The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity.
Allergic airway inflammation is associated with activation of innate immune pathways by allergens. Acute exacerbations of asthma are commonly associated with rhinovirus infection. Here we show that, after exposure to house dust mite (HDM) or rhinovirus infection, the E3 ubiquitin ligase midline 1 (MID1) is upregulated in mouse bronchial epithelium. HDM regulates MID1 expression in a Toll-like receptor 4 (TLR4)- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. MID1 decreases protein phosphatase 2A (PP2A) activity through association with its catalytic subunit PP2Ac. siRNA-mediated knockdown of MID1 or pharmacological activation of PP2A using a nonphosphorylatable FTY720 analog in mice exposed to HDM reduces airway hyperreactivity and inflammation, including the expression of interleukin-25 (IL-25), IL-33 and CCL20, IL-5 and IL-13 release, nuclear factor (NF)κB activity, p38 mitogen-activated protein kinase (MAPK) phosphorylation, accumulation of eosinophils, T lymphocytes and myeloid dendritic cells, and the number of mucus-producing cells. MID1 inhibition also limited rhinovirus-induced exacerbation of allergic airway disease. We found that MID1 was upregulated in primary human bronchial epithelial cells upon HDM or rhinovirus exposure, and this correlated with TRAIL and CCL20 expression. Together, these findings identify a key role of MID1 in allergic airway inflammation and links innate immune pathway activation to the development and exacerbation of asthma.


Twenty-Year Follow-Up of Cataract Surgery in Car-Drivers: Associations Between Subjective Visual Difficulties and Objective Visual Function.
Driving especially at night is a visually demanding task. Long-time outcome of cataract surgery in drivers is important to study, as many patients live for decades after surgery. The purpose of this study is to longitudinally investigate visual function in active car drivers, 20 years after cataract surgery. From a population-based, prospective, cohort of cataract surgery patients, initiated in 1997-98, 114 of the 133 surviving patients were included. Preoperatively, postoperatively 5, 10, 15 and 20 years after surgery, the patients answered a visual function questionnaire including driving status and difficulty. Habitual visual acuity, best corrected visual acuity (BCVA), and low contrast acuity (LCVA) 10% and 2.5% were measured. The driving difficulties in daylight were almost absent after surgery and did not change over 20 years. Nighttime driving was more difficult and declined longitudinally after surgery, p=0.013, but were at 20 years still less than before cataract surgery. Patients with better BCVA experienced less difficulties driving in darkness, p=0.005. Self-reported problems with glare were significantly associated with BCVA of the better-seeing eye, LCVA 10% and LCVA 2.5% (p=0.046, p=0.033, and 0.024 respectively). Self-reported difficulties with seeing in low-contrast conditions were also significantly associated with BCVA, p=0.004. Twenty years after cataract surgery, most active drivers have no or minor visual functional problems during driving in daytime. Difficulties in nighttime driving are more common and increase significantly over time. Twenty years after surgery, all current drivers had still better subjective ability to drive, compared with before surgery.


CARM1 deficiency inhibits osteoblastic differentiation of bone marrow mesenchymal stem cells and delays osteogenesis in mice.
Bone repair remains a clinical challenge due to low osteogenic capacity. Coactivator associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that mediates arginine methylation and endochondral ossification. However, the roles of CARM1 in osteoblastic differentiation and bone remodeling have not been explored. In our study, heterozygous CARM1-knockout (KO) mice were generated using the CRISPR-Cas9 system and a model of femoral defect was created. At day 7 postsurgery, CARM1-KO mice exhibited obvious bone loss compared with wild type (WT) mice, as evidenced by reduced bone mineral density (BMD), bone volume/total volume (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). Deletion of CARM1 in mice lowered synthesis and accumulation of collagen at the injury sites. The alkaline phosphatase (ALP) activity and osteogenic-related gene expression were declined in CARM1-KO mice. To further understand the role of CARM1 in osteoblastic differentiation, bone marrow mesenchymal stem cells (BMSCs) were isolated from the tibia and femur of WT or CARM1-KO mice. CARM1 deletion decreased histone arginine methylation and inhibited osteoblastic differentiation and mineralization. The mRNA sequencing of CARM1-KO BMSCs revealed the possible regulatory molecules by CARM1, which could deepen our understanding of CARM1 regulatory mechanisms. These data could be of interest to basic researchers and provide the direction for future research into bone-related disorders.


Preparation and characteristics of high performance paper containing titanium dioxide photocatalyst supported on inorganic fiber matrix.
A novel paper-based material containing titanium dioxide (TiO(2)) photocatalyst was successfully prepared by a papermaking technique with the internal addition of inorganic fibers on which TiO(2) particles were supported. Photodegradation performance of acetaldehyde gas, an indoor pollutant, and the durability of the TiO(2)-containing papers were investigated under UV irradiation. Ceramic fiber suspension and polydiallyldimethylammonium chloride as a cationic flocculant were mixed, followed by the addition of TiO(2) suspension and anionic polyacrylamide. Subsequently, the inorganic mixture was poured into a pulp suspension, and TiO(2) handsheets then prepared by a papermaking method. The tensile strength of TiO(2)-containing paper without a ceramic carrier decreased by more than 30% after 240-h UV irradiation (2 mW/cm(2)), although the strength of the TiO(2) sheet with ceramic fibers remained reasonably stable. The efficiency of acetaldehyde decomposition by the TiO(2) paper containing an inorganic carrier was nearly equal to that of the carrier-free TiO(2) paper. Scanning electron microscopic observation suggested that most TiO(2) particles were predominantly supported on the inorganic fiber matrix, and were mostly out of contact with organic pulp fibers. The TiO(2) paper with an inorganic carrier demonstrated both excellent photocatalytic performance and durability, which before had been mutually incompatible for organic materials containing TiO(2) photocatalyst. The two-stage mixing procedure for TiO(2) sheet-making is promising for the simple manufacture of high performance paper with photocatalytic ability.


[Centrosomatic tuberculous vertebral osteitis. General review apropos of 4 cases].
Defined by the localisation of tuberculous infection in the vertebral body, centrosomatic tuberculous vertebral osteitis, which is rarer than Pott's spondylodiscitis, is more frequently seen in the cases of multifocal tuberculosis occurring preferentially in male black African immigrants approximately 30 years of age. Central area destruction, which has been the initial and pathognomonic radiological sign since its description by Calve and Galland , may progress towards wedging of the vertebral body, and even to its complete disappearance, accompanied by reactive osteocondensation . Infection from this particular localisation of vertebral tuberculosis may spread via arterial branches posterior to the vertebral bodies.


Distribution and elimination of hexachlorocyclopentadiene in rats and mice.
14C-Hexachlorocyclopentadiene (HEX, C56 ) was administered to adult rats and mice as a single oral dose (2.5 and 25 mg/kg) and as a component of the diet (1, 5 and 25 ppm) for a maximum of 30 days. The primary route of excretion was via the feces (-70% of dose) with low elimination in the urine (approximately 15%). Biliary excretion of only 16% with 66% still voided in the feces of bile duct cannulated rats suggested that the majority of orally consumed HEX was not absorbed. However, extensive degradation apparently occurred in the gut since little of the fecal material was of an apolar nature. The kidney, liver, ovaries and fat were the major sites of deposition of 14C-HEX equivalents. In rats, the kidney contained the highest levels of residues, whereas in mice the residues in the liver exceeded those in the kidney. Other than this difference, the fate of HEX in rats and mice, both male and female, was quite similar and in each case the tissue residues reached a plateau after about two weeks on the HEX-containing diets.


Phenotypic engineering of sperm-production rate confirms evolutionary predictions of sperm competition theory.
Sperm production is a key male reproductive trait and an important parameter in sperm competition theory. Under sperm competition, paternity success is predicted to depend strongly on male allocation to sperm production. Furthermore, because sperm production is inherently costly, individuals should economize in sperm expenditure, and conditional adjustment of the copulation frequency according to their sperm availability may be expected. However, experimental studies showing effects of sperm production on mating behaviour and paternity success have so far been scarce, mainly because sperm production is difficult to manipulate directly in animals. Here, we used phenotypic engineering to manipulate sperm-production rate, by employing dose-dependent RNA interference (RNAi) of a spermatogenesis-specific gene, macbol1, in the free-living flatworm Macrostomum lignano. We demonstrate (i) that our novel dose-dependent RNAi approach allows us to induce high variability in sperm-production rate; (ii) that a reduced sperm-production rate is associated with a decreased copulation frequency, suggesting conditional adjustment of mating behaviour; and (iii) that both sperm production and copulation frequency are important determinants of paternity success in a competitive situation, as predicted by sperm competition theory. Our study clearly documents the potential of phenotypic engineering via dose-dependent RNAi to test quantitative predictions of evolutionary theory.


Human epithelial thymic tumours: heterogeneity in immunostaining of epithelial cell markers and thymic hormones.
Different hormones (thymulin, thymosin alpha 1, vasopressin), antigenic markers of cortical and subcapsular/medullary thymic areas and tumour associated antigens were studied on paraffin or frozen section and cultures of human epithelial thymic tumours ('thymomas'). Thymulin, thymosin alpha 1 and for the first time vasopressin are found in most tumours. The epithelial cells of five 'thymomas' had markers of both cortical (TE3) and subcapsular/medullary thymic regions (A2B5 and/or TE4 and/or anti-p19). Leu-7, a marker of subcapsular epithelial cells was positive only in two tumours. The histological classification into cortical and medullary tumours does not correspond to our immunofluorescence results. The presence of these markers does not support the theory of different embryologic origin of the cortical and subcapsular/medullary epithelial cells. Transferrin receptors were detected on only some epithelial cells of thymic 'carcinomas'. Adenocarcinoma related antigen and carcino embryonic antigen only stained a few epithelial cells of all the tumours. There is no expected correlation between the presence of epidermal growth factor receptors on cell membranes and the number of proliferative cells stained by the anti-Ki67 antibodies. Immunostainings were heterogeneous according to the epithelial thymic tumours, independent of histological classification and not yet useful for prognosis.


