Primary non-Hodgkin's lymphoma of the vagina: A case report.
Primary non-Hodgkin's lymphoma (NHL) of the vagina is uncommon. The present case study reports the case of a 54-year-old female with a palpable mass between the rectum and vagina. The patient presented with symptoms consistent with vaginal cancer but lacked any of the 'B' symptoms often associated with systemic lymphoma, including fever, weight loss, night sweats and fatigue. The mass was resected under anesthesia. Immunohistochemistry and biopsy confirmed diffuse large B-cell NHL (DLBCL). Following surgery, six cycles of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone were administered. Subsequently, a vertebral body metastasis was observed using a computed tomography scan and whole-body bone imaging. The patient received palliative radiation for the vertebral body metastasis. Additionally, the available literature was reviewed in order to further characterize this rare disease.


Split notochord syndrome with dorsal enteric fistula and sacral agenesis.
Split notochord syndrome of the lumbosacral spine in association with dorsal enteric fistula is a rare phenomenon. To date, only nine human cases have been reported in the English literature. We present another case of this type, with sacral agenesis as an additional and unique finding. Several etiological theories are discussed including the persistence of the neurenteric canal, the occurrence of an ectopic or accessory neurenteric canal, a division or local redundancy of the notochord, an entodermal-ectodermal adhesion, neural tube rupture caused by oversecretion of fluid, and failure or aberrancy of dorsal aortic distribution to the region of the neural folds resulting in prevention of timely neural tube closure.


Thermodynamics constrains allometric scaling of optimal development time in insects.
Development time is a critical life-history trait that has profound effects on organism fitness and on population growth rates. For ectotherms, development time is strongly influenced by temperature and is predicted to scale with body mass to the quarter power based on 1) the ontogenetic growth model of the metabolic theory of ecology which describes a bioenergetic balance between tissue maintenance and growth given the scaling relationship between metabolism and body size, and 2) numerous studies, primarily of vertebrate endotherms, that largely support this prediction. However, few studies have investigated the allometry of development time among invertebrates, including insects. Abundant data on development of diverse insects provides an ideal opportunity to better understand the scaling of development time in this ecologically and economically important group. Insects develop more quickly at warmer temperatures until reaching a minimum development time at some optimal temperature, after which development slows. We evaluated the allometry of insect development time by compiling estimates of minimum development time and optimal developmental temperature for 361 insect species from 16 orders with body mass varying over nearly 6 orders of magnitude. Allometric scaling exponents varied with the statistical approach: standardized major axis regression supported the predicted quarter-power scaling relationship, but ordinary and phylogenetic generalized least squares did not. Regardless of the statistical approach, body size alone explained less than 28% of the variation in development time. Models that also included optimal temperature explained over 50% of the variation in development time. Warm-adapted insects developed more quickly, regardless of body size, supporting the "hotter is better" hypothesis that posits that ectotherms have a limited ability to evolutionarily compensate for the depressing effects of low temperatures on rates of biological processes. The remaining unexplained variation in development time likely reflects additional ecological and evolutionary differences among insect species.


The Who, Why, and How of Small-Molecule Production in Invertebrate Microbiomes: Basic Insights Fueling Drug Discovery.
Bacteria have supplied us with many bioactive molecules for use in medicine and agriculture. However, rates of discovery have decreased as the biosynthetic capacity of the culturable biosphere has been continuously mined for many decades. The as-yet-uncultured biosphere is likely to hold far greater biosynthetic potential, especially where ecological niches favor the selection of therapeutically useful bioactivities. I outline here how metagenomics and other systems biology approaches can be used to gain insight into small-molecule biosynthesis and the selective forces which shape it. I also argue that we need a greater understanding of the function of small molecules in complex microbiomes and rational synthetic biology methods to functionally reconstruct large biosynthetic pathways in heterologous hosts.


Solubility, lipophilicity and membrane permeability of some fluoroquinolone antimicrobials.
Aqueous solubility and distribution of ciprofloxacin, enrofloxacin, norfloxacin and levofloxacin antimicrobials drugs in octanol/buffer system has been measured by the isothermal saturation method using buffer solutions pH2.0 and 7.4 in the temperature range of 293.15-313.15K. Thermophysical characteristics for the compounds have been determined by the DSC method. It has been established that the solubility of levofloxacin in these buffers is higher than that of the other fluoroquinolones. HYBOT descriptors for biologically active compounds have been calculated and the impact of the donor-acceptor capacity of the molecules on drugs solubility has been studied. According to the lipophilicity parameter fluoroquinolones are ranged in the following order: enrofloxacin>levofloxacin>ciprofloxacin>norfloxacin. The thermodynamic solubility and distribution functions of the studied compounds have been obtained. The permeability coefficients of the substances through an artificial phospholipid membrane were determined. The drugs with a lower aqueous solubility were estimated to have higher distribution coefficients and membrane permeability.


Bryophyte flora of Mount Tebu Forest Reserve, Terengganu, Peninsular Malaysia.
A checklist of the bryophyte flora of Mount Tebu Forest Reserve in Terengganu, Peninsular Malaysia, is presented. A total of 189 taxa in 71 genera and 26 families were enumerated. This figure represents 63% of the 298 bryophyte species recorded so far for the State of Terengganu. Out of 189 taxa of bryophytes, 26 liverworts are new additions to the bryoflora of Terengganu. The most prominent liverwort family is represented by Lejeuneaceae, with 54 species from 17 genera, while the moss family is the Sematophyllaceae, with 34 taxa in 13 genera. The majority of the species are epiphytes, either corticolous or ramicolous. Almost half of the bryophyte species have wider elevational ranges and occur from the lowlands to the summit of Mount Tebu.


Injury of the dentato-rubro-thalamic tract in a patient with mild traumatic brain injury.
Several studies using diffusion tensor tractography (DTT) have demonstrated injury of the dentato-rubro-thalamic tract (DRTT) in various brain pathologies. However, no study on traumatic brain injury (TBI) has been reported. This case study attempted to demonstrate injury of the DRTT in a patient with mild TBI, using DTT. A 41-year-old female patient suffered from head trauma resulting from flexion-hyperextension injury by being hit from behind by a running car while stopped at an intersection. The patient lost consciousness and experienced post-traumatic amnesia for ∼1minute from the time of the car-accident. The patient's Glasgow Coma Scale score was 15. No specific lesion was observed on brain MRI. At 2 weeks after onset, the patient began to show resting and intentional tremor (more severe in the right upper and lower extremities) and ataxic gait. Her symptoms had been aggravated with the passage of time. On 1-month DTT, the left DRTT, which originated from the left dentate nucleus of the cerebellum, was thinner than the right DRTT. This study demonstrated injury of the DRTT in a patient with tremor and ataxia following mild TBI, using DTT. It is believed that analysis of the DRTT using DTT would be useful in elucidating the cause of post-traumatic abnormal movements.


Translocation of Endo-Functionalized Molecular Tubes across Different Lipid Bilayers: Atomistic Molecular Dynamics Simulation Study.
Various artificial receptors, such as calixarenes, cyclodextrins, cucurbit[n]urils, and their acyclic compounds, pliiar[n]arenes, deep cavitands, and molecular tweezers, can permeate the lipid membranes and they are used as drug carriers to improve the drug solubility, stability, and bioavailability. Inspired by these, we have employed atomistic molecular dynamics simulation to examine the effects of endo-functionalized molecular tubes or naphthotubes (host-1a and host-1b) on seven different types of model lipid bilayers and the permeation properties of these receptors through these model lipid bilayers. Lipid types include six model lipid bilayers (POPC, POPE, DOPC, POPG, DPPE, POPE/POPG) and one realistic membrane (Yeast). We observe that these receptors are spontaneously translocated toward these model lipid bilayer head regions and do not proceed further into these lipid bilayer tail regions (reside at the interface between lipid head and lipid tail region), except for the DPPE-containing systems. In the DPPE model lipid bilayer-containing systems (1a-dppe and 1b-dppe), receptor molecules are only adsorbed on the bilayer surface and reside at the interface between lipid head and water. This finding is also supported by the biased free-energy profiles of these translocation processes. Passive transport of these receptors may be possible through these model lipid bilayers (due to low barrier height), except for DPPE bilayer-containing systems (that have a very high energy barrier at the center). The results from these simulations provide insight into the biocompatibility of host-1a or host-1b in microscopic detail. Based on this work, more research is needed to fully comprehend the role of these synthesized receptors as a prospective drug carrier.


