many endoscopy cases. It is unknown how this affected the anxiety of patients preparing for advanced endoscopy procedures. Patients with higher anxiety require higher doses of anesthetic medications, and experience increased pain and decreased satisfaction. The purpose of this study was to describe the biological, psychological, and social attributes of patients and identify whether social support, COVID-19-related anxiety, delay of procedure, patient's physical status, and procedural indication category were predictors of state anxiety levels in patients undergoing advanced gastrointestinal endoscopy during the COVID-19 pandemic. The research study was a cross-sectional descriptive design with 90 patients. Patients were classified into low state and high state anxiety groups. Fifty-eight percent of patients had high state anxiety scores. Using logistic regression, social support was identified as a predictor of preprocedural anxiety (odds ratio [OR] = 0.318 [95% confidence interval, CI = 0.170, 0.597, p < .001]) as less social support was associated with higher anxiety. It is imperative that strategies to maximize social support are reinforced.


Autonomic dysreflexia due to medication: misadventure in the use of an isometheptene combination to treat migraine.
Autonomic dysreflexia, a syndrome sometimes occurring in spinal cord injured (SCI) individuals, may be life-threatening. It involves, in varying degrees, hypertension, diaphoresis, headache, bradycardia, anxiety, and flushing and is believed due to unrestricted sympathetic activity below the level of the lesion in individuals with injuries above T4-6. The most frequent causes of the syndrome are urinary infections, rectal impaction, bladder distention, and decubitus ulcers. To our knowledge, medication has seldom been described as causal agent. We report here on an autonomic dysreflexic syndrome following use of an isometheptene combination (Midrin), to treat migraine. The individual involved is a C4-quadriplegic man with a long history of migraines. He was given a standard initial adult dose of the medication. Over a one-hour period, he was initially relieved of the headache, but then noted a new more severe headache, diaphoresis, and flushing. His vital signs showed progressive BP elevation to 210/130 and a relative bradycardia. Treatment over the next three hours was limited to elevation of the head of the bed and observation, during which his vital signs returned to baseline and he became asymptomatic. This experience reinforces the belief that sympathomimetic drugs in general, and isometheptene in particular, should be used in caution in patients with high-level SCI.


Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain.
While there is an abundance of pharmacological and biochemical evidence to suggest the existence of multiple opioid receptors, their precise localization within the brain is unclear. To help clarify this issue, the present study examined the distributions of the mu, delta, and kappa opioid receptor subtypes in the rat forebrain and midbrain using in vitro autoradiography. Mu and delta receptors were labeled with the selective ligands 3H-DAGO (Tyr- D-Ala-Gly-MePhe-Gly-ol), and 3H-DPDPE (D-Pen2, D-Pen5-enkephalin), respectively, while the kappa receptors were labeled with 3H-(-)bremazocine in the presence of unlabeled DAGO and DPDPE. Based on previous findings in our laboratory, the labeling conditions were such that each ligand selectively occupied approximately 75% of each of the opioid sites. The results demonstrated that all 3 opioid receptor subtypes were differentially distributed in the rat brain. Mu binding was dense in anterior cingulate cortex, neocortex, amygdala, hippocampus, ventral dentate gyrus, presubiculum, nucleus accumbens, caudate putamen, thalamus, habenula, interpeduncular nucleus, pars compacta of the substantia nigra, superior and inferior colliculi, and raphe nuclei. In contrast, delta binding was restricted to only a few brain areas, including anterior cingulate cortex, neocortex, amygdala, olfactory tubercle, nucleus accumbens, and caudate putamen. Kappa binding, while not as widespread as observed with mu binding, was densely distributed in the amygdala, olfactory tubercle, nucleus accumbens, caudate putamen, medial preoptic area, hypothalamus, median eminence, periventricular thalamus, and interpeduncular nucleus. While all 3 opioid receptor subtypes could sometimes be localized within the same brain area, their precise distribution within the region often varied widely. For example, in the caudate putamen, mu binding had a patchy distribution, while delta and kappa sites were diffusely distributed, with delta sites being particularly dense ventrolaterally and kappa sites being concentrated ventromedially. These results support the existence of at least 3 distinct opioid receptors with possibly separate functional roles.