Immunomagnetic colloids for the enrichment of tumor cells from peripheral blood and bone marrow: a model system.
The characterization of tumor cells in bone marrow harvested for autologous bone marrow rescue remains a problem due to the limited sensitivities of the techniques available for their analysis. This complicates the use of purging techniques as their usefulness is debated, specifically because it is not known if they can remove all residual tumor cells from either peripheral blood stem cell harvests or bone marrow. Apart from developing more sensitive techniques for tumor detection, one way of increasing our efficiency at identifying rare malignant cells in normal hematopoietic cells is to develop approaches to enrich the population of interest prior to analysis. Here, we describe a laboratory-based system for tumour enrichment employing panels of monoclonal antibodies (MAbs) and an immunomagnetic colloid. In model systems, tumor cells could be enriched approximately 100-fold with high yield and purity. The adaptations of this technology to permit further cell enrichment and the choice of either an immunological technique or a molecular approach to tumor identification are discussed in detail.


Genomic landscape of platinum resistant and sensitive testicular cancers.
While most testicular germ cell tumours (TGCTs) exhibit exquisite sensitivity to platinum chemotherapy, ~10% are platinum resistant. To gain insight into the underlying mechanisms, we undertake whole exome sequencing and copy number analysis in 40 tumours from 26 cases with platinum-resistant TGCT, and combine this with published genomic data on an additional 624 TGCTs. We integrate analyses for driver mutations, mutational burden, global, arm-level and focal copy number (CN) events, and SNV and CN signatures. Albeit preliminary and observational in nature, these analyses provide support for a possible mechanistic link between early driver mutations in RAS and KIT and the widespread copy number events by which TGCT is characterised.


Regulation of hormone-stimulated cyclic AMP accumulation in intact human mononuclear leukocytes by blood plasma.
Several hormones, including catecholamines, histamine, and prostaglandin E1, regulate the function of human mononuclear leukocytes (MNL) by stimulating the accumulation of cAMP. Isoproterenol-stimulated cAMP accumulation in MNL isolated and washed at 4 degrees is five times greater than in cells prepared at ambient temperature. The current study was aimed at understanding this difference. cAMP accumulation in MNL prepared at ambient temperature could not be increased by chilling the cells for 4 hours. Warming MNL prepared at 4 degrees for 30 min, however, reduced later isoproterenol-, histamine-, and PGE1-stimulated cAMP accumulation by 65-85% without altering forskolin-stimulated cAMP accumulation and without altering cellular viability or ATP content. In broken cell preparations, there was no difference in either adenylate cyclase or phosphodiesterase activities, and no difference in the binding of isoproterenol to the beta-adrenergic receptors. The reduction in isoproterenol-stimulated cAMP accumulation in warmed intact cells was reversed when the MNL were incubated with autologous leukocyte-depleted blood or with plasma. These data suggest the presence of one or more factors in plasma that enhances hormone-stimulated adenylate cyclase activity in intact MNL.


Investigation of the structure and function of a Shewanella oneidensis arsenical-resistance family transporter.
The toxic metalloid arsenic is an abundant element and most organisms possess transport systems involved in its detoxification. One such family of arsenite transporters, the ACR3 family, is widespread in fungi and bacteria. To gain a better understanding of the molecular mechanism of arsenic transport, we report here the expression and characterization of a family member, So_ACR3, from the bacterium Shewanella oneidensis MR-1. Surprisingly, expression of this transporter in the arsenic-hypersensitive Escherichia coli strain AW3110 conferred resistance to arsenate, but not to arsenite. Purification of a C-terminally His-tagged form of the protein allowed the binding of putative permeants to be directly tested: arsenate but not arsenite quenched its intrinsic fluorescence in a concentration-dependent fashion. Fourier transform infrared spectroscopy showed that the purified protein was predominantly alpha-helical. A mutant bearing a single cysteine residue at position 3 retained the ability to confer arsenate resistance, and was accessible to membrane impermeant thiol reagents in intact cells. In conjunction with successful C-terminal tagging with oligohistidine, this finding is consistent with the experimentally-determined topology of the homologous human apical sodium-dependent bile acid transporter, namely 7 transmembrane helices and a periplasmic N-terminus, although the presence of additional transmembrane segments cannot be excluded. Mutation to alanine of the conserved residue proline 190, in the fourth putative transmembrane region, abrogated the ability of the transporter to confer arsenic resistance, but did not prevent arsenate binding. An apparently increased thermal stability is consistent with the mutant being unable to undergo the conformational transitions required for permeant translocation.


Analysis and comparison of wrist splint designs using the finite element method: Multi-material three-dimensional printing compared to typical existing practice with thermoplastics.
Rheumatoid arthritis is a chronic disease affecting the joints. Treatment can include immobilisation of the affected joint with a custom-fitting splint, which is typically fabricated by hand from low temperature thermoplastic, but the approach poses several limitations. This study focused on the evaluation, by finite element analysis, of additive manufacturing techniques for wrist splints in order to improve upon the typical splinting approach. An additive manufactured/3D printed splint, specifically designed to be built using Objet Connex multi-material technology and a virtual model of a typical splint, digitised from a real patient-specific splint using three-dimensional scanning, were modelled in computer-aided design software. Forty finite element analysis simulations were performed in flexion-extension and radial-ulnar wrist movements to compare the displacements and the stresses. Simulations have shown that for low severity loads, the additive manufacturing splint has 25%, 76% and 27% less displacement in the main loading direction than the typical splint in flexion, extension and radial, respectively, while ulnar values were 75% lower in the traditional splint. For higher severity loads, the flexion and extension movements resulted in deflections that were 24% and 60%, respectively, lower in the additive manufacturing splint. However, for higher severity loading, the radial defection values were very similar in both splints and ulnar movement deflection was higher in the additive manufacturing splint. A physical prototype of the additive manufacturing splint was also manufactured and was tested under normal conditions to validate the finite element analysis data. Results from static tests showed maximum displacements of 3.46, 0.97, 3.53 and 2.51 mm flexion, extension, radial and ulnar directions, respectively. According to these results, the present research argues that from a technical point of view, the additive manufacturing splint design stands at the same or even better level of performance in displacements and stress values in comparison to the typical low temperature thermoplastic approach and is therefore a feasible approach to splint design and manufacture.


The role of size polydispersity in magnetic fluid hyperthermia: average vs. local infra/over-heating effects.
An efficient and safe hyperthermia cancer treatment requires the accurate control of the heating performance of magnetic nanoparticles, which is directly related to their size. However, in any particle system the existence of some size polydispersity is experimentally unavoidable, which results in a different local heating output and consequently a different hyperthermia performance depending on the size of each particle. With the aim to shed some light on this significant issue, we have used a Monte Carlo technique to study the role of size polydispersity in heat dissipation at both the local (single particle) and global (macroscopic average) levels. We have systematically varied size polydispersity, temperature and interparticle dipolar interaction conditions, and evaluated local heating as a function of these parameters. Our results provide a simple guide on how to choose, for a given polydispersity degree, the more adequate average particle size so that the local variation in the released heat is kept within some limits that correspond to safety boundaries for the average-system hyperthermia performance. All together we believe that our results may help in the design of more effective magnetic hyperthermia applications.


Diagnosis and management of idiopathic pulmonary fibrosis: Thoracic Society of Australia and New Zealand and Lung Foundation Australia position statements summary.
Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with debilitating symptoms of dyspnoea and cough, resulting in respiratory failure, impaired quality of life and ultimately death. Diagnosing IPF can be challenging, as it often shares many features with other interstitial lung diseases. In this article, we summarise recent joint position statements on the diagnosis and management of IPF from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia, specifically tailored for physicians across Australia and New Zealand. Main suggestions: A comprehensive multidisciplinary team meeting is suggested to establish a prompt and precise IPF diagnosis. Antifibrotic therapies should be considered to slow disease progression. However, enthusiasm should be tempered by the lack of evidence in many IPF subgroups, particularly the broader disease severity spectrum. Non-pharmacological interventions including pulmonary rehabilitation, supplemental oxygen, appropriate treatment of comorbidities and disease-related symptoms remain crucial to optimal management. Despite recent advances, IPF remains a fatal disease and suitable patients should be referred for lung transplantation assessment.


The Jaipur limb and foot.
In the 12 years which have elapsed since the United Nations declared 1981 to be the Year of the Disabled, the number of amputees world-wide has risen alarmingly, continuing the pattern of the past 40 years, which have seen innumerable conflicts, large and small, with ever-increasing and indiscriminate use of 'improved' antipersonnel mines which have been sown in enormous numbers in rural areas. Even after fighting has ceased--as in Vietnam, which currently has some 200,000 amputees--fresh injuries are caused daily, often to children, by the long-delayed detonation of these weapons. Much of the research and development in prosthetics since World War II has concentrated on producing artificial limbs suitable for an affluent and industrialized society. These, being made from the most modern materials and incorporating the latest technology, are of necessity expensive even for affluent Americans or Europeans and quite out of reach for the 80 per cent of the world's amputees who live in the developing world and for the vast majority of whom these splendid prostheses may be entirely inappropriate. This article describes a foot and leg specifically designed to fit in with the customs and practices of just such people.


Multi-Omics Analyses Revealed GOLT1B as a Potential Prognostic Gene in Breast Cancer Probably Regulating the Immune Microenvironment.
As recently reported by The International Agency for Research on Cancer (IARC), breast cancer has the highest incidence of all cancers in 2020. Many studies have revealed that golgi apparatus is closely associated with the development of breast cancer. However, the role of golgi apparatus in immune microenvironment is still not clear. In this study, using RNA-Seq datasets of breast cancer patients from the public database (n = 1080), we revealed that GOLT1B, encoding a golgi vesicle transporter protein, was significantly higher expressed in human breast cancer tissues versus normal tissues. Besides, we verified GOLT1B expression in five breast cancer cell line using our original data and found GOLT1B was significantly up-regulated in MDA-MB-231, MCF-7, SKBR3. Subsequently, we identified GOLT1B as a potential independent prognostic factor for breast cancer. After a multi-omics analysis, we uncovered that the higher expression of GOLT1B in breast cancer tissues versus normal tissues might be due to the amplification of GOLT1B and altered phosphorylation of its potential transcriptional factors, including JUN and SIN3A. Subsequently, we discovered that GOLT1B potentially regulated the immune microenvironment basing on the finding that its expression was closely related to the tumor microenvironment score and infiltration of immune cells. Moreover, we revealed that GOLT1B might affect the overall survival rates of breast cancer through regulating the immune cell infiltration. Finally, we disclosed the potential pathways involved in the functions of GOLT1B in breast cancer, including metabolism and ECM-receptor interaction pathways. To sum up, we identified GOLT1B as a potential prognostic gene for breast cancer and disclosed its role in regulating the immune microenvironment.