Peak oxygen consumption during cardiopulmonary exercise test improves risk stratification in candidates to major lung resection.
The objective of this investigation was to assess the association of peak oxygen consumption (Vo(2)) with postoperative outcome in a prospective cohort of patients undergoing major lung resection for the treatment of lung cancer. Preoperative symptom-limited cardiopulmonary exercise testing (CPET) performed using cycle ergometry was conducted in 204 consecutive patients who had undergone pulmonary lobectomy or pneumonectomy. Peak Vo(2) was tested for possible association with postoperative cardiopulmonary complications and mortality. Logistic regression analysis, validated by a bootstrap analysis, was used to adjust for the effect of other perioperative factors. The role of peak Vo(2) in stratifying the surgical risk was further assessed in different groups of patients subdivided according to their cardiorespiratory status. Logistic regression showed that peak Vo(2) was an independent and reliable predictor of pulmonary complications (p = 0.04). All six deaths occurred in patients with a peak Vo(2) of < 20 mL/kg/min (four deaths in patients with a peak Vo(2) of < 12 mL/kg/min). The mortality rate in this high-risk group was 10-fold higher (4 of 30 patients; 13%) compared to those with higher peak Vo(2) (p = 0.006). Compared to patients with a peak Vo(2) of > 20 mL/kg/min, those with a peak Vo(2) of < 12 mL/kg/min had 5-fold, 8-fold, 5-fold, and 13-fold higher rates, respectively, of total cardiopulmonary complications pulmonary complications, cardiac complications, and mortality. The present study supports a more liberal use of CPET before lung resection compared to the current guidelines since this test can help in stratifying the surgical risk and optimizing perioperative care.


Myths about the proton. The nature of H+ in condensed media.
Recent research has taught us that most protonated species are decidedly not well represented by a simple proton addition. What is the actual nature of the hydrogen ion (the "proton") when H(+), HA, H2A(+), and so forth are written in formulas, chemical equations, and acid catalyzed reactions? In condensed media, H(+) must be solvated and is nearly always dicoordinate, as illustrated by isolable bisdiethyletherate salts having H(OEt2)2(+) cations and weakly coordinating anions. Even carbocations such as protonated alkenes have significant C-H···anion hydrogen bonding that gives the active protons two-coordinate character. Hydrogen bonding is everywhere, particularly when acids are involved. In contrast to the normal, asymmetric O-H···O hydrogen bonding found in water, ice, and proteins, short, strong, low-barrier (SSLB) H-bonding commonly appears when strong acids are present. Unusually low frequency IR νOHO bands are a good indicator of SSLB H-bonds, and curiously, bands associated with group vibrations near H(+) in low-barrier H-bonding often disappear from the IR spectrum. Writing H3O(+) (the Eigen ion), as often appears in textbooks, might seem more realistic than H(+) for an ionized acid in water. However, this, too, is an unrealistic description of H(aq)(+). The dihydrated H(+) in the H5O2(+) cation (the Zundel ion) gets somewhat closer but still fails to rationalize all the experimental and computational data on H(aq)(+). Researchers do not understand the broad swath of IR absorption from H(aq)(+), known as the "continuous broad absorption" (cba). Theory has not reproduced the cba, but it appears to be the signature of delocalized protons whose motion is faster than the IR time scale. What does this mean for reaction mechanisms involving H(aq)(+)? For the past decade, the carborane acid H(CHB11Cl11) has been the strongest known Brønsted acid. (It is now surpassed by the fluorinated analogue H(CHB11F11).) Carborane acids are strong enough to protonate alkanes at room temperature, giving H2 and carbocations. They protonate chloroalkanes to give dialkylchloronium ions, which decay to carbocations. By partially protonating an oxonium cation, they get as close to the fabled H4O(2+) ion as can be achieved outside of a computer.


Safer vesicant administration: improving communication across provider lines.
The administration of vesicant drugs involves nurses and physicians as stakeholders in providing safe patient care. Improving communication often is the first step to increasing the awareness and problem-solving for the patient care team.


Enhanced lithium storage performances of hierarchical hollow MoS₂ nanoparticles assembled from nanosheets.
MoS(2), because of its layered structure and high theoretical capacity, has been regarded as a potential candidate for electrode materials in lithium secondary batteries. But it suffers from the poor cycling stability and low rate capability. Here, hierarchical hollow nanoparticles of MoS(2) nanosheets with an increased interlayer distance are synthesized by a simple solvothermal reaction at a low temperature. The formation of hierarchical hollow nanoparticles is based on the intermediate, K(2)NaMoO(3)F(3), as a self-sacrificed template. These hollow nanoparticles exhibit a reversible capacity of 902 mA h g(-1) at 100 mA g(-1) after 80 cycles, much higher than the solid counterpart. At a current density of 1000 mA g(-1), the reversible capacity of the hierarchical hollow nanoparticles could be still maintained at 780 mAh g(-1). The enhanced lithium storage performances of the hierarchical hollow nanoparticles in reversible capacities, cycling stability and rate performances can be attributed to their hierarchical surface, hollow structure feature and increased layer distance of S-Mo-S. Hierarchical hollow nanoparticles as an ensemble of these features, could be applied to other electrode materials for the superior electrochemical performance.


Lactose intolerance in idiopathic ulcerative colitis in north Indians.
The incidence of lactose intolerance in 60 patients with idiopathic ulcerative colitis (IUC) from northern India and the effect of disease activity and extent of colonic involvement on the occurrence of lactose intolerance, was studied. Twenty controls matched for age and sex were also studied using 50 g lactose hydrogen breath test. The incidence of lactose intolerance in patients with IUC (41.7%) was no different from that in the control group (40%). There was however, a significant difference (P < 0.05) in the incidence of lactose intolerance in patients with active colitis (59.1%) as compared to those with quiescent disease (31.5%).


Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice.
Statins are effective cholesterol-lowering drugs to treat CVDs. Bile acids (BAs), the end products of cholesterol metabolism in the liver, are important nutrient and energy regulators. The present study aims to investigate how statins affect BA homeostasis in the enterohepatic circulation. Male C57BL/6 mice were treated with atorvastatin (100 mg/kg/day po) for 1 week, followed by BA profiling by ultra-performance LC-MS/MS. Atorvastatin decreased BA pool size, mainly due to less BA in the intestine. Surprisingly, atorvastatin did not alter total BAs in the serum or liver. Atorvastatin increased the ratio of 12α-OH/non12α-OH BAs. Atorvastatin increased the mRNAs of the BA-synthetic enzymes cholesterol 7α-hydroxylase (Cyp7a1) (over 10-fold) and cytochrome P450 27a1, the BA uptake transporters Na⁺/taurocholate cotransporting polypeptide and organic anion transporting polypeptide 1b2, and the efflux transporter multidrug resistance-associated protein 2 in the liver. Noticeably, atorvastatin suppressed the expression of BA nuclear receptor farnesoid X receptor (FXR) target genes, namely small heterodimer partner (liver) and fibroblast growth factor 15 (ileum). Furthermore, atorvastatin increased the mRNAs of the organic cation uptake transporter 1 and cholesterol efflux transporters Abcg5 and Abcg8 in the liver. The increased expression of BA-synthetic enzymes and BA transporters appear to be a compensatory response to maintain BA homeostasis after atorvastatin treatment. The Cyp7a1 induction by atorvastatin appears to be due to suppressed FXR signaling in both the liver and intestine.


Pathophysiological Role of Synovitis in Hemophilic Arthropathy Development: A Two-Hit Hypothesis.
Despite an increasing access to prophylaxis with clotting factor concentrates, arthropathy still represents the main chronic complication of hemophilia. Whereas previous studies described hemophilic arthropathy (HA) as a degenerative arthropathy, somehow resembling osteoarthritis (OA), most recent evidence suggests that complex inflammatory and immunologic mechanisms are also involved in the pathophysiology of HA. In the present review, we described available data on major mechanisms leading to arthropathic changes in patients with hemophilia, with a specific focus on the role of synovium. The presence of hemosiderin in the joint space induces synovium proliferation, thus leading to formation of several lytic enzymes determining chondrocytes apoptosis and proteoglycans levels reduction. This leads to a direct joint "chemical" damage representing early damages in the pathogenesis of HA (first hit). In parallel, synovial membrane and synovial endothelial cells become a dynamic reservoir of inflammatory cells and mediators, and propagate the inflammatory response (second hit), switching the process from a chemical damage to an inflammatory damage. Overall, consistent data pointed out synovitis as the keystone in HA pathophysiology. This opens novel potential therapeutic targets in this clinical setting.