Personality Characteristics of Viet Nam veterans identified as heroin abusers.
The author presents data on the Minnesota Multiphasic Personality Inventory (MMPI) characteristics of a sample of enlisted Army men returning from Viet Nam identified as heroin abusers. Although a marked heterogeneity of MMPI profile types was found, a significant percentage of the subjects showed indications of marked psychopathology, and only a minority performed within normal limits on the MMPI. Theses military subjects showed neither greater nor less psychopathology and sociopathology than previously reported samples of civilian addicts.


A phase II study of the halichondrin B analog eribulin mesylate in gemcitabine refractory advanced pancreatic cancer.
Eribulin mesylate is a halichondrin B analog that inhibits microtubule dynamics. Pre-clinical studies have suggested anti-tumor activity in pancreatic cancer. This phase II study of eribulin in patients with advanced pancreatic cancer previously treated with gemcitabine was conducted by the Princess Margaret Hospital Phase II consortium. Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and previous treatment with gemcitabine. The study was a single arm phase II trial using a Simon 2-stage design. The primary endpoint was response rate, secondary endpoints included time to progression and overall survival. Fifteen patients were enrolled, 14 received treatment, and 12 were evaluable for response. The median age was 61, and the majority of patients were ECOG performance status 1. Grade 3 or greater adverse events included neutropenia (29%), fatigue (14%), peripheral neuropathy (7%) and thrombosis (7%). There were no complete or partial responses and therefore the study was closed after the first stage. The best response was stable disease in 5/12 (42%) of patients. Of these five patients, three had stable disease for 9 months or greater. Median time to progression was 1.4 months, and median overall survival was 6.1 months. Eribulin was well tolerated but did not result in any objective responses in gemcitabine refractory pancreatic cancer. However, several patients had prolonged stable disease, suggesting that further studies of eribulin in pancreatic cancer may be warranted.


Regulation of Listeria monocytogenes Virulence.
Whereas obligate human and animal bacterial pathogens may be able to depend upon the warmth and relative stability of their chosen replication niche, environmental bacteria such as Listeria monocytogenes that harbor the ability to replicate both within animal cells and in the outside environment must maintain the capability to manage life under a variety of disparate conditions. Bacterial life in the outside environment requires adaptation to wide ranges of temperature, available nutrients, and physical stresses such as changes in pH and osmolarity as well as desiccation. Following ingestion by a susceptible animal host, the bacterium must adapt to similar changes during transit through the gastrointestinal tract and overcome a variety of barriers associated with host innate immune responses. Rapid alteration of patterns of gene expression and protein synthesis represent one strategy for quickly adapting to a dynamic host landscape. Here, we provide an overview of the impressive variety of strategies employed by the soil-dwelling, foodborne, mammalian pathogen L. monocytogenes to straddle diverse environments and optimize bacterial fitness both inside and outside host cells.


Oophoropexy and the management of Hodgkin's disease. A reevaluation of the risks and benefits.
Female patients with Hodgkin's disease who undergo staging laparotomy frequently have oophoropexy performed to preserve both fertility and hormone production. Because of recent changes in therapy favoring systemic chemotherapy rather than total nodal irradiation for patients with stage III Hodgkin's disease, the need for oophoropexy may be less than previously described. Thirty-nine women of childbearing age underwent laparotomy at the University of North Carolina, Chapel Hill, from 1970 to 1984. Twenty-seven patients underwent oophoropexy. Only three of these patients would have needed this procedure based on their subsequent therapy. Two patients required additional gynecologic surgery because of complications related to the oophoropexy. The success rate in preservation of menstrual function and fertility is also discussed. We review the previous experience with oophoropexy and suggest an alternative approach to the routine use of this procedure.