Crossover from Fermi liquid to multichannel Luttinger liquid in high-mobility quantum wires.
We investigate the electrical conductance of long, high-mobility quantum wires formed by the split-gate technique, which allows for adjustment of the wire width and the number of one-dimensional electron subbands, n. In wires with 3<or=n<or=8, a logarithmic temperature dependence of the conductance is observed for 1<T<10 K, which reaches as much as 30% of the Drude conductance. In even narrower wires, the logarithmic dependence changes to a power-law variation. Our observations are shown to be in good agreement with recent theoretical studies, which attribute the logarithmic term to interaction effects in a weakly disordered quasi-one-dimensional conductor. This interaction correction is associated with the emergence of a crossover from a quasi-one-dimensional weakly disordered Fermi liquid to a multichannel Luttinger liquid.


Reassessment of effects on lignification and vascular development in the irx4 Arabidopsis mutant.
The Arabidopsis thaliana irregular xylem4 (irx4) cinnamoyl-CoA reductase 1 (CCR1) mutant was reassessed for its purported exclusive rate-limiting or key effects on lignification. Analyses of gross growth characteristics and stem cross-section anatomy, from seedling emergence to senescence, revealed that stunted irx4 mutant lines were developmentally delayed, which in turn indirectly but predictably led to modest reductions (ca. 10-15%) in overall lignin amounts. Such developmental changes are not generally observed in suppression of other monolignol pathway forming enzymes (e.g., 4-coumarate CoA ligase) even when accompanied by significant reductions in lignin amounts. With the greatly arrested development of the irx4 mutant, formation of the lignin-derived syringyl moieties was also predictably delayed (by about 1-2 weeks), although at maturation the final guaiacyl:syringyl ratios were essentially identical to wild-type. No evidence was obtained for so-called abnormal lignin precursors being incorporated into the lignin, as shown by solid-state 13C NMR spectroscopic analysis in contrast to a claim to the contrary [Jones, L., Ennos, A.R., Turner, S.R., 2001. Cloning and characterization of irregular xylem4 (irx4): a severely lignin-deficient mutant of Arabidopsis. Plant J. 26, 205-216]. A previous claim of an "abnormal" lignin present in stunted CCR downregulated tobacco was also not substantiated, with only trace differences being noted in the presumed cell-wall constituent levels. More importantly, a linear correlation between total lignin amounts and lignin-derived fragmentation products was observed at all stages of Arabidopsis growth/development in both wild-type and irx4 mutant lines, regardless of lignin content, i.e., in harmony with an exquisitely controlled and predictable macromolecular assembly process. Recombinant CCR1 displayed fairly broad substrate versatility for all phenylpropanoid CoA substrates, with both feruloyl and 5-hydroxyferuloyl CoA being the best substrates. Taken together, these data indicate that other CCR isoforms are apparently capable of generating monolignol-derived lignified elements in irx4 when CCR1 is impaired, i.e., indicative of a functionally redundant CCR metabolic network operative in Arabidopsis. Other dwarfed phenotypes have also been observed following downregulation/disruption of unrelated metabolic processes but which also involve CoA ester metabolism, i.e., with hydroxymethylglutaryl CoA reductases in Arabidopsis and a bacterial enoyl CoA hydratase/lyase overexpressed in tobacco. Although the reasons for dwarfing in each case are unknown, a common mechanism for the various pleiotropic effects is proposed through perturbation of CoASH pool levels. Finally, this study demonstrates the need for progressive analyses over the lifespan of an organism, rather than at a single time point which cannot reveal the progressive developmental changes occurring.


Structural behaviour of mixed cationic surfactant micelles: a small-angle neutron scattering study.
Self-assembly in mixtures of two single-chain cationic surfactants, with different tail lengths (CTAB and DTAB) as well as of a single-chain (DTAB) and a double-chain (DDAB) cationic surfactant, with identical tail lengths, have been investigated with small-angle neutron scattering (SANS) and rationalised in terms of bending elasticity properties. The growth behaviour of micelles with respect to surfactant composition appears completely different in the two surfactant mixtures. DTAB form small oblate spheroidal micelles in presence of [NaBr]=0.1 M that transform into prolate spheroidal mixed CTAB/DTAB micelles upon adding moderate amounts of CTAB, so as to give a mole fraction y=0.20 in solution. Most unexpectedly, upon further addition of CTAB the mixed CTAB/DTAB micelles grow with an almost equal rate in both length and width directions to form tablets. In contrast to this behaviour, mixed DDAB/DTAB micelles grow virtually exclusively in the length direction, in presence of [NaBr]=0.1 M, to form elongated ellipsoidal (tablet-shaped) and subsequently long wormlike micelles as the fraction of DDAB in the micelles increases. Mixed DDAB/DTAB micelles grow to become as long as 2000Å before an abrupt transition to large bilayer structures occurs. This means that the micelles are much longer at the micelle-to-bilayer transition as compared to the same mixture in absence of added salt. It is found that the point of transition from micelles to bilayers is significantly shifted towards higher fractions of aggregated DTAB as an appreciable amount of salt is added to DDAB/DTAB mixtures, indicating a considerable reduction of the spontaneous curvature with an increasing [NaBr]. By means of deducing the various bending elasticity constants from our experimental results, according to a novel approach by ours, we are able to conclude that the different growth behaviours appear as a consequence of a considerably lower bending rigidity, as well as higher saddle-splay constant, for DDAB/DTAB surfactant mixtures in presence of [NaBr]=0.1 M, as compared to mixtures of CTAB/DTAB in [NaBr]=0.1 M and DDAB/DTAB in absence of added salt.


Survival after hip fracture.
Although it is known that overall mortality is increased after hip fracture, the influence of hip fracture risk factors on the subsequent mortality and cause of death has not been well studied. The objective of this study was to establish the survival after hip fracture in women and to assess the impact of comorbidity on mortality. We identified a complete population-based set of 2,245 incident hip fracture cases and 4,035 randomly selected population-based controls among women 50-81 years old in Sweden and followed these subjects for an average of 5 years through the Swedish National Inpatient and Cause-of-Death Registers. Information on factors related to hip fracture was obtained through linkage to hospital discharge data and through a mailed questionnaire. We studied excess mortality of hip fracture patients compared to controls using survival curves and proportional hazard regression models. During follow-up, 896 hip fracture patients (40%) and 516 (13%) controls died. The relative risk (RR) of death, adjusted for age and previous hospitalization for serious disease, was 2.3 (95% CI 2.0-2.5). Although the highest mortality risks were in the 1st 6 months post-fracture, RRs for fractures versus controls were increased for at least 6 years. Increased mortality was apparent both in those with evidence of comorbidity and those without. Hip fracture patients have a substantially increased risk of death that persists for at least 6 years post-fracture. The relative excess mortality is independent of comorbidity and known hip fracture risk factors.


[The clinical and psychological aspects of the reaction to disease (the problem of nosogenias)].
"Nosogenias" is the term describing some reactive states. They account for 15-90% of all the patients of somatic hospital. They are due to constellation of some psychotraumatic events related to somatic disease. A total of 166 patients were examined, among them 55 patients with ischemic heart disease, 56 cases with hypertension and 56 ones with bronchial asthma. The results evidence for the existence of two independent vectors which characterise "extremal" points of continuum of disease perception. The importance of somatic trouble (hyper- or hyponosognomia) was the basis of the first vector while the degree of completeness of independent and the whole image of disease as something which differed from "self" (ego-dystonic and ego-syntonic perception of disease) was the basis of the second vector. Combination of the above vectors with clinical and psychological characteristics in the whole clinical pattern of disease was recorded.


Presence of an intracompartmental septum detected by ultrasound is associated with the failure of ultrasound-guided steroid injection in de Quervain's syndrome.
The purpose of this study was to find clinical or ultrasound characteristics that might predict the failure of conservative treatment in de Quervain's syndrome. A total of 42 ultrasound-guided injections have been performed in 41 patients after clinical and ultrasound examination. Patients were immobilized for 3 weeks with a spica splint cast, and clinically evaluated at 3 and 6 weeks and by phone call at the end of the study. Ultrasound showed a septum between the tendons of the first comportment in 34% of the wrists. At last follow-up (mean 15.6 months after the injection) ten patients (24%) had undergone surgery. When comparing ultrasound and clinical characteristics of the operated and non-operated wrists, we found that patients with a high baseline visual analogue scale, with all positive clinical tests and with a persistent intracompartmental septum, had a significantly higher risk of failure following conservative treatment. III.


Is surface roughness of direct resin composite restorations material and polisher-dependent? A systematic review.
Direct resin composite bonding offers a highly esthetic, minimally invasive option for the treatment of anterior teeth however the challenge to improve their longevity remains. Direct resin composite restorations are limited by the risk of staining which may be influenced by the final surface roughness (Ra) of composite achieved. The purpose of this review is to investigate, using a systematic approach, whether the final surface roughness of anterior composite restorations is affected by the interaction between resin composite and polishing systems. The review was conducted by 3 independent reviewers and included articles published up to January 21, 2021. Three electronic databases were searched: Medline, Embase, and Web of Science. Studies assessing a quantitative effect of polishing methods on the Ra of direct composite resin materials published after the year 2000 and restricted to the English language were included. The database search for the effect of polishing systems on composite materials retrieved 125 eligible studies. Twelve duplicate records were removed. The resulting records were screened using title and abstract leading to 38 reports which were sought for retrieval. Application of eligibility criteria led to 11 studies included in the review. Hand searching of these studies yielded no additional papers. There is insufficient evidence to determine whether combination of composite and polisher influences final Ra. More research is required to determine if there is an optimum combination of polisher and composite. Polishing should be completed following planned finishing procedures. The approximation to the final surface and which finishing burs to use, if any, should be considered when planning a restoration. Durafill VS predictably achieves an acceptable Ra by different polishers.