Bracing superior to neuromuscular training for the prevention of self-reported recurrent ankle sprains: a three-arm randomised controlled trial.
Ankle sprain is the most common sports-related injury with a high rate of recurrence and associated costs. Recent studies have emphasised the effectiveness of both neuromuscular training and bracing for the secondary prevention of ankle sprains. To evaluate the effectiveness of combined bracing and neuromuscular training, or bracing alone, against the use of neuromuscular training on recurrences of ankle sprain after usual care. 384 athletes, aged 18-70, who had sustained a lateral ankle sprain, were included (training group n=120; brace group n=126; combi group n=138). The training group received an 8-week home-based neuromuscular training programme, the brace group received a semirigid ankle brace to be worn during all sports activities for 12 months, and the combi group received both the training programme, as well as the ankle brace, to be worn during all sports activities for 8 weeks. The main outcome measure was self-reported recurrence of the ankle sprain. During the 1-year follow-up, 69 participants (20%) reported a recurrent ankle sprain: 29 (27%) in the training group, 17 (15%) in the brace group and 23 (19%) in the combi group. The relative risk for a recurrent ankle sprain in the brace group versus the training group was 0.53 (95% CI 0.29 to 0.97). No significant differences were found for time losses or costs due to ankle sprains between the intervention groups. Bracing was superior to neuromuscular training in reducing the incidence but not the severity of self-reported recurrent ankle sprains after usual care.


Nanoparticles alloying in liquids: Laser-ablation-generated Ag or Pd nanoparticles and laser irradiation-induced AgPd nanoparticle alloying.
Laser irradiation of a mixture of single-element micro/nanomaterials may lead to their alloying and fabrication of multi-element structures. In addition to the laser induced alloying of particulates in the form of micro/nanopowders in ambient atmosphere (which forms the basis of the field of additive manufacturing technology), another interesting problem is the laser-induced alloying of a mixture of single-element nanoparticles in liquids since this process may lead to the direct fabrication of alloyed-nanoparticle colloidal solutions. In this work, bare-surface ligand-free Ag and Pd nanoparticles in solution were prepared by laser ablation of the corresponding bulk target materials, separately in water. The two solutions were mixed and the mixed solution was laser irradiated for different time durations in order to investigate the laser-induced nanoparticles alloying in liquid. Nanoparticles alloying and the formation of AgPd alloyed nanoparticles takes place with a decrease of the intensity of the surface-plasmon resonance peak of the Ag nanoparticles (at ∼405 nm) with the irradiation time while the low wavelength interband absorption peaks of either Ag or Pd nanoparticles remain unaffected by the irradiation for a time duration even as long as 30 min. The nanoalloys have lattice constants with values between those of the pure metals, which indicates that they consist of Ag and Pd in an approximately 1:1 ratio similar to the atomic composition of the starting mixed-nanoparticle solution. Formation of nanoparticle networks consisting of bimetallic alloyed nanoparticles and nanoparticles that remain as single elements (even after the end of the irradiation), joining together, are also formed. The binding energies of the 3d core electrons of both Ag and Pd nanoparticles shift to lower energies with the irradiation time, which is also a typical characteristic of AgPd alloyed nanoparticles. The mechanisms of nanoparticles alloying and network formation are also discussed.


Axo-axonic chandelier cells in the rat fascia dentata: Golgi-electron microscopy and immunocytochemical studies.
Synaptic transmission can be blocked very efficiently by inhibitory synapses on axon initial segments. Inhibitory chandelier cells forming synapses on the axon initial segment of pyramidal neurons have been found in the neocortex and hippocampus proper. Here we describe an axo-axonic local circuit neuron in the rat fascia dentata that establishes synaptic contacts with axon initial segments of numerous dentate granule cells. Examination of a large number of Golgi-impregnated nongranule cells in the fascia dentata of rats revealed a group of neurons with characteristics of chandelier cells. Thus these cells exhibited an extensive axonal plexus within the granular layer that characteristically formed vertical aggregations of axonal varicosities. The cell bodies of these neurons were located in the inner molecular layer or in the outer part of the granular layer. Their dendrites invaded the molecular layer, suggesting an afferent innervation similar to that of the granule cells. Well impregnated putative axo-axonic cells were gold-toned for an electron microscopic analysis. The cell bodies and dendrites of these neurons exhibited characteristic ultrastructural features of nongranule cells, i.e., large amounts of perinuclear cytoplasm, infoldings of the nuclear membrane, and a large number of synaptic contacts on the perikaryon and on the smooth dendritic shafts. The axon originating from the cell body or from a proximal dendrite gave rise to numerous vesicle-filled varicosities that almost exclusively formed symmetric synaptic contacts with axon initial segments. A semiquantitative study of five axonal complexes demonstrated that 92.3% of identified postsynaptic elements were initial segments of granule cell axons. Immunostaining with antibodies against glutamate decarboxylase (GAD) and parvalbumin (PARV) revealed a subpopulation of neurons that very much resembled the Golgi-impregnated axo-axonic cells with regard to cell body location, dendritic arborization, and fine structural characteristics of perikarya and dendrites. GAD and PARV were found to be coexistent in these cells. Moreover, we found GAD- and PARV-immunoreactive terminals in symmetric synaptic contact with axon initial segments of granule cells. The present study has shown a hitherto unknown axo-axonic cell in the rat fascia dentata. On the basis of our immunocytochemical findings, we hypothesize that this cell exerts a strong inhibitory effect on dentate granule cells. This way, signal transmission from the fascia dentata to the hippocampus proper within the "trisynaptic pathway" can efficiently be controlled by a group of highly specialized neurons.


Sex differences in myocardial remodeling and extracellular volume in aortic regurgitation.
Whether sex differences exist in the cardiac remodeling related to aortic regurgitation (AR) is unclear. Cardiac magnetic resonance (CMR) is the current non-invasive reference standard for cardiac remodeling assessment and can evaluate tissue characteristics. This prospective cohort included patients with AR undergoing CMR between 2011 and 2020. We excluded patients with confounding causes of remodeling. We quantified left ventricular (LV) volume, mass, AR severity, replacement fibrosis by late Gadolinium enhancement (LGE), and extracellular expansion by extracellular volume fraction (ECV). We studied 280 patients (109 women), median age 59.5 (47.2, 68.6) years (P for age = 0.25 between sexes). Women had smaller absolute LV volume and mass than men across the spectrum of regurgitation volume (RVol) (P ≤ 0.01). In patients with ≥ moderate AR and with adjustment for body surface area, indexed LV end-diastolic volume and mass were not significantly different between sexes (all P > 0.5) but men had larger indexed LV end systolic volume and lower LV ejection fraction (P ≥ 0.01). Women were more likely to have NYHA class II or greater symptoms than men but underwent surgery at a similar rate. Prevalence and extent of LGE was not significantly different between sexes or across RVol. Increasing RVol was independently associated with increasing ECV in women, but not in men (adjusted P for interaction = 0.03). In conclusion, women had lower LV volumes and mass than men across AR severity but their ECV increased with higher regurgitant volume, while ECV did not change in men. Indexing to body surface area did not fully correct for the cardiac remodeling differences between men and women. Women were more likely to have symptoms but underwent surgery at a similar rate to men. Further research is needed to determine if differences in ECV would translate to differences in the course of AR and outcomes.


[Overcoming of multidrug resistance by anti-P-glycoprotein monoclonal antibody].
P-glycoprotein is one of the key molecules in multidrug resistance. Monoclonal antibodies against P-glycoprotein could be useful tools for killing MDR tumor cells. To overcome multidrug resistance, many anti-P-glycoprotein monoclonal antibodies have been made such as MRK16 and MRK17. Conjugated moAb, such as bispecific antibody, immunotoxin and radioisotope conjugates have also been constructed to enhance the anti-tumor activity of moAb. Cytokine-gene transduction for accumulation and activation of monocytes may be hopeful to augment the therapeutic efficiency of anti-P-glycoprotein antibody. For clinical use, construction of human moAb, overcoming tumor heterogeneity, and protection of normal tissue by specifically targeting the tumor cells should be essential.