Multifunctional Immunoliposomes Enhance the Immunotherapeutic Effects of PD-L1 Antibodies against Melanoma by Reprogramming Immunosuppressive Tumor Microenvironment.
The immunosuppressive tumor microenvironment (TME) can significantly limit the immunotherapeutic effects of the PD-L1 antibody (aPDL1) by inhibiting the infiltration of CD8+ cytotoxic T cells (CTLs) into the tumor tissues. However, how to reprogram the immunosuppressive TME and promote the infiltration of CTLs remains a huge challenge for aPDL1 to achieve the maximum benefits. Herein, the authors design a multifunctional immunoliposome that encapsulates the adrenergic receptor blocker carvedilol (CAR) and connects the "don't eat me" signal antibody (aCD47) and aPDL1 in series via a reactive oxygen species (ROS)-sensitive linker on the surface. In ROS-enriched immunosuppressive TME, the multifunctional immunoliposome (CAR@aCD47/aPDL1-SSL) can first release the outer aCD47 to block the "do not eat me" pathway, promote the phagocytosis of tumor cells by phagocytic cells, and activate CTLs. Then, the aPDL1 on the liposome surface is exposed to block the PD-1/PD-L1 signaling pathway, thereby inducing CTLs to kill tumor cells. CAR encapsulated in CAR@aCD47/aPDL1-SSL can block the adrenergic nerves in the tumor tissues and reduce their densities, thereby inhibiting angiogenesis in the tumor tissues and reprogramming the immunosuppressive TME. According to the results, CAR@aCD47/aPDL1-SSL holds an effective way to reprogram the immunosuppressive TME and significantly enhance immunotherapeutic efficiency of aPDL1 against the primary cancer and metastasis.


Serological biomarker profiles of rapidly progressive osteoarthritis in tanezumab-treated patients.
There is a need for efficacious and safe pain treatments for OA (osteoarthritis). The nerve growth factor (NGF) antibody tanezumab is associated with high efficacy, but when combined with chronic NSAID treatment shows an increased risk of rapidly progressive osteoarthritis (RPOA) in a small group of patients. The aim of this study was to phenotype with biochemical biomarkers of bone, cartilage, soft tissue, synovial metabolism OA patients who are at risk of developing RPOA type-2, for both limited and chronic NSAIDs users. The dataset consisted of OA patients participating in tanezumab trials who used NSAIDs <90 days (limited NSAID users) or chronic users (NSAIDs ≥90 days) over an average 10 month period. Biomarker data were available for 47 cases (RPOA type-2) and 92 controls. Non-linear and linear multivariable predictive models were developed. By use of two biomarkers at baseline the receiver operating characteristic (ROC) curve area for RPOA type-2 in limited NSAID users was 71%, [CI] (60-83%). OA subjects with this biomarker phenotype had 8-fold higher confidence interval [CI][(2-33)] relative risk of developing RPOA type-2 as compared to OA patients without this phenotype. The AUC of the model in chronic NSAIDs users based on 5 biomarkers was 78%, [CI](69-88%), with 4-fold [CI (2-6)] relative risk of developing RPOA type-2. In this hypothesis generating and exploratory study, we identified combinations of biomarkers associated with OA patients who develop RPOA type-2, which may be related to the pathology of the RPOA type-2 joint.


The biology of airway dendritic cells.
Recent work from our laboratory has identified a network of constitutively class II MHC (Ia) bearing dendritic cells (DC) within the epithelium of the conducting airways of laboratory animal species and in humans. The density of DC within the respiratory tract is highest in those areas exposed to greater amounts of inhaled antigen and further work has identified these DC as being critically important in controlling the induction of immune responses within the airways. The DC population in the airway epithelium is renewed every 48-72 h; this represents a more rapid turnover than DC in other tissues which are exposed to a smaller antigenic load. In addition to these results we will discuss other work which shows that airway DC are a very reactive population, comparable with neutrophils in their response to acute inflammatory stimuli and that their numbers and Ia content can be modulated following exposure to topical and systemic steroids. Finally we will discuss the development of these cells after birth and how this may influence the pathogenesis of immune regulated diseases such as asthma and allergic rhinitis.