The Surgical Treatment and Outcome of Nonmetastatic Extremity Osteosarcoma with Pathological Fractures.
Recent studies have suggested that the presence of a pathological fracture does not impact on oncologic outcomes and the feasibility of limb salvage surgery (LSS) in appropriately selected patients when combined with neoadjuvant chemotherapy. These have largely been single institutional studies with limited numbers. The Eastern Asian Musculoskeletal Oncology Group reviewed the data from three large volume Asian orthopedic oncology centers to determine whether the presence of a pathologic fracture affected outcomes in osteosarcoma patients. A retrospective review of the data was conducted. Ninety-five cases of nonmetastatic extremity osteosarcoma with a pathological fracture and 887 cases without fracture treated during the same period were compared. In the fracture group, the LSS rate was 62.1%, and the rate of amputation was 37.9%. In the nonfracture group, the LSS rate was 74.7%, and the amputation was 25.3%. In patients with a pathologic fracture, the rate of local recurrence for LSS and amputation groups was 8.5% and 2.8%, respectively. In this group, the 5-year survival in the LSS group was 66% as against. 46.8% in the amputation group. Our study suggests that surgically treated patients with pathologic fractures in osteosarcoma have adequate local control and do not have a poorer outcome compared to patients without a fracture. Though osteosarcoma with a pathologic fracture is not a contraindication for limb salvage, appropriate case selection is important when deciding local control options to ensure adequate oncologic clearance.


Mitochondrial diversity and phylogeography of Acrossocheilus paradoxus (Teleostei: Cyprinidae).
Mitochondrial DNA cytochrome b sequences (1141 bp) in 229 specimens of Acrossocheilus paradoxus from 26 populations were identified as four lineages. The pairwise genetic distances among these four lineages ranged from 1.57 to 2.37% (mean= 2.00%). Statistical dispersal-vicariance analysis suggests that the ancestral populations were distributed over mainland China and Northern and Western Taiwan. Approximate Bayesian computation approaches show that the three lineages in Taiwan originated from the lineage in mainland China through three colonization routes during two glaciations. The results indicated that during the glaciation and inter-glacial periods, the Taiwan Strait was exposed and sank, which contributed to the dispersion and differentiation of populations. Furthermore, the populations of A. paradoxus colonized Taiwan through a land bridge to the north of the Formosa Bank, and the Miaoli Plateau in Taiwan was an important barrier that limited gene exchange between populations on both the sides.


Word structures of Granada Spanish-speaking preschoolers with typical versus protracted phonological development.
Research on children's word structure development is limited. Yet, phonological intervention aims to accelerate the acquisition of both speech-sounds and word structure, such as word length, stress or shapes in CV sequences. Until normative studies and meta-analyses provide in-depth information on this topic, smaller investigations can provide initial benchmarks for clinical purposes. To provide preliminary reference data for word structure development in a variety of Spanish with highly restricted coda use: Granada Spanish (similar to many Hispano-American varieties). To be clinically applicable, such data would need to show differences by age, developmental typicality and word structure complexity. Thus, older typically developing (TD) children were expected to show higher accuracy than younger children and those with protracted phonological development (PPD). Complex or phonologically marked forms (e.g. multisyllabic words, clusters) were expected to be late developing. Participants were 59 children aged 3-5 years in Granada, Spain: 30 TD children, and 29 with PPD and no additional language impairments. Single words were digitally recorded by a native Spanish speaker using a 103-word list and transcribed by native Spanish speakers, with confirmation by a second transcriber team and acoustic analysis. The program Phon 1.5 provided quantitative data. In accordance with expectations, the TD and older age groups had better-established word structures than the younger children and those with PPD. Complexity was also relevant: more structural mismatches occurred in multisyllabic words, initial unstressed syllables and clusters. Heterosyllabic consonant sequences were more accurate than syllable-initial sequences. The most common structural mismatch pattern overall was consonant deletion, with syllable deletion most common in 3-year-olds and children with PPD. The current study provides preliminary reference data for word structure development in a Spanish variety with restricted coda use, both by age and types of word structures. Between ages 3 and 5 years, global measures (whole word match, word shape match) distinguished children with typical versus protracted phonological development. By age 4, children with typical development showed near-mastery of word structures, whereas 4- and 5-year-olds with PPD continued to show syllable deletion and cluster reduction, especially in multisyllabic words. The results underline the relevance of multisyllabic words and words with clusters in Spanish phonological assessment and the utility of word structure data for identification of protracted phonological development.


Reproductive traits of Glenea cantor (Coleoptera: Cerambycidae: Lamiinae).
Glenea cantor (F.) is a cerambycid species that attacks living trees of at least seven plant families in Asia, and has the potential to become an invasive pest. Here we investigated its reproductive biology in the laboratory to provide vital information for the development of pest control measures and preparation of pest risk analysis. Both sexes required a period of maturation feeding before mating, with the mean premating period of males (5.87 +/- 1.68 d) being significantly longer than that of females (4.59 +/- 2.34 d). This was a synovigenic species with the mean preoviposition and oviposition period being 13.50 +/- 3.15 d and 49.46 +/- 16.16 d, respectively. If no food was available after emergence, adult males died before reaching sexual maturation and females vanished before oviposition. Paired couples mated an average of 15.12 +/- 7.02 times; 28- to 53-d-old beetles mated significantly more frequently than younger and older ones. The mean fecundity was 133.24 +/- 9.67 eggs. The oviposition rate significantly increased in the first 5 wk of the oviposition period, peaking when females were 40- to 54-d-old, and then significantly decreased in the following weeks. Reproductive activities occurred almost exclusively during the day, with most ovipositions taking place in the morning and matings in the afternoon with some overlaps.


Cochlear and brainstem audiologic findings in normal hearing tinnitus subjects in comparison with non-tinnitus control group.
While most tinnitus cases have some degree of hearing impairment, a small percent of the patients admitted to Ear, Nose and Throat Clinics or Hearing Evaluation Centers are those who complain of tinnitus despite having normal hearing thresholds. Present study was performed in order to better understanding of the probable causes of tinnitus and to investigate possible changes in the cochlear and auditory brainstem function in normal hearing patients with chronic tinnitus. Altogether, 63 ears (31 ears with tinnitus and 32 ears without tinnitus) were examined. The prevalence of transient evoked otoacoustic emissions and characteristics of the auditory brainstem response components including wave latencies and wave amplitudes was determined in the two groups and analyzed with appropriate statistical methods. There was no difference between the prevalence of transient evoked emissions in the two groups. The mean difference between absolute latencies of waves I, III and V was less than 0.1 ms between the two groups that were not statistically significant. Also, the interpeak latency values of I-III, III-V and I-V in both groups had no significant difference. Only the V/I amplitude ratio in the tinnitus group was significantly larger than the other group (p =0.04). The changes observed in amplitude of waves, especially in the later ones, can be considered as an Audiologic finding in normal hearing tinnitus subjects and its possible role in generation of tinnitus in these patients must be investigated.


Investigation into an outbreak of Border disease virus in pigs in England.
Border disease (BD) was first reported in 1959 in lambs from the border region of England and Wales. The causative virus (BD virus; BDV) has since been identified in several other ruminant species and pigs. The virus is prevalent in sheep flocks of UK, Europe and USA and has potential to inflict substantial economic losses. Natural BDV infection of pigs was first reported in the UK in 1992 from pigs with haemorrhagic lesions and more recently from healthy pigs in Spain and Japan. Here, a persistent problem of poor growth and anaemia in a small proportion of growing pigs on a mixed pig and sheep holding was investigated and tissues were tested in a pan viral microarray. The microarray detected BDV RNA in several tissues which was further confirmed by sequencing, specific BDV PCR and immunohistochemistry. Phylogenetically, the virus clustered with other BDVs in the sub-genotype 1b. This investigation highlights likely interspecies transmission of pestiviruses and their impact on pestivirus detection and eradication programs.


[Reversible cortical blindness associated with bilateral occipital lesions caused by cyclosporin A: report of two cases].
We report two cases of encephalopathy with cortical blindness associated with reversible bioccipital lesions in transplanted patients (of the kidney and bone marrow) who were being treated with cyclosporin A. We briefly discuss the pathogenesis of symptoms and review the literature.


Murder by poisoning: successful analytical investigations of spectacular cases in Austria.
To prove murder by poisoning requires the application of analytical toxicology to detect the fatal substance and clear up the cause of death. Improvements in the development of mass spectrometry in combination with high-resolution chromatographic methods are steadily enhancing detection and identification power but making use of these advances relies on proper sample preparation as well as on knowledge about the chemical nature of the substances and their bio-transformation products. This review gives examples of case reports with successful analytical investigations of murder by poisoning in spectacular Austrian cases involving low molecular weight.


[Value of physical activity for proper bone mass and bone mineral density attaining in children and adolescents].
Physical activity is an important factor for healthy life of the humans. Its significance regards mostly the developmental age, when natural mobility of the youth prones to the proper growing of the skeleton and is important in the prevention and therapy of many diseases. The advantageous effect of regular physical activity and different sport disciplines on bone mass and density is described. In the young age, puberty is an ideal moment for attaining the maximal bone mass and density gain due to physical exercising. The possible harmful effect of exaggerated physical activity has been shown. It is connected with hormonal disorders - secondary amenorrhea, delay of menarche, increased injuries and BMD loss together with significant body mass reduction.


[Genetic testing in polygenic diseases : Atrial fibrillation, arterial hypertension and coronary artery disease].
Genetic testing plays an increasing role in cardiovascular medicine. Advances in technology and the development of novel and more affordable (high throughput) methods have led to the identification of genetic risk factors in research and clinical practice. Also, this progress has simplified the screening of patients and individuals at risk. In case of rare monogenic diseases, diagnostics, risk stratification, and, in some cases, treatment decisions have become easier. For common, polygenic cardiovascular diseases, the situation is more complex due to interaction of modifiable external risk factors and nonmodifiable factors like genetic predisposition. Over the last few years, it has been shown that multiple genes are involved in the pathophysiology of these cardiovascular diseases rather than one single gene. In the following article, we give an overview of the genetic risk factors in polygenic cardiovascular diseases as atrial fibrillation, arterial hypertension and coronary artery disease. Furthermore, we aim to illustrate in which cases genetic testing is recommended in these diseases.


Adenovirus VAI RNA facilitates the initiation of translation in virus-infected cells.
The adenovirus VAI RNA is a small polymerase III-transcribed species that is required for optimal translation of mRNAs late after infection. Mutant dl331 fails to produce this RNA species and, as a result, grows poorly. Mutant-infected cells contain normal levels of late mRNAs, but reduced levels of polypeptides are synthesized late after infection. Translational elongation occurs at normal rates in mutant, as compared to wild-type, virus-infected cells. Initiation of translation occurs with reduced efficiency in dl331 -infected cells. VAI RNA is required for formation of a stable 48S preinitiation complex and very likely functions to facilitate the interaction between 43S preinitiation complex and mRNA to form the 48S species.