The Role of Sulfotransferases in Liver Diseases.
The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes that catalyze the transfer of a sulfonate group from the universal sulfate donor 3'-phosphoadenosine-5'-phosphosulfate to a nucleophilic group of their substrates to generate hydrophilic products. Sulfation has a major effect on the chemical and functional homeostasis of substrate chemicals. SULTs are widely expressed in metabolically active or hormonally responsive tissues, including the liver and many extrahepatic tissues. The expression of SULTs exhibits isoform-, tissue-, sex-, and development-specific regulations. SULTs display a broad range of substrates including xenobiotics and endobiotics. The expression of SULTs has been shown to be transcriptionally regulated by members of the nuclear receptor superfamily, such as the peroxisome proliferator-activated receptors, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, liver X receptors, farnesoid X receptor, retinoid-related orphan receptors, estrogen-related receptors, and hepatocyte nuclear factor 4α These nuclear receptors can be activated by numerous xenobiotics and endobiotics, such as fatty acids, bile acids, and oxysterols, many of which are substrates of SULTs. Due to their metabolism of xenobiotics and endobiotics, SULTs and their regulations are implicated in the pathogenesis of many diseases. This review is aimed to summarize the central role of major SULTs, including the SULT1 and SULT2 subfamilies, in the pathophysiology of liver and liver-related diseases. SIGNIFICANCE STATEMENT: Sulfotransferases (SULTs) are indispensable in the homeostasis of xenobiotics and endobiotics. Knowing SULTs and their regulations are implicated in human diseases, it is hoped that genetic or pharmacological manipulations of the expression and/or activity of SULTs can be used to affect the clinical outcome of diseases.


An outbreak of equine influenza virus in vaccinated horses in Italy is due to an H3N8 strain closely related to recent North American representatives of the Florida sub-lineage.
In December 2005, equine influenza virus infection was confirmed as the cause of clinical respiratory disease in vaccinated horses in Apulia, Italy. The infected horses had been vaccinated with a vaccine that contained strains representatives from both the European (A/eq/Suffolk/89) and American (A/eq/Newmarket/1/93) H3N8 influenza virus lineages, and the H7N7 strain A/eq/Praga/56. Genetic characterization of the hemagglutinin (HA) and neuraminidase (NA) genes of the virus from the outbreak, indicated that the isolate (A/eq/Bari/2005) was an H3N8 strain closely related to recent representatives (Kentucky/5/02-like) of the American sub-lineage Florida, that was introduced in Italy through movement of infected horses from a large outbreak described in 2003 in United Kingdom. Strain A/eq/Bari/2005 displayed 9 amino acid changes in the HA1 subunit protein with respect to the reference American strain A/eq/Newmarket/1/93 contained in the vaccine. Four changes were localized in the antigenic regions C-D and likely accounted for the vaccine failure.


The Role of High Dose Interleukin-2 in the Era of Targeted Therapy.
We assessed survival outcomes following high dose interleukin-2 in a contemporary cohort of patients during the era of targeted agents. We retrospectively reviewed the records of patients with metastatic renal cell carcinoma treated with high dose interleukin-2 between July 2007 and September 2014. Clinicopathological data were abstracted and patient response to therapy was based on RECIST (Response Evaluation Criteria In Solid Tumors), version 1.1 criteria. The Kaplan-Meier method was used to estimate progression-free and overall survival in the entire cohort, the response to high dose interleukin-2 in regard to previous targeted agent therapy and the response to the targeted agent in relation to the response to high dose interleukin-2. We identified 92 patients, of whom 87 had documentation of a response to high dose interleukin-2. Median overall survival was 34.4 months from the initiation of high dose interleukin-2 therapy in the entire cohort. Patients who received targeted therapy before high dose interleukin-2 had overall survival (median 34.4 and 30.0 months, p = 0.88) and progression-free survival (median 1.5 and 1.7 months, p = 0.8) similar to those in patients who received no prior therapy, respectively. Additionally, patients with a complete or partial response to high dose interleukin-2 had similar outcomes for subsequent targeted agents compared to patients whose best response was stable or progressive disease (median overall survival 30.1 vs 25.4 months, p = 0.4). Our data demonstrate that patient responses to high dose interleukin-2 and to targeted agents before and after receiving high dose interleukin-2 are independent. As such, carefully selected patients should be offered high dose interleukin-2 for the possibility of a complete and durable response without the fear of limiting the treatment benefit of targeted agents.


Trichloroethylene degradation by Ralstonia sp. KN1-10A constitutively expressing phenol hydroxylase: transformation products, NADH limitation, and product toxicity.
Ralstonia sp. KN1-10A, which was constructed by inserting the tac promoter upstream of the phenol hydroxylase (PH) gene in the chromosomal DNA of the wild-type strain, Ralstonia sp. KN1, is a useful recombinant strain for eliminating trichloroethylene (TCE) from contaminated sites because it exhibits constitutive TCE oxidation activity. During TCE degradation by Ralstonia sp. KN1-10A, noxious chlorinated compounds, such as dichloroacetic acid, trichloroacetic acid, 2,2,2-trichloroethanol, and chloral, were not detected, and more than 95% of chlorine in TCE was released as chloride ions. Among the possible TCE transformation products, only carbon monoxide was detected, and its conversion percentage was 7 mol%. The addition of formate, which Ralstonia sp. KN1-10A could use as an exogenous electron donor, did not enhance the TCE degradation performance, suggesting that NADH depletion did not limit the degradation. The phenol degradation activity of Ralstonia sp. KN1-10A that previously degraded TCE was not markedly lower than that of cells not exposed to TCE, suggesting that Ralstonia sp. KN1-10A was not susceptible to product toxicity associated with TCE degradation. Furthermore, to clarify the mechanisms underlying TCE degradation by PH from Ralstonia sp. KN1, this enzyme was compared with another enzyme, a hybrid aromatic ring dioxygenase exhibiting a high TCE degradation activity in Escherichia coli and Pseudomonas sp. The initial TCE degradation rate of Ralstonia sp. KN1 (pKTP100), which produced PH, was 1 50 lower than that of Ralstonia sp. KN1 (pKTF200), which produced the hybrid aromatic ring dioxygenase. However, because of its lower product toxicity, the strain producing PH could degrade 2.3 times more TCE than that generated by the strain producing the hybrid aromatic ring dioxygenase.


Huge mediastinal mass with minimal symptoms: thymolipoma.
A 35-year-old Indian working in Dubai had come to India for his annual vacation. He presented with a shortness of breath and mild chest discomfort of 3 months duration. Routine investigations gave normal results, except for his chest x-ray that showed homogenous opacity in the right mid and lower zones. Chest CT scan revealed a huge mass with fat and soft tissue involving the anterior mediastinum predominantly on the right side extending into the pericardiac region. The mass was pushing the right hemidiaphragm inferiorly and was compressing the right lung superiorly with atelectasis. The patient underwent surgical excision of the mass and recovered uneventfully. Gross specimen showed an encapsulated mass weighing 2.585 kg. Histopathological examination revealed lobules of mature adipose tissue interspersed with islands of mature thymic tissue and prominent Hassal's corpuscles suggesting thymolipoma. There was no evidence of malignancy.


Innate B cell helpers reveal novel types of antibody responses.
Antibody responses are classified according to whether B cells receive help from T cells--that is, whether they are thymus-dependent (TD) responses or thymus-independent (TI) responses. The latter can be elicited by microbial ligands (TI type 1) or by extensive crosslinking of the B cell antigen receptor (BCR; TI type 2). The hallmark of a TD response is the induction of germinal centers in which follicular helper T cells (T(FH) cells) select B cells with somatically mutated high-affinity BCRs to become memory cells. Studies have shown that B cells can also receive innate TD help from natural killer T cells (NKT cells) and innate TI help from cells such as neutrophils but that the outcome of such help differs from conventional TD and TI responses. Here we update the classification of antibody responses to take into account these emerging types of B cell helpers.


Test of nonequilibrium thermodynamics in glassy systems: the soft-sphere case.
The scaling properties of the soft-sphere potential allow the derivation of an exact expression for the pressure of a frozen liquid, i.e., the pressure corresponding to configurations which are local minima in its multidimensional potential energy landscape. The existence of such a relation offers the unique possibility for testing the recently proposed extension of the liquid free energy to glassy out-of-equilibrium conditions and the associated expression for the temperature of the configurational degrees of freedom. We demonstrate that the nonequilibrium free energy provides an exact description of the soft-sphere pressure in glass states.


Medication management in older persons: what can be achieved in the international community?
As the population ages worldwide, it is important to examine the challenges that are presented in the use of pharmaceutical treatments. This article comments on what is being done in the international community to promote rational use of medications and elimination of medication-related problems. Efforts are underway to identify elders at highest risk and to encourage communication and collaboration between the patient and the health care team, as well as collaboration among disciplines. Solutions to improve medication management are discussed, particularly those presented at a recent conference on Medication Management in Older Patients held under the aegis of the United Nations' International Institute on Ageing (INIA), Malta. These include evidence- based prescribing, interdisciplinary collaboration with increased clinical pharmacist involvement, and implementing programs that increase concordance between patient and health practitioner. Among the conference's conclusions is that more resources need to be allocated for medication management in the home arena.