Mapping fast protein folding with multiple-site fluorescent probes.
Fast protein folding involves complex dynamics in many degrees of freedom, yet microsecond folding experiments provide only low-resolution structural information. We enhance the structural resolution of the five-helix bundle protein λ6-85 by engineering into it three fluorescent tryptophan-tyrosine contact probes. The probes report on distances between three different helix pairs: 1-2, 1-3, and 3-2. Temperature jump relaxation experiments on these three mutants reveal two different kinetic timescales: a slower timescale for 1-3 and a faster one for the two contacts involving helix 2. We hypothesize that these differences arise from a single folding mechanism that forms contacts on different timescales, and not from changes of mechanism due to adding the probes. To test this hypothesis, we analyzed the corresponding three distances in one published single-trajectory all-atom molecular-dynamics simulation of a similar mutant. Autocorrelation analysis of the trajectory reveals the same "slow" and "fast" distance change as does experiment, but on a faster timescale; smoothing the trajectory in time shows that this ordering is robust and persists into the microsecond folding timescale. Structural investigation of the all-atom computational data suggests that helix 2 misfolds to produce a short-lived off-pathway trap, in agreement with the experimental finding that the 1-2 and 3-2 distances involving helix 2 contacts form a kinetic grouping distinct from 1 to 3. Our work demonstrates that comparison between experiment and simulation can be extended to several order parameters, providing a stronger mechanistic test.


Peer education for hepatitis C prevention.
The purpose of this article is to describe a model of education about hepatitis C virus prevention tested in a county correctional facility. The Teach One Method and Relational Communication models inform this work. Using a one-group pretest-posttest prospective design our aims were to (1) convey education about prevention, protection, and safety; (2) provide this information through relationship-centered communication; (3) test the reliability and validity of the instruments; and (4) measure changes in behavior, knowledge, and relationship in the learner. A convenience sample of 25 men was recruited at a Massachusetts county jail. Subscale reliability was 0.78 and 0.79 for the relationship and behavior subscales, respectively. Knowledge questions were evaluated using face and content validity by teachers before and during this study. All subscale mean scores improved in the posttest condition. The level of significance of the calculated t value for the behavior subscale was 0.16. The level of significance for the relationship t value was nonsignificant at 0.65. Knowledge, behavior, and relationship scores improved after the intervention. Recommendations include retesting study instruments on a larger sample and using a control group.


[Mastocytosis, classification, biological diagnosis and therapy].
In mast cell (MC) disorders (mastocytosis), clinical symptoms are caused by the release of chemical mediators from MCs, the pathologic infiltration of neoplastic MCs in tissues, or both. Cutaneous mastocytosis is a benign disease in which MC infiltration is confined to the skin. In pediatric cases cutaneous mastocytosis might regress spontaneously. Systemic mastocytosis (SM) is more frequently diagnosed in adults and is a persistent (clonal) disease of bone marrow-derived myelomastocytic progenitors. The somatic c-kit mutation D816V is found in the majority of such patients. The natural clinical course in SM is variable. Whereas most patients remain at the indolent stage for many years, some have aggressive SM (ASM) at diagnosis. Other patients have an associated clonal hematologic none MC lineage disease (AHNMD). MC leukemia (MCL) is a rare disease variant characterized by circulating MCs and fatal disease progression. Two important diagnostic clues in SM are an increased serum tryptase level and the presence of abnormal mast cells in the bone marrow. The current review provides an overview of mastocytosis and its subvariants, the new classification of these diseases, a practical guide for the biological diagnosis and advances and future directions in therapy of these pathologies.


Challenging biopower: "Liquid cuffs" and the "Junkie" habitus.
Methadone maintenance treatment program (MMTP) is associated with improved quality of life amongst many heroin users. Still, program adherence problems remain a fact. To improve our understanding of MMTP "adherence problems". Using snowball sampling, two subgroups were recruited: MMTP enrollees and non-enrollees. A semi-structured questionnaire guided all in-depth interviews. Interviews were recorded, transcribed, hand-coded and analyzed using a grounded theory approach. Of 28 participants, 23 were male and Fifteen were in MMTP. All were NYC residents. Most were Hispanic (57%) and Caucasian (32%). The average age was 38 years. Twenty-two had a General Educational Development or less. All were poor and 64% were homeless. Many do not enroll in MMTP to quit heroin but to avoid physical withdrawals. Once enrolled, problems emerge with program regulations and methadone's pharmacology. These they refer to as "liquid cuffs". Drawing on Michel Foucault, methadone may be considered a disciplinary biopower technology that participants challenge using specific strategies. A "Junkie" habitus, crystallized by emotional and identitarian heroin-dispositions, also challenges biopower. The "liquid cuffs" experience along with the "Junkie" habitus effectively challenge disciplinary biopower. Loosening program regulations may improve quality of services and reduce harm.