Keeping pace with ACE: are ACE inhibitors and angiotensin II type 1 receptor antagonists potential doping agents?
In the decade since the angiotensin-converting enzyme (ACE) gene was first proposed to be a 'human gene for physical performance', there have been numerous studies examining the effects of ACE genotype on physical performance phenotypes such as aerobic capacity, muscle function, trainability, and athletic status. While the results are variable and sometimes inconsistent, and corroborating phenotypic data limited, carriers of the ACE 'insertion' allele (the presence of an alu repeat element in intron 16 of the gene) have been reported to have higher maximum oxygen uptake (VO2max), greater response to training, and increased muscle efficiency when compared with individuals carrying the 'deletion' allele (absence of the alu repeat). Furthermore, the insertion allele has been reported to be over-represented in elite athletes from a variety of populations representing a number of endurance sports. The mechanism by which the ACE insertion genotype could potentiate physical performance is unknown. The presence of the ACE insertion allele has been associated with lower ACE activity (ACEplasma) in number of studies, suggesting that individuals with an innate tendency to have lower ACE levels respond better to training and are at an advantage in endurance sporting events. This could be due to lower levels of angiotensin II (the vasoconstrictor converted to active form by ACE), higher levels of bradykinin (a vasodilator degraded by ACE) or some combination of the two phenotypes. Observations that individuals carrying the ACE insertion allele (and presumably lower ACEplasma) have an enhanced response to training or are over-represented amongst elite athletes raises the intriguing question: would individuals with artificially lowered ACEplasma have similar training or performance potential? As there are a number of drugs (i.e. ACE inhibitors and angiotensin II type 1 receptor antagonists [angiotensin receptor blockers--ARBs]) that have the ability to either reduce ACEplasma activity or block the action of angiotensin II, the question is relevant to the study of ergogenic agents and to the efforts to rid sports of 'doping'. This article discusses the possibility that ACE inhibitors and ARBs, by virtue of their effects on ACE or angiotensin II function, respectively, have performance-enhancing capabilities; it also reviews the data on the effects of these medications on VO2max, muscle composition and endurance capacity in patient and non-patient populations. We conclude that, while the direct evidence supporting the hypothesis that ACE-related medications are potential doping agents is not compelling, there are insufficient data on young, athletic populations to exclude the possibility, and there is ample, albeit indirect, support from genetic studies to suggest that they should be. Unfortunately, given the history of drug experimentation in athletes and the rapid appropriation of therapeutic agents into the doping arsenal, this indirect evidence, coupled with the availability of ACE-inhibiting and ACE-receptor blocking medications may be sufficiently tempting to unscrupulous competitors looking for a shortcut to the finish line.


[Genetic characterization of two Seoul virus strains isolated from patients and rats in Hebei province].
Complete S and M segments of two Seoul virus (SEOV) strains were obtained to determine their genetic types and characteristics. The complete S and M segments from the isolate Li and lung tissue (sample LF18) were amplified by RT-PCR. Genetic analyses were performed by using DNAStar and PHYLIP program package. Their sequences consisted of 1772 nucleotides, and had an open reading frame (ORF, 43 to 1332 nt) encoding a nucleoprotein of 429 amino acids for both two strains. The complete M segment sequences consisted of 3653 nucleotides and had an ORF encoding a GnGc precursor of 1133 amino acids. The GnGc precursor of the two strains had 62 cysteine and 6 N-glycosylation sites. Both two strains shared a high degree of homology with other known SEOV strains including strains L99, Gou3, and vaccine strain Z37, with 87.6% to 99.2% and 83.6% to 97.3% nucleotide identities, respectively. On the S- and M-trees, the two strains LF18 and Li were grouped into the third cluster of SEOV. Both LF18 and Li strains belonged to SEOV and shared the congruent genetic characteristics with the vaccine strains Z37. Thus, the bivalent vaccine including the strain Z37 could effectively prevent HFRS which was caused by SEOV in Hebei province.


Effect of chronic electrical stimulation of laryngeal muscle on voice.
Conventional surgical therapies for bilateral laryngeal paralysis sacrifice voice to enlarge the airway. Electrical pacing of the posterior cricoarytenoid (PCA) muscle to restore glottal opening and allow ventilation offers a new treatment approach. The purpose of this investigation was to determine whether long-term stimulation of the PCA muscle altered perceptual, acoustic, and aerodynamic parameters of voice. Two patients underwent implantation of a Medtronic Itrel II laryngeal pacemaker. Voice evaluation was performed before surgery and at monthly postoperative sessions with the pacemaker off. Months of PCA stimulation did not change perceptual descriptors of voice quality. Measures of fundamental frequency and intensity, upper and lower limits of the dynamic frequency and intensity range, and phonatory flow rates were largely unaltered. The results indicated that there was no effect of laryngeal pacing on voice.


Severe acute asthma caused by Chlamydophila pneumoniae infection.
Asthma exacerbation is associated with respiratory infections, including those by viruses and atypical bacteria. We herein report a case of severe acute asthma in an adult caused by Chlamydophila pneumoniae (C. pneumoniae) infection. A 39-year-old woman without a history of asthma reported to the emergency department with progressive worsening of cough, shortness of breath, and wheezing with low oxygen saturation. A computed tomography (CT) scan revealed patchy ground-glass opacity and bronchial wall thickening. She was treated with systemic corticosteroids, inhaled short-acting β2 agonists, aminophylline, doripenem, and levofloxacin. Through successful treatment in the intensive care unit (ICU), her condition and the chest X-ray and CT findings improved. Chlamydophila pneumoniae infection was confirmed by elevated paired serum C. pneumoniae-specific IgA antibodies. Chlamydophila pneumoniae infection is an important cause of severe acute asthma. On CT, findings typical of C. pneumoniae pneumonia were noted.


Levetiracetam-induced myoclonic status epilepticus in myoclonic-astatic epilepsy: a case report.
We report on a 3-year-old boy with myoclonic-astatic epilepsy who developed myoclonic status epilepticus with continuous twitching of the face and unresponsiveness under monotherapy with levetiracetam. Recently, a nonconvulsive status epilepticus in an adult epilepsy patient has also been described. Our observation points to the possibility of a causal relationship between the induction of myoclonic status by levetiracetam in certain patients with Doose's syndrome. However, a spontaneous evolution cannot be excluded. Levetiracetam is a well-known drug for the control of myoclonic seizures. A controlled study would provide a better understanding of any possible aggravating role in certain forms of myoclonic-astatic epilepsy.


Recent positive selection signatures reveal phenotypic evolution in the Han Chinese population.
Characterizing natural selection signatures and relationships with phenotype spectra is important for understanding human evolution and both biological and pathological mechanisms. Here, we identified 24 genetic loci under recent selection by analyzing rare singletons in 3946 high-depth whole-genome sequencing data of Han Chinese. The loci include immune-related gene regions (MHC cluster, IGH cluster, STING1, and PSG), alcohol metabolism-related gene regions (ADH1B, ALDH2, and ALDH3B2), and the olfactory perception gene OR4C16, in which the MHC cluster, ADH1B, and ALDH2 were also identified by TOPMed and WestLake Biobank. Among the signals, the IGH cluster is particularly interesting, in which the favored allele of variant 14_105737776_C_T (rs117518546, IgG1-G396R) promotes immune response, but also increases the risk of an autoimmune disease systemic lupus erythematosus (SLE). It is also surprising that our newly discovered ALDH3B2 evolved in the opposite direction to ALDH2 for alcohol metabolism. Besides monogenic traits, we found that multiple complex traits experienced polygenic adaptation. Particularly, multi-methods consistently revealed that lower blood pressure was favored in natural selection. Finally, we built a database named RePoS (recent positive selection, http://bigdata.ibp.ac.cn/RePoS/) to integrate and display multi-population selection signals. Our study extended our understanding of natural evolution and phenotype adaptation in Han Chinese as well as other populations.


A combination of the PI3K pathway inhibitor plus cell cycle pathway inhibitor to combat endocrine resistance in hormone receptor-positive breast cancer: a genomic algorithm-based treatment approach.
Cyclin-dependent kinase 4 (CDK4) and CDK6 together with D-type cyclins (D1, D2 and D3) to promote cell cycle entry and progression through G1 by inactivating retinoblastoma protein (RB) by inhibiting an INK4 family of CDK inhibitors (CDKN2A/B). Selective cyclin-dependent kinase inhibitors are game changers in the clinical management of hormone receptor-positive/HER2-negative advanced breast cancers. There are currently three CDK4/6 inhibitors that have been approved by the US Food and Drug administration: palbociclib, ribociclib, and abemaciclib. Although, the bulk of the data supporting the use of selective CDK4/6 inhibitors is currently in breast cancer patients with other tumor types are expected to benefit as well from this class of agents, which can counter proliferative signaling pathways and arrest cell cycle in early G1 phase. Areas of active interest include identifying predictive biomarkers for CDK4/6 inhibitors, deciding whether to continue CDK4/6 inhibitor after disease progression, creating novel treatment combinations and expanding the use of CDK4/6 inhibitors beyond hormone receptor-positive/HER2-negative advanced breast cancer. Right now, CCND1 amplification and CDKN2A/B loss have not sorted out biomarkers useful for the purpose. One of the most important clinical questions is how to use a CDK4/6 inhibitor with other targeted therapies. Here we provide a rationale that oncologists can use to sequence the CDK4/6 inhibitors along with the PI3K-AKT-mTOR pathway-specific inhibitor(s); future data will better guide this approach. In this review we have tried to (a) describe the specific cellular signals initiated following alterations in the cell cycle pathway genes and the PI3K pathway genes, (b) interrogate how these alterations/co-alterations influence the action of PI3K and cell cycle pathway-targeted drugs in different clinical trials and (c) understand the role of co-alterations towards the development of cell cycle inhibitors induced drug-resistance in ER+ breast cancers.