HLA-DRB1 typing by micro-bead array assay identifies the origin of early lymphoproliferative disorder in a heart transplant recipient.
We report the case of a 68-year-old woman who underwent heart transplantation for hypertrophic cardiomyopathy. Two months after the transplant she developed mild fever and dyspnea with a marked drop in left ventricle ejection fraction of 31%. Coronary angiography was negative for cardiac allograft vasculopathy. Endomyocardial biopsy revealed ischemic damage with no evidence of acute cellular rejection, antibody-mediated rejection or viral myocarditis. A neoplastic process was suspected even though full-body computerized tomography was negative for malignancy. The patient died 4 months after transplantation. The autopsy showed acute antero-septal myocardial infarction due to a nodular epicardial EBV-related posttransplant lymphoproliferative disorder (PTLD) infiltrating the left anterior descending coronary artery with occlusive neoplastic thrombosis. We highlight two major aspects of this case: (1) the unusual occurrence of early PTLD involving the cardiac allograft and causing a fatal outcome, (2) the application of an immunological technique for HLA-DRB1 typing to posttransplant paraffin-embedded autopsy material to identify the recipient origin of this early malignancy, thus excluding a possible donor-transmitted neoplasm.


Influence of the Posterior Mandible Ridge Morphology on Virtual Implant Planning.
The purpose of this study was to examine the anatomy of the mandibular posterior region to develop an anatomical categorization for implant-prosthodontic planning. Using cone beam computed tomography scans, 313 cross-sectional views of edentulous posterior mandibular sites were evaluated with respect to the anatomical ridge morphology. Virtual implant planning was performed, and the need for bone grafting was assessed. The level of complexity for planning implants in those positions was assessed. Sites were classified as straightforward, advanced, or complex sites based on the need for bone grafting. Five well-defined cross-sectional configurations were observed: straight (53.6%), oblique (26.2%), s-shape (7.4%), hourglass shape (1.9%), and basal bone (10.8%). There was a statistically significant association between the ridge shape and the feasibility of placing an implant with or without bone grafting; the straight and oblique ridge shapes were more likely to be associated with a favorable anatomy for implant placement. The ridge shape significantly influenced the ease or difficulty of placing an implant. The s-shape, hourglass, and basal bone posterior mandibular cross-sectional shapes were associated with a higher degree of difficulty.


Administration of recombinant enkephalinase (neutral endopeptidase) prevents capsaicin-induced miosis in the rabbit eye in vivo.
Substance P induced a dose-dependent contraction of iris sphincter muscles when applied in the presence of atropine to the isolated rabbit iris in vitro as evidenced by a decreased pupil diameter. Pretreatment of the iris with 20 micrograms of recombinant enkephalinase (neutral endopeptidase; EC 220.127.116.11) totally abolished the contractile response to substance P. Injection of 10 micrograms of capsaicin into the anterior chamber of atropine-treated rabbit eyes in vivo induced an immediate and intense miosis. Injection of 100 micrograms of recombinant enkephalinase, 1 or 5 min before capsaicin injection, significantly inhibited this miosis. This effect of enkephalinase was totally abolished by preincubating the enzyme with thiorphan, a high-affinity enkephalinase inhibitor. These results show that enkephalinase, which is known to hydrolyze substance P in vitro with high efficiency, also hydrolyzes endogenously released substance P in vivo. Furthermore, our results suggest that enkephalinase application may represent a novel therapeutic approach to treat substance P-mediated pathologies.


Study on the cross-flow ultrafiltration of mixtures of macromolecular organic and inorganic salts.
Ultrafiltration (UF) has been widely applied to water treatment in the past few decades, but severe membrane fouling is one of the most significant obstacles for its further development. In reality, the constituents of feed water are complex, and the fouling behavior could be different from that induced by a single foulant. In this study, the membrane fouling induced by mixed organic foulant (sodium alginate, SA) and inorganic ions under various conditions were investigated. The effects of ion concentration and valence on the combined fouling as well as the rejection performance were examined. The results showed that compared to SA alone, the presence of inorganic ions could aggravate the organic fouling of UF membranes significantly. The fouling became more severe as the ion concentration increased. Also, ions with higher valence tended to exacerbate the fouling compared with monovalent ions. It was also found that the existence of inorganic ions had negligible effects on the rejection of organic molecules, however, the rejection of salts can be improved because of the organic matter. In addition, the analysis of the classic fouling models showed that the complete blocking model is the main fouling mechanism of the mixed SA and inorganic salts.


The predictive value of radiomics-based machine learning for peritoneal metastasis in gastric cancer patients: a systematic review and meta-analysis.
For patients with gastric cancer (GC), effective preoperative identification of peritoneal metastasis (PM) remains a severe challenge in clinical practice. Regrettably, effective early identification tools are still lacking up to now. With the popularization and application of radiomics method in tumor management, some researchers try to introduce it into the early identification of PM in patients with GC. However, due to the complexity of radiomics, the value of radiomics method in the early identification of PM in GC patients remains controversial. Therefore, this systematic review was conducted to explore the feasibility of radiomics in the early identification of PM in GC patients. PubMed, Cochrane, Embase and the Web of Science were comprehensively and systematically searched up to 25 July, 2022 (CRD42022350512). The quality of the included studies was assessed using the radiomics quality score (RQS). To discuss the superiority in diagnostic accuracy of radiomics-based machine learning, a subgroup analysis was performed by machine learning (ML) based on clinical features, radiomics features, and radiomics + clinical features. Finally, 11 eligible original studies covering 78 models were included in this systematic review. According to the meta-analysis, the radiomics + clinical features model had a c-index of 0.919 (95% CI: 0.871-0.969), pooled sensitivity and specificity of 0.90 (0.83-0.94) and 0.87 (0.78-0.92), respectively, in the training set, and a c- index of 0.910 (95% CI: 0.886-0.934), pooled sensitivity and specificity of 0.78 (0.71-0.84) and 0.83 (0.74-0.89), respectively, in the validation set. The ML methods based on radiomics + clinical features had satisfactory accuracy for the early diagnosis of PM in GC patients, and can be used as an auxiliary diagnostic tool for clinicians. However, the lack of guidelines for the proper operation of radiomics has led to the diversification of radiomics methods, which seems to limit the development of radiomics. Even so, the clinical application value of radiomics cannot be ignored. The standardization of radiomics research is required in the future for the wider application of radiomics by developing intelligent tools of radiomics. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=350512, identifier CRD42022350512.


Regenerative dentistry: translating advancements in basic science research to the dental practice.
Scientific advances in the creation of restorative biomaterials, in vitro cell culture technology, tissue engineering, molecular biology and the human genome project provide the basis for the introduction of new technologies into dentistry. This review provides an assessment of how tissue engineering, stem cell, genetic transfer, biomaterial and growth factor therapies can be integrated into clinical dental therapies to restore and regenerate oral tissues. In parallel to the creation of a new field in general medicine called "regenerative medicine," we call this field "regenerative dentistry." While the problems of introducing regenerative therapies are substantial, the potential benefits to patients and the profession are equally ground-breaking. In this review, we outline a few areas of interest for the future of oral and dental medicine in which advancements in basic science have already been adapted to fit the goals of 21st century dentistry.


Concentration-dependent dissociation of factor VIII in 1 M NaCl.
Plasma, cryoprecipitate, Hemofil, and human factor VIII concentrate were dissolved in 1.0 M NaCl and chromatographed on Bio-Gel A-5m. With high concentrations of factor VIII the activity eluted as a symmetrical peak in the void volume; with a low factor VIII concentration the procoagulant activity was retarded. Dilution curves were performed for several human factor VIII concentrates. When the concentration of factor VIII was decreased, elution patterns showed a gradual transition from a peak in the void volume to a peak with a Ve/Vo of 1.7. Cryoprecipitate exhibited a similar behavior in 1.0 M NaCl, but the percent dissociation was greater than expected at high concentrations of factor VIII. When gel filtration was performed with 0.25 M CaCl2, significant dissociation occurred at all concentrations of factor VIII tested. The behavior of factor VIII in 1.0 M NaCl closely fit a theoretically derived curve for the dissociation of a protein from its binder. We conclude that the dissociation of factor VIII in 1 M NaCl is dependent on the concentration and purification of the procoagulant protein.