Cerebrospinal fluid levels of amyloid precursor protein are associated with ventricular size in post-hemorrhagic hydrocephalus of prematurity.
Neurological outcomes of preterm infants with post-hemorrhagic hydrocephalus (PHH) remain among the worst in infancy, yet there remain few instruments to inform the treatment of PHH. We previously observed PHH-associated elevations in cerebrospinal fluid (CSF) amyloid precursor protein (APP), neural cell adhesion molecule-L1 (L1CAM), neural cell adhesion molecule-1 (NCAM-1), and other protein mediators of neurodevelopment. The objective of this study was to examine the association of CSF APP, L1CAM, and NCAM-1 with ventricular size as an early step toward developing CSF markers of PHH. CSF levels of APP, L1CAM, NCAM-1, and total protein (TP) were measured in 12 preterm infants undergoing PHH treatment. Ventricular size was determined using cranial ultrasounds. The relationships between CSF APP, L1CAM, and NCAM-1, occipitofrontal circumference (OFC), volume of CSF removed, and ventricular size were examined using correlation and regression analyses. CSF levels of APP, L1CAM, and NCAM-1 but not TP paralleled treatment-related changes in ventricular size. CSF APP demonstrated the strongest association with ventricular size, estimated by frontal-occipital horn ratio (FOR) (Pearson R = 0.76, p = 0.004), followed by NCAM-1 (R = 0.66, p = 0.02) and L1CAM (R = 0.57,p = 0.055). TP was not correlated with FOR (R = 0.02, p = 0.95). Herein, we report the novel observation that CSF APP shows a robust association with ventricular size in preterm infants treated for PHH. The results from this study suggest that CSF APP and related proteins at once hold promise as biomarkers of PHH and provide insight into the neurological consequences of PHH in the preterm infant.


Amygdala kindling modifies interhemispheric dopaminergic asymmetry.
Brain dopamine is known to retard the development of kindled seizures, but it is uncertain whether kindling affects dopamine function. In the present study, rats were screened for cerebral dominance by recording their preferred direction of rotation when injected with d-amphetamine. Bipolar stimulating electrodes were then implanted in the amygdaloid complex of either the dominant or nondominant hemisphere (i.e., respectively, contra- and ipsilateral to the preferred direction of rotation; the dominant hemisphere identified in this way has been shown to contain higher concentrations of dopamine than the nondominant hemisphere). Kindling stimulation (or sham-kindling, in control rats) was applied through the electrodes two or three times daily for 21 days, and the rats were reassessed for amphetamine- and apomorphine-induced rotation, during and after the course of treatment. Kindling of the originally dominant hemisphere caused a diminution of rotational asymmetry as measured in tests 2 to 3 h after stimulation sessions, and in some rats led to a reversal in the preferred direction of amphetamine-induced rotation. Kindling of the nondominant hemisphere tended to accentuate the original amphetamine-induced asymmetry. The direction of rotation induced by a direct postsynaptic DA-receptor agonist (apomorphine) was not significantly affected by kindling of either hemisphere. It appears that kindling stimulation brings about a relatively inferior level of DA function on the stimulated vs. the nonstimulated side of the brain, and that this process depends mainly on changes occurring at a presynaptic level.