High Prevalence of Pain Sensitization in Knee Osteoarthritis: A Meta-Analysis with Meta-Regression.
The aim of this meta-analysis was to study the evidence on pain sensitization in knee osteoarthritis (OA), providing a quantitative synthesis of its prevalence and impact. Factors associated with pain sensitization were also investigated. Meta-analysis; PubMed (MEDLINE), Cochrane Central Register (CENTRAL), and Web of Science were searched on February 2021. Level I to level IV studies evaluating the presence of pain sensitization in patients with symptomatic knee OA, documented through a validated method (questionnaires or quantitative sensory testing), were included. The primary outcome was the prevalence of pain sensitization. Factors influencing the prevalence were also evaluated, as well as differences in terms of pain thresholds between knee OA patients and healthy controls. Fifty-three articles including 7,117 patients were included. The meta-analysis of proportion documented a prevalence of pain sensitization of 20% (95% confidence interval [CI] = 16%-26%) with a significant heterogeneity of results (I2 = 89%, P < 0.001). The diagnostic tool used was the main factor influencing the documented prevalence of pain sensitization (P = 0.01). Knee OA patients presented higher pain sensitivity compared with healthy controls, both in terms of local pressure pain threshold (standardized mean difference [SMD] = -1.00, 95% CI = -1.67 to -0.32, P = 0.007) and distant pressure pain threshold (SMD = -0.54, 95% CI = -0.76 to -0.31, P < 0.001). Knee OA pain presents features that are consistent with a significant degree of pain sensitization. There is a high heterogeneity in the reported results, mainly based on the diagnostic tool used. The identification of the best methods to detect pain sensitization is warranted to correctly evaluate and manage symptoms of patients affected by knee OA. PROSPERO CRD42019123347.


The effect of immunotherapy on the serum levels of eosinophil cationic protein in seasonal allergic rhinitis.
The role of serum eosinophil cationic protein levels in allergic rhinitis is controversial. It is also unclear whether with immunotherapy it is possible to reduce these serum levels in allergic diseases. We studied serum eosinophil cationic protein levels in patients with cedar-induced allergic rhinitis and compared them with non-atopic controls. The second aim of this study was to elucidate whether immunotherapy is capable of decreasing the seasonal elevation in serum eosinophil cationic protein levels in seasonal allergic rhinitis. The serum eosinophil cationic protein levels of the untreated patient group were significantly higher than those of the non-atopic controls. The levels in patients who received immunotherapy for 2 yr were also significantly higher than those of the non-atopic controls. However, the levels were not different between the patients undergoing immunotherapy for over 3 yr and the non-atopic controls. The serum levels of the 31 patients treated with immunotherapy correlated with the duration of immunotherapy. In conclusion, the serum eosinophil cationic protein levels are higher in untreated patients with seasonal allergic rhinitis and this seasonal activation in circulating eosiohophils decreases gradually during immunotherapy, but this inhibitory effect becomes apparent only after a number of years of immunotherapy. This prevention of seasonal eosinophil activation is one of the mechanisms responsible for the clinical effect of immunotherapy.


Endoscopic skull base and transoral surgery during COVID-19 pandemic: Minimizing droplet spread with negative-pressure otolaryngology viral isolation drape.
The coronavirus disease (COVID-19) pandemic has raised concern of transmission of infectious organisms through aerosols formation in endonasal and transoral surgery. Retrospective review. We introduce the negative-pressure otolaryngology viral isolation drape (NOVID) system to reduce the risk of aerosol. NOVID consists of a plastic drape suspended above the patient's head and surgical field with a smoke evacuator suction placed inside the chamber. Four patients underwent endonasal (4) and endo-oral surgery (1). Fluorescein was applied to the surgical field. Black light examination of fluorescein-treated operative fields revealed minimal contamination distant to the surgical field. In two prolonged cases with high-speed drilling, droplets were identified under the barrier and on the tip of the smoke evacuator. Instruments and cottonoids appeared to be a greater contributor to field contamination. Negative-pressure aspiration of air under a chamber barrier, which appears to successfully keep aerosol and droplet contamination to a minimum.


Anaphylaxis secondary to Parietaria judaica (wall pellitory).
Aeroallergens are an unusual cause of anaphylaxis with sparse reports in the literature. We describe a case of suspected anaphylaxis to Parietaria judaica pollen and the difficulties encountered in confirming this diagnosis.


Sylvian cistern arachnoid cyst--a rare cause of precocious puberty.
Precocious puberty still remains an elusive diagnosis in the majority of patients. Infrequently, lesions of the central nervous system are associated with sexual precocity. Depending on their location, these cysts may affect many systems, however, there is little information concerning their involvement in endocrinological disorders. We report a case of a sylvian cistern arachnoid cyst presenting with precocious puberty in a 3-year-old girl. The child recovered following a cystoperitoneal shunt. The mass effect of the arachnoid cyst upon the hypothalamus was, at least in part, responsible for the development of precocious puberty. To the best of our knowledge, this is the 1st case of a sylvian cistern arachnoid cyst presenting with precocious puberty. The role of surgical decompression of the cyst is also discussed.


Testing the domain-general nature of monitoring in the spatial and verbal cognitive domains.
While it is well-established that monitoring the environment for the occurrence of relevant events represents a key executive function, it is still unclear whether such a function is mediated by domain-general or domain-specific mechanisms. We investigated this issue by combining event-related potentials (ERPs) with a behavioral paradigm in which monitoring processes (non-monitoring vs. monitoring) and cognitive domains (spatial vs. verbal) were orthogonally manipulated in the same group of participants. They had to categorize 3-dimensional visually presented words on the basis of either spatial or verbal rules. In monitoring blocks, they additionally had to check whether the word displayed a specific spatial configuration or whether it contained a certain consonant. The behavioral results showed slower responses for both spatial and verbal monitoring trials compared to non-monitoring trials. The ERP results revealed that monitoring did not interact with domain, thus suggesting the involvement of common underlying mechanisms. Specifically, monitoring acted on low-level perceptual processes (as expressed by an enhanced visual N1 wave and a sustained posterior negativity for monitoring trials) and on higher-level cognitive processes (involving larger positive modulations by monitoring trials over frontal and parietal scalp regions). The source reconstruction analysis of the ERP data confirmed that monitoring was associated with increased activity in visual areas and in right prefrontal and parietal regions (i.e., superior and inferior frontal gyri and posterior parietal cortex), which previous studies have linked to spatial and temporal monitoring. Our findings extend this research by supporting the domain-general nature of monitoring in the spatial and verbal domains.


Point-of-Care Peptide Hormone Production Enabled by Cell-Free Protein Synthesis.
In resource-limited settings, it can be difficult to safely deliver sensitive biologic medicines to patients due to cold chain and infrastructure constraints. Point-of-care drug manufacturing could circumvent these challenges since medicines could be produced locally and used on-demand. Toward this vision, we combine cell-free protein synthesis (CFPS) and a 2-in-1 affinity purification and enzymatic cleavage scheme to develop a platform for point-of-care drug manufacturing. As a model, we use this platform to synthesize a panel of peptide hormones, an important class of medications that can be used to treat a wide variety of diseases including diabetes, osteoporosis, and growth disorders. With this approach, temperature-stable lyophilized CFPS reaction components can be rehydrated with DNA encoding a SUMOylated peptide hormone of interest when needed. Strep-Tactin affinity purification and on-bead SUMO protease cleavage yield peptide hormones in their native form that are recognized by ELISA antibodies and that can bind their respective receptors. With further development to ensure proper biologic activity and patient safety, we envision that this platform could be used to manufacture valuable peptide hormone drugs in a decentralized way.


Two in one: Double free flap from a single free fibula osteocutaneous unit.
In the past two decades, the advancement in the microsurgical techniques has revolutionised the reconstruction of post-oncological head and neck defects. Free fibula osteocutaneous flap (FFOCF) has been considered as the treatment of choice by many for mandible reconstruction. The improvement in the surgical resection and adjuvant treatment has improved the survival rates even in patients with advanced cancer. Simultaneously the reconstruction is addressed towards more functional and aesthetic aspects to improve the quality of life in these patients. In this respect, a double free flap is advocated in certain cases of extensive composite oromandibular defects (COMDs). But in our institute, we have managed two such cases of extensive COMD with a single FFOCF unit - fibula bone with a skin paddle for inner lining and a perforator-based skin paddle from the proximal part of the FFOCF unit, anastomosed separately for outer cover. Compared to two separate free flaps, this method has the advantage of single donor site and reduction in reconstruction time. Though the technique of divided paddle, deepithelisation and supercharging has been mentioned for FFOCF, no such clinical cases of two free flaps from a single FFOCF unit have been mentioned in the literature.


When is Menzerath-Altmann law mathematically trivial? A new approach.
Menzerath's law, the tendency of Z (the mean size of the parts) to decrease as X (the number of parts) increases, is found in language, music and genomes. Recently, it has been argued that the presence of the law in genomes is an inevitable consequence of the fact that Z=Y/X, which would imply that Z scales with X as Z ∼ 1/X. That scaling is a very particular case of Menzerath-Altmann law that has been rejected by means of a correlation test between X and Y in genomes, being X the number of chromosomes of a species, Y its genome size in bases and Z the mean chromosome size. Here we review the statistical foundations of that test and consider three non-parametric tests based upon different correlation metrics and one parametric test to evaluate if Z ∼ 1/X in genomes. The most powerful test is a new non-parametric one based upon the correlation ratio, which is able to reject Z ∼ 1/X in nine out of 11 taxonomic groups and detect a borderline group. Rather than a fact, Z ∼ 1/X is a baseline that real genomes do not meet. The view of Menzerath-Altmann law as inevitable is seriously flawed.


The Spectrum of α-Thalassemia Mutations in Kurdistan Province, West Iran.
In order to identify the α-thalassemia (α-thal) mutation spectrum in Kurdistan Province, West Iran, a total of 217 individuals, including 154 α-thal carriers and 63 normal subjects were investigated in this study. Molecular analysis of α1- and α2-globin genes using multiplex gap-polymerase chain reaction (gap-PCR), amplification refractory mutation system (ARMS)-PCR or direct DNA sequencing, showed 11 different α-globin variants. The -α3.7 (rightward) deletion (NG_000006.1: g.34164_37967del3804) (70.32%), polyadenylation signal (polyA2) site (AATAAA>AATGAA) (αpolyA2α) (HBA2: c.*92A>G) (7.74%), -α4.2 (leftward) deletion (6.45%) and codon 59 (or Hb Adana) (G>A) (ααcodon 59) (HBA1: c.179G>A) (4.52%) were the most frequent mutations in the present study. In conclusion, the spectrum of α-thal mutations in Kurdistan Province is closest to that in western provinces of Iran (Kurdish and Laki populations). In addition, it was revealed that the codon 59 mutation is common in the Kurdish population. On the other hand, despite the same ethnic background of Kurds in Iran and Iraq, the - -MED I double gene deletion and polyA2 point mutation have different distributions in these two populations. Therefore, further studies are needed to identify the cause of these differences.