Fluorometric detection of EGFR exon 19 deletion mutation in lung cancer cells using graphene oxide.
Mutations in epidermal growth factor receptor (EGFR) are known as biomarkers that cause non-small cell lung cancer. Particularly, approximately 45% of non-small cell lung cancer patients possess a deletion in exon 19 of the EGFR gene. A less invasive method for detecting the EGFR mutation is required; thus, we developed a simple polymerase chain reaction (PCR)-based method for detecting EGFR exon 19 deletion by using a quencher-free fluorescent probe DNA and graphene oxide (GO). In the presence of the exon 19 deletion mutation, the fluorophore-labeled DNA probe was designed to be fully complementary to the mutant sequences. The fully annealed DNA probe was degraded by the 5' to 3' exonuclease activity of Taq DNA polymerase during PCR, releasing the fluorophore from the probe DNA. In contrast, a wild-type gene only allowed partial annealing of the probe DNA to the amplicon because of the absence of the deletion sequences, with Taq polymerase digestion releasing unannealed fragments of probe DNA. When GO was added to each reaction solution, starkly different fluorescence signals were obtained; enhanced fluorescence was observed because of the released fluorophore from the probe DNA that was not adsorbed onto GO, whereas fluorescence was quenched when the fragmented single-stranded probe DNA was readily adsorbed onto GO. Our method enabled the detection of as low as 49 pg of EGFR exon 19 deletion DNA with a detection limit of 0.1% when the mutant genomic DNA was mixed with wild-type DNA.


isiXhosa translation of the Patient Health Questionnaire (PHQ-9) shows satisfactory psychometric properties for the measurement of depressive symptoms [Stage 2].
Depression is a debilitating illness, and stigma associated with it often prevents people from seeking support. Easy-to-administer and culturally- inclusive tools can allow for early screening for depressive symptoms in primary care clinics, especially in resource-limited settings. In this pre-registered pilot study (Stage 1 Report available at DOI: 10.3389/fpsyt.2022.840912), we produced an open-access isiXhosa-language version of the nine-item Patient Health Questionnaire (PHQ-9), a well-validated measure of depression incidence and severity, using a transcultural translation framework. We validated this isiXhosa PHQ-9 in a sample of N = 47 adolescents living with and without HIV in Cape Town, South Africa who speak isiXhosa at home. Reliability, convergent validity, and criterion validity were assessed, with T scores on the Achenbach System of Empirically Based Assessment Youth Self Report (YSR) form completed previously as reference standard. Our isiXhosa PHQ-9 exhibited satisfactory reliability, with Cronbach's α=0.866, inter-item correlations ranging from 0.229 to 0.730, and mean item-total correlation of 0.69. PHQ-9 score and Withdrawn/Depressed component T scores on the Youth Self Report were moderately associated (Spearman's ρ=0.40,p=0.011), indicating acceptable convergent validity. The isiXhosa PHQ-9 showed satisfactory criterion validity (area under the receiver operating characteristic curve, AUC = 0.706), but these analyses were under-powered. Principal component analysis revealed a one-factor solution, with 45.8% of variance explained by the first principal component and all factor loadings above conventional thresholds. Our isiXhosa translation of the PHQ-9 thus exhibited satisfactory psychometric properties in this pilot validation study and performed comparably to other PHQ-9 versions validated in different languages in African and global contexts. This questionnaire may serve as an invaluable culturally-inclusive screening tool for measuring depressive symptoms among isiXhosa speakers. Caution must be exercised as screening tools including the PHQ-9 may over- or under-estimate prevalence of depression. Further validation in larger, independent cohorts may enable wider use of our isiXhosa PHQ-9 as a screening tool in clinics, research studies, and mental health non-profits who serve amaXhosa.


Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as "clinically relevant" variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.


Inhibitory effect of 3-hydroxybenzo(a)pyrene on the mutagenicity and tumorigenicity of (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene.
The 12 isomeric phenols of benzo(a)pyrene were tested for their ability to inhibit the mutagenic activity of (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene [B(a)P 7,8-diol-9,10-epoxide-2], an ultimate mutagenic and carcinogenic metabolite of benzo(a)pyrene. 3-Hydroxybenzo(a)pyrene [3-HO-B(a)P], a major metabolite of benzo(a)pyrene, was the most potent antagonist tested. Approximately 3 nmol of 3-HO-B(a)P, 14 nmol of 10-HO-B(a)P, and 5-8 nmol of 1-, 2-, 4-, 5-, 6-, 7-, 8-, 9-, 11-, and 12-HO-B(a)P inhibited the mutagenic activity of 0.05 nmol of B(a)P 7,8-diol-9,10-epoxide-2 by 50% in Salmonella typhimurium strain TA 100. The importance of the phenolic group for antimutagenic activity was indicated by the lack of antimutagenic activity of benzo(a)pyrene itself. 3-HO-B(a)P also inhibited the mutagenic activity resulting from the metabolic activation of benzo(a)pyrene and (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene by rat liver microsomes. This inhibition may have resulted from an effect of 3-HO-B(a)P on the metabolic activation of these carcinogens and/or from a direct effect on the action of B(a)P 7,8-diol-9,10-epoxide-2. In a mammalian cell culture system utilizing Chinese hamster V79 cells, 3-HO-B(a)P (8 microM) inhibited the mutagenicity of B(a)P 7,8-diol-9,10-epoxide-2 (0.2 microM) by 50%. Although 3-HO-B(a)P was a potent inhibitor of the mutagenic activity of bay-region diol epoxides of benzo(a)pyrene, dibenzo(a,h)pyrene, and dibenzo(a,i)pyrene in S. typhimurium strain TA 100, higher concentrations of 3-HO-B(a)P were needed to inhibit the mutagenicity of the chemically less reactive benzo(a)pyrene 4,5-oxide and the bay-region diol epoxides of benz(a)anthracene, chrysene, and benzo(c)phenanthrene. Both 3-HO-B(a)P and 10-HO-B(a)P accelerated the disappearance of B(a)P 7,8-diol-9,10-epoxide-2 from 1:9 dioxane-water solutions at pH 7 and 25 degrees C. 3-HO-B(a)P, the most effective antimutagen of the B(a)P phenols tested, was much more reactive with the diol epoxide than 10-HO-B(a)P, the least effective antimutagen. The rate constant for the reaction of 3-HO-B(a)P with the diol epoxide exhibited a nonlinear (greater than first-order) dependence on the concentration of the phenol. Evidence was obtained for covalent adduct formation between the diol epoxide and each of the two phenols.(ABSTRACT TRUNCATED AT 400 WORDS)


Peaks of endogenous G-CSF serum concentrations are followed by an increase in respiratory burst activity of granulocytes in patients with septic shock.
The relationship between peaks of G-CSF serum concentrations and respiratory burst activity of polymorphonuclear cells (PMN) was investigated in patients with postoperative or post-traumatic severe sepsis and septic shock. Over a 12 month period, a longitudinal analysis of G-CSF, TNF-alpha and IFN-gamma serum concentrations, burst activity of PMN, and expression of CD64 on the surface of PMN, were performed by ELISA technique and flow cytometric analysis, respectively, in 58 patients admitted to the intensive care unit (ICU) on a daily basis until discharge from the ICU or death. Out of these 58 patients, 27 with proven infections were in septic shock for at least 4 days' duration. Seventeen of these patients survived, whereas ten died. In 15 out of these 27 patients, 26 episodes of G-CSF peaks were observed, which were followed in most patients (13/15) by an increase in PMN burst activity, from 28% up to 540% (median 188%). Following the G-CSF peaks, CD64 expression on PMN remained at an increased level, followed by a marked decline 3 days later. TNF-alpha serum concentrations were elevated in most episodes (22/26), whereas IFN-gamma serum concentrations were below the detection level in 23/26 episodes. Taken together, peaks in G-CSF serum concentrations are followed by enhanced CD64 expression and increased burst activity of PMN in most patients with severe sepsis and septic shock. Thus, endogenous G-CSF increases neutrophil function in patients with severe sepsis and septic shock, necessary for resolution of bacterial infections in these patients.


Modification of transcriptional activity induced by protein synthesis inhibitors in salivary gland cells of Chironomus thummi.
Uridine incorporation in salivary gland cells of Chironomus thummi may be increased by short treatments with cycloheximide, anisomycin or emetine. Accordingly, the rate of UTP incorporation in drug pre-treated permeabilized glands is higher than in control glands. Electrophoretical analyses indicate that when the aforementioned inhibitors are given to whole larvae, the synthesis of glandular giant-heterogeneous RNA and, to a higher extent, that of low molecular weight (4-5S) RNA, are enhanced, while nucleolar 38S pre-rRNA synthesis is generally depressed. On the contrary, when the inhibitors are directly applied to excised glands, the the synthesis of all RNAs, including the pre-ribosomal one, is higher than in control glands. These results suggest that the transcription of various RNA species in polytene cells of C. thummi appears to be specifically regulated by mechanisms in which newly synthesized proteins are involved. In addition, the response of nucleolar genes transcription to treatments with protein synthesis inhibitors seems to be dependent on the environmental conditions of the glands.