Early post-mortem AMP-activated protein kinase (AMPK) activation leads to phosphofructokinase-2 and -1 (PFK-2 and PFK-1) phosphorylation and the development of pale, soft, and exudative (PSE) conditions in porcine longissimus muscle.
Pale, soft, and exudative (PSE) meat has been recognized for decades. Fast glycolysis during early post-mortem stage while the muscle temperature is still high is the cause of PSE meat. To elucidate the molecular mechanism underlying this fast glycolysis in muscle to become PSE meat, post-mortem ATP metabolism, fructose-2,6-diphosphate content, and the activities of AMPK, glycogen phosphorylase, and pyruvate kinase were examined in post-mortem muscle. Earlier and faster post-mortem AMPK activation was responsible for the significantly lower pH and higher lactic acid accumulation (p<0.05) seen in PSE muscle, which resulted in the occurrence of PSE meat. In muscle that became PSE meat, AMPK was activated at 0 h post-mortem and reached maximal activation at 0.5 h post-mortem, whereas AMPK reached maximal activation at 1 h post-mortem in the normal pork loin. Higher fructose-2,6-diphosphate content (p<0.05) was detected in PSE muscle compared to normal muscle at early post-mortem stage. However, no difference in the activities of glycogen phosphorylase and pyruvate kinase, rate-controlling enzymes in glycogenolysis and glycolysis, respectively, was detected between PSE and normal pork loins. Because fructose-2,6-diphosphate is a product of phosphofructokinase-2 (PFK-2), these data suggest that AMPK regulates post-mortem glycolysis through its phosphorylation and activation of PFK-2, which then up-regulates the activity of phosphofructokinase-1 (PFK-1), a key rate-controlling enzyme in glycolysis. Early AMPK activation in PSE muscle is associated with early consumption of ATP, because higher AMP and IMP contents and lower ATP content were detected in PSE meat compared to normal meat. Other mechanisms causing early AMPK activation in PSE meat may exist, which warrants further investigation.


A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility.
To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, P = 2.55 × 10-191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.See related commentary by Lachance, p. 1637.


The roles of prostate-specific antigen (PSA) density, prostate volume, and their zone-adjusted derivatives in predicting prostate cancer in patients with PSA less than 20.0 ng/mL.
The aim of this study was to develop nomograms for predicting prostate cancer and its zonal location using prostate-specific antigen density, prostate volume, and their zone-adjusted derivatives. A total of 928 consecutive patients with prostate-specific antigen (PSA) less than 20.0 ng/mL, who underwent transrectal ultrasound-guided transperineal 12-core prostate biopsy at West China Hospital between 2011 and 2014, were retrospectively enrolled. The patients were randomly split into training cohort (70%, n = 650) and validation cohort (30%, n = 278). Predicting models and the associated nomograms were built using the training cohort, while the validations of the models were conducted using the validation cohort. Univariate and multivariate logistic regression was performed. Then, new nomograms were generated based on multivariate regression coefficients. The discrimination power and calibration of these nomograms were validated using the area under the ROC curve (AUC) and the calibration curve. The potential clinical effects of these models were also tested using decision curve analysis. In total, 285 (30.7%) patients were diagnosed with prostate cancer. Among them, 131 (14.1%) and 269 (29.0%) had transition zone prostate cancer and peripheral zone prostate cancer. Each of zone-adjusted derivatives-based nomogram had an AUC more than 0.75. All nomograms had higher calibration and much better net benefit than the scenarios in predicting patients with or without different zones prostate cancer. Prostate-specific antigen density, prostate volume, and their zone-adjusted derivatives have important roles in detecting prostate cancer and its zonal location for patients with PSA 2.5-20.0 ng/mL. To the best of our knowledge, this is the first nomogram using these parameters to predict outcomes of 12-core prostate biopsy. These instruments can help clinicians to increase the accuracy of prostate cancer screening and to avoid unnecessary prostate biopsy.


Alternative medicine complements standard. Various forms focus on holistic concepts.
Western or conventional medical practices are founded on the principle of Newtonian physics; the body is viewed as a large clock whose broken parts are fixed or replaced. The placebo effect, hypnosis, psychoneuroimmunology, and spontaneous remission have recently inspired researchers to look beyond this mechanistic model toward a new paradigm of greater understanding regarding the entity we call "human beings." The premise of alternative medicine, based on the paradigm of whole systems, suggests that human beings are more than physical bodies with fixable and replaceable parts; they are a complicated network of pulsating energy frequencies often described in terms of a human aura. Western researchers now call this "the human energy field." Homeopathy, acupuncture, polarity healing, and the healing power of touch are only a few of the more common branches of holistic medicine that unite body, mind, and spirit for optimal health. The U.S. Congress has appropriated more than $2 million to the National Institutes of Health to research the validity of alternative or complementary medicines. In light of proposed changes in the healthcare system, alternative medicine may eventually be incorporated into the American structure of healthcare delivery. Proponents of holistic medicine agree that various forms of alternative medicine should be used to complement, rather than compete, with, the current accepted standard of healthcare.