Structure absorption spectra correlation in a series of 2,6-dimethyl-4-arylpyrylium salts.
A combined experimental and theoretical study of the absorption spectra of a group of closely related pyrylium perchlorates 1-11 are presented. Minor changes in the position of the substituents lead to drastic changes in the absorption spectra in this series of compounds. We have attempted to explain the observed changes using the x,y-band notation developed by Balaban and co-workers. Absorption spectra of all compounds are compared with results from time-dependent density functional theory (TDDFT) and Zerner's intermediate neglect of differential overlap (ZINDO/S) level calculations. Results of the calculations are in good agreement with experimental observations and an interesting correlation between Balaban's notations and the MO transitions are obtained for simple derivatives. It is suggested that for more complex systems such as alpha- and beta-naphthyl substituted systems, the empirical method is not appropriate.


Effects of prepartum lipid supplementation on FSH superstimulation and transferable embryo recovery in multiparous beef cows.
The objective of this experiment was to determine the effect of prepartum lipid supplementation on the number and quality of embryos recovered following ovarian super-ovulation in postpartum suckled beef cows. Mature cows (n = 40) were assigned to one of two treatments (lipid versus. no lipid) and supplemented for approximately 40 days prior to calving. Supplements provided to cows were isocaloric and isonitrogenous. The treatment group was fed 1.6 kg hd(-1) per day of whole soybeans (WSB; 19.8% ether extract, and 41.8% crude protein) and the control group received a supplement consisting of 1.8 kg hd(-1) day of a soybean meal and soy-hull combination (SBS; 2.15% EE and 36.81% CP). Cows were synchronized using a GnRH [Cystorelin((R)) 100 microg im]-GnRH-PGF(2alpha) [Lutalyse 25 mg im] protocol. Cows were administered two injections of GnRH seven days apart and PG seven days after the second GnRH injection. Twenty-eight cows (WSB, n = 15; SBS, n = 13) responded to estrus synchronization and were superstimulated. Super-ovulation was initiated on day 8-10 of the synchronized cycle by twice-daily injections of pFSH (Pluset) over four days in decreasing doses using a total of 608.4 IU per cow. Prostaglandin F(2alpha) was administered 96 and 108 h after super-stimulation was initiated with FSH. Days postpartum (WSB = 59 days; SBS = 57 days) at initiation of FSH treatments were similar (P > 0.10) for both treatments. Cows were monitored for estrus activity by the HeatWatch Estrus Detection System. Twenty-seven cows (WSB, n = 15; SBS, n = 12) exhibited estrus after FSH and inseminated at 0, 12, and 24 h after the onset of estrus with 1, 2, and 1 units of semen, respectively. Embryos were recovered and evaluated 7-8 days later. Only cows that responded to FSH and that were inseminated were used for statistical analysis. Data were analyzed using the General Linear Models Procedure of SAS. Body condition scores did not differ (P > 0.10) between treatments when cows were evaluated at the initiation of the experiment, two weeks prior to calving, and at initiation of superovulation with FSH. Estrous cyclicity prior to the initiation of estrus synchronization did not differ (P > 0.10) between treatments. There was no difference (P > 0.10) between treatments in recovery of total embryos (WSB, 14.7 +/- 3.5; SBS, 17.5 +/- 3.0), transferable embryos (WSB, 10.3 +/- 2.5; SBS, 13.6 +/- 2.6), degenerate embryos (WSB, 3.3 +/- 1.1; SBS, 1.6 +/- 1.7) or unfertilized ova (WSB, 1.1 +/- 0.5; SBS, 2.3 +/- 1.2). Cows that were supplemented with whole soybeans prior to parturition failed to produce an increased total number of ova or transferable embryos following super-ovulation.


AbsCN-seq: a statistical method to estimate tumor purity, ploidy and absolute copy numbers from next-generation sequencing data.
Detection and quantification of the absolute DNA copy number alterations in tumor cells is challenging because the DNA specimen is extracted from a mixture of tumor and normal stromal cells. Estimates of tumor purity and ploidy are necessary to correctly infer copy number, and ploidy may itself be a prognostic factor in cancer progression. As deep sequencing of the exome or genome has become routine for characterization of tumor samples, in this work, we aim to develop a simple and robust algorithm to infer purity, ploidy and absolute copy numbers in whole numbers for tumor cells from sequencing data. A simulation study shows that estimates have reasonable accuracy, and that the algorithm is robust against the presence of segmentation errors and subclonal populations. We validated our algorithm against a panel of cell lines with experimentally determined ploidy. We also compared our algorithm with the well-established single-nucleotide polymorphism array-based method called ABSOLUTE on three sets of tumors of different types. Our method had good performance on these four benchmark datasets for both purity and ploidy estimates, and may offer a simple solution to copy number alteration quantification for cancer sequencing projects. The R package absCNseq is available from http://biostats.mcc.ucsd.edu/files/absCNseq_1.0.tar.gz CONTACT: email@example.com Supplementary information: Supplementary data are available at Bioinformatics online.


Potential tactics with vitamin D and certain phytochemicals for enhancing the effectiveness of immune-checkpoint blockade therapies.
Immunotherapy strategies targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) are revolutionizing oncology. However, its effectiveness is limited in part due to the loss of effector cytotoxic T lymphocytes. Interestingly, supplementation of vitamin D could abolish the repressive effect of programmed cell death-ligand 1 (PD-L1) on CD8+ T cells, which might prevent the lymphocytopenia. In addition, vitamin D signaling could contribute to the differentiation of T-regulatory (Treg) cells associated with the expression of Treg markers such as forkhead box P3 (FOXP3) and CTLA-4. Furthermore, vitamin D may be associated with the stimulation of innate immunity. Peroxisome proliferator-activated receptor (PPAR) and estrogen receptor (ESR) signaling, and even the signaling from phosphoinositide-3 kinase (PI3K)/AKT pathway could have inhibitory roles in carcinogenesis possibly via the modulation of immune checkpoint molecules. In some cases, certain small molecules including vitamin D could be a novel therapeutic modality with a promising potential for the better performance of immune checkpoint blockade cancer therapies.


Cartography of hevin-expressing cells in the adult brain reveals prominent expression in astrocytes and parvalbumin neurons.
Hevin, also known as SPARC-like 1, is a member of the secreted protein acidic and rich in cysteine family of matricellular proteins, which has been implicated in neuronal migration and synaptogenesis during development. Unlike previously characterized matricellular proteins, hevin remains strongly expressed in the adult brain in both astrocytes and neurons, but its precise pattern of expression is unknown. The present study provides the first systematic description of hevin mRNA distribution in the adult mouse brain. Using isotopic in situ hybridization, we showed that hevin is strongly expressed in the cortex, hippocampus, basal ganglia complex, diverse thalamic nuclei and brainstem motor nuclei. To identify the cellular phenotype of hevin-expressing cells, we used double fluorescent in situ hybridization in mouse and human adult brains. In the mouse, hevin mRNA was found in the majority of astrocytes but also in specific neuronal populations. Hevin was expressed in almost all parvalbumin-positive projection neurons and local interneurons. In addition, hevin mRNA was found in: (1) subsets of other inhibitory GABAergic neuronal subtypes, including calbindin, cholecystokinin, neuropeptide Y, and somatostatin-positive neurons; (2) subsets of glutamatergic neurons, identified by the expression of the vesicular glutamate transporters VGLUT1 and VGLUT2; and (3) the majority of cholinergic neurons from motor nuclei. Hevin mRNA was absent from all monoaminergic neurons and cholinergic neurons of the ascending pathway. A similar cellular profile of expression was observed in human, with expression of hevin in parvalbumin interneurons and astrocytes in the cortex and caudate nucleus as well as in cortical glutamatergic neurons. Furthermore, hevin transcript was enriched in ribosomes of astrocytes and parvalbumin neurons providing a direct evidence of hevin mRNAs translation in these cell types. This study reveals the unique and complex expression profile of the matricellular protein hevin in the adult brain. This distribution is compatible with a role of hevin in astrocytic-mediated adult synaptic plasticity and in the regulation of network activity mediated by parvalbumin-expressing neurons.


The downregulation of miR-200c/141 promotes ZEB1/2 expression and gastric cancer progression.
Gastric cancer is the fourth most common malignancy in the world. Although microRNA-200 (miR-200) family members are thought to play roles in tumorigenesis, their functions in carcinogenesis are tumor specific, and the underlying mechanism of action still remains elusive. Few studies to date have addressed the dysregulation and function of miR-200 family members in gastric cancer progression. Here, we report that the miR-200 family members, miR-200c and miR-141, were significantly downregulated in gastric cancer specimens and gastric cancer cell lines. Importantly, on clinical samples, the expression of miR-200c and miR-141 was inversely correlated with TNM stage, tumor invasion depth (T), tumor embolus and disease-free survival. Wound-healing assay results showed that co-transfected miR-200c/141 could inhibit the migration and invasion capability of the gastric cell line SGC-7901. We also found that miR-200c and miR-141 directly targeted zinc finger E-box-binding homeobox 1/2 (ZEB1/2) and upregulated E-cadherin expression. In specimens from gastric cancer patients, reduced expression of miR-200c/141 was associated with increased expression of ZEB1 and/or ZEB2. In addition, the downregulation of miR-200c and miR-141 was found to be due to a highly methylated CpG island located upstream of their genomic sequence and/or upregulated TGF-β signaling. Treatment with the chemotherapeutic agent decitabine, a known DNA methyltransferase inhibitor, increased miR-200c/141 expression and ameliorated decreased expression of miR-200c/141 induced by TGF-β in SGC-7901 cells. Our study revealed that miR-200c/141 was downregulated by CpG island methylation and TGF-β signaling, which decreased ZEB1/2 expression and increased E-cadherin expression to inhibit migration and invasion of gastric cancer cells and provides powerful evidence for the application of decitabine in gastric cancer treatment.