First seizure presentation: do multiple seizures within 24 hours predict recurrence?
We compared clinical features and prognosis of 72 adults with a first-ever seizure presentation comprising multiple discrete seizures within 24 hours to 425 patients presenting with a single seizure. Those presenting with multiple seizures were no more likely to have seizure recurrence, irrespective of etiology or treatment. Hence, a presentation with multiple seizures within 24 hours should be regarded as a single event, in keeping with the International League Against Epilepsy recommendations.


A double-blind controlled clinical trial to assess the role of anti-histamines in the treatment of multi-bacillary leprosy.
A double blind controlled clinical trial to assess the role of anti-histamines as a supplement in the treatment of leprosy was conducted in multi-bacillary cases of leprosy. In all, 120 patients with lepromatous or borderline leprosy were randomly allocated to a regimen of clofazimine and dapsone for 12 months with or without a supplement of pheniramine maleate for the first 3 months. During the 12-month period, 92% of the patients who received the supplement and 86% of the patients who had not received it had moderate or marked clinical improvement. The BI values decreased from 4.1 to 3.4 and 4.2 to 3.3, respectively. The results over the 12-month period showed that the addition of the antihistamine had not enhanced the efficacy of the regimen as evidenced by clinical and bacteriological findings.


A multivariate Box-Behnken assessment of elevated branched-chain amino acid concentrations in reduced crude protein diets offered to male broiler chickens.
In a Box-Behnken assessment of elevated branched-chain amino acids (BCAA), 13 nutritionally equivalent maize-based diets were offered to a total of 390 off-sex male Ross 308 broiler chickens from 7 to 28 days post-hatch. The BCAA concentrations investigated in reduced-crude protein diets were 12.5, 15.5, 18.3 g/kg leucine (125, 155, 183); 8.9, 10.2, 12.5 g/kg valine (89, 102, 125) and 7.2, 8.9, 10.8 g/kg isoleucine (72, 89, 109), where their relativity to 11.0 g/kg digestible lysine are shown in parentheses. Determined parameters included growth performance, relative abdominal fat-pad weights, nutrient utilisation, apparent digestibility coefficients, disappearance rates of 16 amino acids and free amino acid systemic plasma concentrations. Increasing dietary leucine linearly depressed weight gain and quadratically influenced FCR where the estimated minimum FCR of 1.418 was with 14.99 g/kg leucine. Polynomial regression analysis and surface response curves of determined parameters were generated for significant (P < 0.05) BCAA variables, based on lack of fit (P > 0.005). Quadratic and cross-product responses were observed for weight gain, FCR, AME, AMEn, N retention and apparent digestibility of 13 amino acids. Relative fat-pad weights declined linearly with increasing isoleucine and valine. The lowest N retention was estimated at a combination of 15.25 and 10.50 g/kg leucine and valine respectively whilst the highest mean digestibility coefficient (0.793) of amino acids was estimated at a combination of 15.74 and 10.47 g/kg of leucine and valine respectively. The remaining parameter minima or maxima responses were not able to be determined since they were outside the extreme BCAA treatment levels. Increasing dietary BCAA significantly increased apparent ileal digestibilities and disappearance rates of BCAA. Systemic plasma concentrations of valine increased (P < 0.001) with increasing dietary valine but leucine was not influenced (P > 0.25). Systemic plasma concentration of isoleucine was maximised (P < 0.001) only when accompanied by elevated dietary leucine. Also, dietary treatments influenced (P < 0.05) apparent disappearance rates of all the essential amino acids analysed, with the exception of methionine. Whilst overall growth performance was not disadvantaged (P > 0.10) by elevated BCAA levels, compared with 2019 Ross 308 performance objectives, polynomial regression analysis suggested both interaction and antagonism between BCAA.


Professional caregivers' perceived barriers hindering the prevention and reduction of involuntary treatment among older persons receiving long-term care: A mixed methods study.
To gain insights into the barriers towards the prevention and/or reduction of involuntary treatment in long-term geriatric care. Mixed methods. Measures to which a person resists and/or does not provide consent for are defined as involuntary treatment. The use of involuntary treatment violates the autonomy of (older) persons and causes more harm than benefit. Moreover, it contradicts the values of person-centred care. Nevertheless, its use among people living with dementia (PLWD) is still common practice. We conducted a cross-sectional, mixed methods study, including an online survey for professional caregivers and a semistructured focus group interview with professional caregivers. A total of 218 participants completed the questionnaire. The percentage of participants who perceived barriers in one of the 22 survey items ranged from 15% to 42%. Lack of time, the experienced need to use involuntary treatment, uncertainty about responsibilities of stakeholders and a lack of knowledge on methods to prevent and/or reduce the use of involuntary treatment were most seen as barriers. Nursing staff perceived a lack of time hindering them in the prevention or reduction of involuntary treatment more often than other professional caregivers. Working in home care and having no former experience with involuntary treatment usage increased perceived barriers. Participants of the focus group interview confirmed these findings and added that professional caregivers in general lack awareness on the concept of involuntary treatment. One out of four professional caregivers experiences barriers hindering prevention and/or reduction of involuntary treatment. More research is needed to gain a better understanding of how professional caregivers can be supported to remove barriers and, consequently, prevent and/or reduce the use of involuntary treatment. Professional caregivers experience many barriers towards the prevention and reduction of involuntary treatment. Future initiatives should aim to remove the perceived barriers.


Gadoxetic acid-enhanced MRI combined with T1 mapping and clinical factors to predict Ki-67 expression of hepatocellular carcinoma.
To explore the predictive value of gadoxetic acid-enhanced magnetic resonance imaging (MRI) combined with T1 mapping and clinical factors for Ki-67 expression in hepatocellular carcinoma (HCC). A retrospective study was conducted on 185 patients with pathologically confirmed solitary HCC from two institutions. All patients underwent preoperative T1 mapping on gadoxetic acid-enhanced MRI. Patients from institution I (n = 124) and institution II (n = 61) were respectively assigned to the training and validation sets. Univariable and multivariable analyses were performed to assess the correlation of clinico-radiological factors with Ki-67 labeling index (LI). Based on the significant factors, a predictive nomogram was developed and validated for Ki-67 LI. The performance of the nomogram was evaluated on the basis of its calibration, discrimination, and clinical utility. Multivariable analysis showed that alpha-fetoprotein (AFP) levels > 20ng/mL, neutrophils to lymphocyte ratio > 2.25, non-smooth margin, tumor-to-liver signal intensity ratio in the hepatobiliary phase ≤ 0.6, and post-contrast T1 relaxation time > 705 msec were the independent predictors of Ki-67 LI. The nomogram based on these variables showed the best predictive performance with area under the receiver operator characteristic curve (AUROC) 0.899, area under the precision-recall curve (AUPRC) 0.946 and F1 score of 0.912; the respective values were 0.823, 0.879 and 0.857 in the validation set. The Kaplan-Meier curves illustrated that the cumulative recurrence probability at 2 years was significantly higher in patients with high Ki-67 LI than in those with low Ki-67 LI (39.6% [53/134] vs. 19.6% [10/51], p = 0.011). Gadoxetic acid-enhanced MRI combined with T1 mapping and several clinical factors can preoperatively predict Ki-67 LI with high accuracy, and thus enable risk stratification and personalized treatment of HCC patients.