Curcumol inhibits breast cancer growth via NCL/ERα36 and the PI3K/AKT pathway.
Background: Breast cancer (BC) is the most common malignancy worldwide. ERα36 (ERα66 variant) is expressed in many breast cancer cells, especially highly expressed in tamoxifen (TAM)-resistant cell lines and triple-negative breast cancer, and our previous work revealed that nucleolin (NCL) is a protein target of curcumol. This study is aimed at investigating the effect and mechanism of curcumol on ERα36 positive breast cancer cells, and the relationship between curcumol's target protein NCL and ERα36. Study design: Application of in vivo and in vitro studies to reveal the mechanism of curcumol in inhibiting BC growth and the relationship between curcumol's target protein NCL and ERα36. Methods: The anti-tumor effect of curcumol was quantified via an MTT assay, colony formation and cycle arrest, respectively. The expressions of ERα36, NCL and the proteins involved in PI3K/AKT signaling were evaluated by western blotting. The interaction between two proteins was detected using co-immunoprecipitation (Co-IP) and an immunofluorescence assay. A mouse xenograft model was established to verify the role of ERα36 in breast cancer cells and curcumol's effect on ERα36 positive cancer cells. Results: Curcumol inhibited the cell growth, caused cell cycle arrest, decreased cell cycle related proteins and inactivated the PI3K/AKT pathway in ERα36 positive breast cancer cells. There is a positive correlation between NCL and ERα36 in breast cancer cells. In addition, ERα36 bound to NCL; the two proteins were distributed in the nucleus, cytoplasm and plasma membrane, where their expression was obviously decreased by curcumol. Moreover, NCL silenced by NCL siRNA blocked the cell cycle progress and inhibited the activation of PI3K/AKT in MDA-MB-231 cells, while overexpressed ERα36 increased the expression of NCL, promoted the cell cycle progress and enhanced the activity of PI3K/AKT in MCF-7 cells. NCL knockdown or ERα36 overexpression attenuated the effect of curcumol on breast cancer cells. Conclusion: Curcumol reduced the proliferation of breast cancer cells by targeting NCL/ERα36 and inactivating the PI3K/AKT pathway.


Magnetic Hysteresis in Nanocomposite Films Consisting of a Ferromagnetic AuCo Alloy and Ultrafine Co Particles.
One fundamental requirement in the search for novel magnetic materials is the possibility of predicting and controlling their magnetic anisotropy and hence the overall hysteretic behavior. We have studied the magnetism of Au:Co films (~30 nm thick) with concentration ratios of 2:1, 1:1, and 1:2, grown by magnetron sputtering co-deposition on natively oxidized Si substrates. They consist of a AuCo ferromagnetic alloy in which segregated ultrafine Co particles are dispersed (the fractions of Co in the AuCo alloy and of segregated Co increase with decreasing the Au:Co ratio). We have observed an unexpected hysteretic behavior characterized by in-plane anisotropy and crossed branches in the loops measured along the hard magnetization direction. To elucidate this phenomenon, micromagnetic calculations have been performed for a simplified system composed of two exchange-coupled phases: a AuCo matrix surrounding a Co cluster, which represents an aggregate of particles. The hysteretic features are qualitatively well reproduced provided that the two phases have almost orthogonal anisotropy axes. This requirement can be plausibly fulfilled assuming a dominant magnetoelastic character of the anisotropy in both phases. The achieved conclusions expand the fundamental knowledge on nanocomposite magnetic materials, offering general guidelines for tuning the hysteretic properties of future engineered systems.