Hypnotic Induction of Deafness to Elementary Sounds: An Electroencephalography Case-Study and a Proposed Cognitive and Neural Scenario.
Hypnosis can be conceived as a unique opportunity to explore how top-down effects can influence various conscious and non-conscious processes. In the field of perception, such modulatory effects have been described in distinct sensory modalities. In the present study we focused on the auditory channel and aimed at creating a radical deafness to elementary sounds by a specific hypnotic suggestion. We report here a single case-study in a highly suggestible healthy volunteer who reported a total hypnotically suggested deafness. We recorded high-density scalp EEG during an auditory odd-ball paradigm before and after hypnotic deafness suggestion. While both early auditory event-related potentials to sounds (P1) and mismatch negativity component were not affected by hypnotic deafness, we observed a total disappearance of the late P3 complex component when the subject reported being deaf. Moreover, a centro-mesial positivity was present exclusively during the hypnotic condition prior to the P3 complex. Interestingly, source localization suggested an anterior cingulate cortex (ACC) origin of this neural event. Multivariate decoding analyses confirmed and specified these findings. Resting state analyses confirmed a similar level of conscious state in both conditions, and suggested a functional disconnection between auditory areas and other cortical areas. Taken together these results suggest the following plausible scenario: (i) preserved early processing of auditory information unaffected by hypnotic suggestion, (ii) conscious setting of an inhibitory process (ACC) preventing conscious access to sounds, (iii) functional disconnection between the modular and unconscious representations of sounds and global neuronal workspace. This single subject study presents several limits that are discussed and remains open to alternative interpretations. This original proof-of-concept paves the way to a larger study that will test the predictions stemming from our theoretical model and from this first report.


Effects to HeLa Cells of the Inhibition of Survivin by Antisense RNA.
To study the function of survivin in cancer cells, survivin cDNA was amplified from HeLa cells by RT-PCR. Then the coding fragment was subcloned into an inducible eukaryotic expression plasmid pHC in reverse direction.The obtained plasmid pHSC was transfected into HeLa cells by Lipofectamine. An inducible cell line which can express antisense RNA of survivin with 2 mmol/L Zn(2 ) was obtained by the selection with 800 nmol/L G418 solution. The expression of antisense RNA of survivin inhibited the expression of survivin protein. Inhibition of survivin expression suppressed the proliferation of HeLa cells and its cell cycle. And it also sensitized HeLa cells to chemotherapeutics.


Tamsulosin shows a higher unbound drug fraction in human prostate than in plasma: a basis for uroselectivity?
The efficacy-tolerability profile of tamsulosin in patients with benign prostatic hyperplasia (BPH) is assumed to be associated both with the α1-adrenoceptor selectivity profile of the drug and a small peak : trough ratio in the plasma pharmacokinetic (PK) profile. Tamsulosin is highly bound to plasma proteins, notably α1-acid glycoprotein (AGP). This protein is a high-affinity binding protein and AGP plasma concentration was found to influence the therapeutic (unbound) plasma concentrations for high-AGP-binding drugs. The study actually assessed unbound tamsulosin concentrations in both blood plasma and prostate tissue and reported that the unbound tamsulosin concentrations after multiple dosing in men with BPH, were much higher in prostate than in blood plasma. The assumption is put forward that differential free drug concentrations in prostate and blood plasma may contribute to the relative 'uroselectivity' of tamsulosin. The aim of this small patient study was to investigate tamsulosin concentrations in prostate and plasma samples in order to identify potential differences in the pharmacokinetics (PK) in plasma and prostate contributing to its pharmacodynamic activity profile in patients. Forty-one patients with benign prostatic hyperplasia (BPH) scheduled for open prostatectomy were given tamsulosin 0.4 mg for 6-21 days in order to reach steady-state PK. Patients were randomized over four groups to allow collection of plasma and tissue samples at different time points after last dose administration. Samples were collected during surgery and assayed for tamsulosin HCl. The free fraction (f(u)) of tamsulosin was determined by ultracentrifugation of plasma and prostate tissue spiked with (14)C-tamsulosin. C(max) in plasma at 4.4 h for total tamsulosin was 15.2 ng ml(-1) and AUC(0,24 h) was 282 ng ml(-1) h, while for prostate C(max) at 11.4 h post-dose was 5.4 ng ml(-1) and AUC(0,24 h) was 120 ng ml(-1) h. AUC(0,24 h) for total tamsulosin in prostate was 43% of the plasma AUC(0,24 h). f(u) was 0.4 % for plasma and 59.1% for prostate. Therefore calculated on unbound tamsulosin, a ratio of 63 resulted for prostate vs. plasma C(max) concentrations. These data indicate that in patients with confirmed BPH the amount of tamsulosin freely available in the target tissue (prostate) is much higher than in plasma.


Assessment of preoperative hypercoagulability in patients with pancreatic ductal adenocarcinoma (PDAC) using rapid thromboelastography (r-TEG).
Patients with malignant tumors are usually accompanied with hypercoagulability state and high incidence risk of venous thromboembolism (VTE), especially in patients with pancreatic ductal adenocarcinoma (PDAC). However, conventional coagulation test is failed to identify this abnormity. We retrospectively reviewed clinical data of 78 PDAC patients and 79 age-matched controls with rapid thromboelastography (r-TEG) and conventional coagulation test. The main index of r-TEG include TEG-ACT (second), R (second), K (second), angleα (°) and MA (mm), and a short TEG-ACT, short R, a short K, a broad angleα and a prolonged MA can identify hypercoagulability. Compared with age-matched controls, the PADC patients were analyzed to have a shorter K value (72. + 24 ± 22.90 vs. 85.63 ± 32.81, P = 0.0014), increased angleα value (76.20 ± 3.68 vs. 74.415 ± 4.73, P = 0.009) and MA value (63.33 ± 7.19 vs. 60.89 ± 5.52, P = 0.18). Both TEG-ACT (101.72 ± 7.57 vs. 103.78 ± 7.33, P = 0.086) and R (32.95 ± 4.72 vs. 34.34 ± 4.61, P = 0.085) value showed no significant difference in two groups. The laboratory values for conventional coagulation test were within normal ranges: PT (11.65 ± 0.95 vs. 11.38 ± 0.79, P = 0.049), INR (1.01 ± 0.09 vs. 0.98 ± 0.08, P = 0.101), aPTT (28.75 ± 3.45 vs. 28.00 ± 2.98, P = 0.149) and TT (19.44 ± 1.12 vs. 19.69 ± 1.35, P = 0.212). Incidence rates of VTE were 3.8% (3 of 78 patients) and 1.3% (1 of 79 patients) respectively (Fisher's exact test: P = 0.367). Several r-TEG indexes can indicate coagulation disorders within PDAC patients, but the incidence rates of VTE for both PDAC patients and normal controls had no significant difference. Compare to the control group, the potential hypercoagulability of PDAC patients did not correlate to thrombotic complications.


[TFAR19 enhances the opening of permeability transition pore in the mitochondrial membrane of mice liver].
TFAR19 TF-1 cell apoptosis related gene 19 is a novel apoptosis-related gene cloned from human leukemia cell line TF-1 cells undergoing apoptosis in 1999 (accession number AF014955 in GenBank). The human TFAR19 encodes a protein which shares significant homology to the corresponding proteins of species ranging from yeast to mice. TFAR19 exhibits a ubiquitous expression pattern and its expression is upregulated in tumor cells undergoing apoptosis. Overexpression of TFAR19 could enhance apoptosis of some tumor cells induced by growth factor withdrawal or serum deprivation. But the exact mechanism of TFAR19 is unclear. Mitochondria not only provides energy for the cell, but also plays a critical role on cell death or survival. The release of apoptosis promoting factor, such as cytochrome c from mitochondria, resulted by the damage of mitochondrial membrane integrity, is the key factor controlling apoptosis. The permeability transition pore (PTP) of mitochondria is a protein complex located between the mitochondrial membranes, and it plays an important role in regulating the integrity of mitochondrial membrane. In this study, the effect of recombinant TFAR19 on isolated mitochondrial PTP, membrane potential, and release of cytochrome c was investigated in vitro. The results indicated that recombinant TFAR19 facilitated the isolated mitochondrial PTP opening, decreased the membrane potential, and promoted the release of cytochrome c. The effect of TFAR19 on mitochondria is implemented by opening the mitochondrial PTP. Experimental results implicate that TFAR19 may positively feedback apoptosis signal of mitochondria, forming a positive loop to promote apoptosis.


A Cancer-Indicative microRNA Pattern in Normal Prostate Tissue.
We analyzed the levels of selected micro-RNAs in normal prostate tissue to assess their potential to indicate tumor foci elsewhere in the prostate. Histologically normal prostate tissue samples from 31 prostate cancer patients and two cancer negative control groups with either unsuspicious or elevated prostate specific antigen (PSA) levels (14 and 17 individuals, respectively) were analyzed. Based on the expression analysis of 157 microRNAs in a pool of prostate tissue samples and information from data bases/literature, we selected eight microRNAs for quantification by real-time polymerase chain reactions (RT-PCRs). Selected miRNAs were analyzed in histologically tumor-free biopsy samples from patients and healthy controls. We identified seven microRNAs (miR-124a, miR-146a & b, miR-185, miR-16 and let-7a & b), which displayed significant differential expression in normal prostate tissue from men with prostate cancer compared to both cancer negative control groups. Four microRNAs (miR-185, miR-16 and let-7a and let-7b) remained to significantly discriminate normal tissues from prostate cancer patients from those of the cancer negative control group with elevated PSA levels. The transcript levels of these microRNAs were highly indicative for the presence of cancer in the prostates, independently of the PSA level. Our results suggest a microRNA-pattern in histologically normal prostate tissue, indicating prostate cancer elsewhere in the organ.


Assessing respiratory status from a distance.
Home care professionals are increasingly required to manage patients with chronic respiratory conditions. Under PPS, an even stronger mandate requires that every intervention be timely, necessary, valuable, cost effective, and lead to positive patient outcomes. This article focuses on the cost benefits, tools, and interventions available that enhance the ability to assess respiratory status "from a distance."


Pharmacological and Therapeutic Aspects of Plants from the Genus Ferula: A Comprehensive Review.
Inspired by nature, humankind has been able to attain significant achievements in the drug and food industries. Particularly, medicinal plants are a rich source of medicinal, cosmetic, sanitary, and aromatic substances. Genus Ferula from the Apiaceae family is a plant genus that possesses over 170 species, which have been carefully documented with regard to their medicinal properties. Ferula spp. affects many body organs, and their respective functions, in humans, such as the immune system, gastrointestinal tract, genitourinary, endocrine, respiratory, cardiovascular, nervous system, bone (skeleton), and teeth. In spite of the benefits, ferulosis (Ferula toxicity) is an important aspect of Ferula consumption in humans and animals. Hemorrhagic problems and infertility are important signs of ferulosis. In this review, we have described all of the effects of the active ingredients of Ferula spp. and their mechanisms of actions, when known, based on an extensive literature review. Thus, our review opens a window of the benefits of Ferula as a phyto-pharmaceutical and its therapeutic applications in pharmacy, dentistry, and medicine.