Police reporting practices for sexual assault cases in which "the victim does not wish to pursue charges".
Prior research examining sexual assault case attrition has focused on the processing of cases across the justice system. Studies have examined arrest decision making and prosecutorial decision making in an attempt to better understand where and when cases drop out of the system. Less explored are police reporting practices during the initial stage of processing for cases in which the officer stated that the victim chose to drop her case. We addressed this gap in the literature by reviewing law enforcement incident reports at their onset, specifically; we examine reports of cases in which the officer reported the victim chose to drop the case. Results indicated that of the 125 cases of sexual assault reported to the police, 41 reports (32.8%) stated that the victim decided to no longer pursue charges. However, few police reports (30.2%) provided a clear rationale for why the victim decided to no longer pursue charges. Results of this study call for more standardized police reporting practices and point to the need for future research into the initial stage of law enforcement involvement in adult sexual assault cases.


Alginate Hydrogel Modified with a Ligand Interacting with α3β1 Integrin Receptor Promotes the Differentiation of 3D Neural Spheroids toward Oligodendrocytes in Vitro.
In this study, we established a long-term three-dimensional (3D) culture system by using integrin ligand modified alginate hydrogels to encapsulate and differentiate neural progenitor cells (NPCs) toward oligodendrocyte (OL) lineage cells. The porosity of the hydrogel was optimized by varying the alginate concentrations and then characterized by scanning electronic microscopy (SEM). The surface plasmon resonance (SPR) test was used to confirm the ligand-integrin interactions indicating adherence between the NPC surfaces and the hydrogels. Following encapsulation in the hydrogels, both mouse and human NPC sphere cultures could be maintained up to 90 days. Mouse NPC spheres were differentiated into viable neurons, astrocytes and mature OLs by day 60 in all groups whereas human NPC spheres were differentiated into neurons and later into GFAP positive astrocytes and O4 positive pre-OL within 90 days. The species difference in the timeline of OL development between mouse and human was reflected in this system. The ligand LXY30 interacting with the α3β1 integrin receptor was more effective in promoting the differentiation of hNPCs to OL lineage cells compared with the ligand LXW64 interacting with the αvβ3 integrin receptor, hyaluronic acid interacting with CD44 receptor or without any ligand. This study is the first to differentiate O4+ pre-OLs from hNPCs in a LXY30-α3β1 (integrin-ligand) modified alginate 3D hydrogel culture. This 3D platform could serve as a valuable tool in disease modeling, drug discovery, and NPC transplantation.


Identification of a Flavin Monooxygenase-Like Flavonoid 8-Hydroxylase with Gossypetin Synthase Activity from Lotus japonicus.
Lotus japonicus is a model legume that accumulates 8-hydroxyflavonol derivatives, such as gossypetin (8-hydroxyquercetin) 3-O-glycoside, which confer the yellow color to its petals. An enzyme, flavonoid 8-hydroxylase (F8H; LjF8H), is assumed to be involved in the biosynthesis, but the specific gene is yet to be identified. The LjF8H cDNA was isolated as a flavin adenine dinucleotide (FAD)-binding monooxygenase-like protein using flower buds and flower-specific EST data of L. japonicus. LjF8H is a single copy gene on chromosome III consisting of six exons. The conserved FAD- and NAD(P)H-dependent oxidase motifs were found in LjF8H. Phylogenetic analysis suggested that LjF8H is a member of the flavin monooxygenase group but distinctly different from other known flavonoid oxygenases. Analysis of recombinant yeast microsome expressing LjF8H revealed that the enzyme catalyzed the 8-hydroxylation of quercetin. Other flavonoids, such as naringenin, eriodictyol, apigenin, luteolin, taxifolin and kaempferol, also acted as substrates of LjF8H. This broad substrate acceptance was unlike known F8Hs in other plants. Interestingly, flavanone and flavanonol, which have saturated C-C bond at positions 2 and 3 of the flavonoid C-ring, produced 6-hyroxylflavonoids as a by-product of the enzymatic reaction. Furthermore, LjF8H only accepted the 2S-isomer of naringenin, suggesting that the conformational state of the substrates might affect product specificity. The overexpression of LjF8H in Arabidopsis thaliana and Petunia hybrida synthesized gossypetin and 8-hydroxykaempferol, respectively, indicating that LjF8H was functional in plant cells. In conclusion, this study represents the first instance of cloning and identification of F8Hs responsible for gossypetin biosynthesis.