Effects of sleeve gastrectomy on lipid and energy metabolism in ZDF rats via PI3K/AKT pathway.
Sleeve Gastrectomy (SG), as the most effective bariatric surgery, has been using to chronically lose weight and control glucose metabolism in Type 2 diabetes mellitus patients. However, the underlining mechanism is still unclear. In this study, we performed SG on Zucker diabetes fatty (ZDF) rat and investigated visceral lipid metabolism and energy metabolism. After performance of SG, weight, food intake, fasting plasma glucose (FPG) and oral glucose tolerance teat (OGTT) of rats were measured. Furthermore, whole-body metabolic parameters were obtained through TSE LabMaster. Blood lipid and renal function were analyzed by serum from rats' tail vein. Furthermore, the renal genes expression was either detected by real-time PCR, while western blotting was employed to detect the AKT/PI3K proteins level in rats' kidney. Compared to control groups, body weight of ZDF rats treated with SG were significantly reduced, simultaneously with glucose homeostasis and energy metabolism improved including RER (P<0.05), energy expenditure (P<0.05) at night and activity of animal. Meanwhile, serum lipid of ZDF rats after SG was decreased, and renal function recovered. Histology analysis confirmed that the size of perirenal adipose from SD treated ZDF rats obviously decreased (P<0.001), effectively stimulating up-regulation of lipogenesis genes (P<0.05), while adipogenesis genes (P<0.05) in kidney was down-regulated. In addition, phosphorylation of PI3K (p-PI3K) and AKT (p-AKT) in rats kidney were significantly decreased in SG group (P<0.05). Weight loss, food intake, fasting plasma glucose and glucose tolerance in SG surgery rats were improved, which were coincident with energy metabolism changes. In conclusion, SG improves lipid and energy metabolism in ZDF rats model due to activating PI3K/Akt signaling pathway, which was contributed to the mechanism of bariatric surgery toward kidney.


The Impact of Oxidative Stress Factors on the Viability, Senescence, and Methylation Status of Olfactory Bulb-Derived Glial Cells Isolated from Human Cadaver Donors.
The olfactory bulb (OB) is a unique structure in the central nervous system that retains the ability to create new neuronal connections. Glial cells isolated from the OB have been recently considered as a novel and promising tool to establish an effective therapy for central nervous system injuries. Due to the hindered access to autologous tissue for cell isolation, an allogeneic source of tissues obtained postmortem has been proposed. In this study, we focused on the morphological and molecular characteristics of human OB-derived glial cells isolated postmortem, at different time points after a donor's death. We evaluated the proliferative activity of the isolated cells, and investigated the ultrastructure of the mitochondria, the accumulation of intracellular reactive oxygen species, and the activity of superoxide dismutase. The data obtained clearly indicate that the duration of ischemia is crucial for the viability/senescence rate of OB-derived glial cells. The OB can be isolated during autopsy and still stand as a source of viable glial cells, but ischemia duration is a major factor limiting its potential usefulness in therapies.


The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function.
Vitamin B6 is a water-soluble vitamin that functions as a coenzyme in many reactions involved in amino acid, carbohydrates and lipid metabolism. Since 2014, >50 cases of sensory neuronal pain due to vitamin B6 supplementation were reported. Up to now, the mechanism of this toxicity is enigmatic and the contribution of the various B6 vitamers to this toxicity is largely unknown. In the present study, the neurotoxicity of the different forms of vitamin B6 is tested on SHSY5Y and CaCo-2 cells. Cells were exposed to pyridoxine, pyridoxamine, pyridoxal, pyridoxal-5-phosphate or pyridoxamine-5-phosphate for 24h, after which cell viability was measured using the MTT assay. The expression of Bax and caspase-8 was tested after the 24h exposure. The effect of the vitamers on two pyridoxal-5-phosphate dependent enzymes was also tested. Pyridoxine induced cell death in a concentration-dependent way in SHSY5Y cells. The other vitamers did not affect cell viability. Pyridoxine significantly increased the expression of Bax and caspase-8. Moreover, both pyridoxal-5-phosphate dependent enzymes were inhibited by pyridoxine. In conclusion, the present study indicates that the neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to pyridoxine. The inactive form pyridoxine competitively inhibits the active pyridoxal-5'-phosphate. Consequently, symptoms of vitamin B6 supplementation are similar to those of vitamin B6 deficiency.


Class IIa bacteriocins from lactic acid bacteria: antibacterial activity and food preservation.
In the last decade, a variety of ribosomally synthesized antimicrobial peptides, or bacteriocins, produced by lactic acid bacteria have been identified and characterized. As a result of these studies, insight has been gained into various fundamental aspects of biology and biochemistry such as bacteriocin processing and secretion, mechanisms of cell immunity, and structure-function relationships. In parallel, there has been a growing awareness that bacteriocins may be developed into useful antimicrobial food additives. Class IIa bacteriocins can be considered as the major subgroup of bacteriocins from lactic acid bacteria, not only because of their large number, but also because of their significant biological activities and potential applications. The present review provides an overview of the knowledge available for class IIa bacteriocins and discusses common features and recent findings concerning these substances. The activity and potential food applications of class IIa bacteriocins are a major focus of this review.


Genome-Wide Association Studies in Diverse Spring Wheat Panel for Stripe, Stem, and Leaf Rust Resistance.
Among several important wheat foliar diseases, Stripe rust (YR), Leaf rust (LR), and Stem rust (SR) have always been an issue of concern to the farmers and wheat breeders. Evolution of virulent pathotypes of these rusts has posed frequent threats to an epidemic. Pyramiding rust-resistant genes are the most economical and environment-friendly approach in postponing this inevitable threat. To achieve durable long term resistance against the three rusts, an attempt in this study was made searching for novel sources of resistant alleles in a panel of 483 spring wheat genotypes. This is a unique and comprehensive study where evaluation of a diverse panel comprising wheat germplasm from various categories and adapted to different wheat agro-climatic zones was challenged with 18 pathotypes of the three rusts with simultaneous screening in field conditions. The panel was genotyped using 35K SNP array and evaluated for each rust at two locations for two consecutive crop seasons. High heritability estimates of disease response were observed between environments for each rust type. A significant effect of population structure in the panel was visible in the disease response. Using a compressed mixed linear model approach, 25 genomic regions were found associated with resistance for at least two rusts. Out of these, seven were associated with all the three rusts on chromosome groups 1 and 6 along with 2B. For resistance against YR, LR, and SR, there were 16, 18, and 27 QTL (quantitative trait loci) identified respectively, associated at least in two out of four environments. Several of these regions got annotated with resistance associated genes viz. NB-LRR, E3-ubiquitin protein ligase, ABC transporter protein, etc. Alien introgressed (on 1B and 3D) and pleiotropic (on 7D) resistance genes were captured in seedling and adult plant disease responses, respectively. The present study demonstrates the use of genome-wide association for identification of a large number of favorable alleles for leaf, stripe, and stem rust resistance for broadening the genetic base. Quick conversion of these QTL into user-friendly markers will accelerate the deployment of these resistance loci in wheat breeding programs.


Health-related quality of life (HRQoL) and its correlates among community-recruited children living with HIV and uninfected children born to HIV-infected parents in West Bengal, India.
Helping children living with HIV (CLH) to attain an optimum quality of life is an important goal for HIV programs around the world. Our principal objectives were to determine the association of HIV infection with different domains of health-related quality of life (HRQoL) among 8- to 15-year-old CLH in India and to compare the HRQoL parameters between CLH and HIV-negative children born to HIV-infected parents ("HIV-affected"). We also assessed whether antiretroviral therapy (ART) and CD4 lymphocyte counts were associated with HRQoL among CLH. Using the "Quality of Life (health-related) of Children Living with HIV/AIDS in India" instrument, we interviewed 199 CLH and 194 HIV-affected children from three districts of West Bengal, India. Participants were asked to quantify the difficulties faced by them in six HRQoL domains: physical, emotional, social, school functioning, symptoms, and discrimination. The mean age of the participants was 11.6 (SD ± 2.5) years. CLH, compared to HIV-affected children, had poorer scores on all HRQoL domains except 'discrimination.' Among CLH, there were no significant differences in HRQoL domain scores (except in the 'discrimination' domain) between ART-treated and -untreated groups. CD4 lymphocyte count was found to be a significant positive predictor of the 'symptom' scale score. In India, interventions for CLH mostly focus on biological disease. However, the current study revealed that HRQoL among CLH was much poorer than that of a socio-demographically comparable group. Culturally and developmentally appropriate psychosocial support measures for Indian CLH are urgently needed.


Detection of apoptosis by electron microscopy and in situ labelling in the rat olfactory pit.
The purpose of this study was to provide further information upon the cell death process by apoptosis occurring in the olfactory pit during the primary palate formation and the vomeronasal organ detachment. Apoptotic cells were detected by coupling ultrastructural observations and in situ end-labelling of DNA breaks (TUNEL labelling) in E12-E15 rat embryos. During the primary palate formation and the vomeronasal organ closure, a strong apoptotic cell death process was observed along the midline epithelial seam after the epithelial fusion. The topographical distribution of labelled nuclei was in agreement with the morphological distribution of dying cells. One day before the nasal swellings fused, numerous degenerating cells were also detected in the regions of prospective contact which thus appeared as regions of programmed cell death.


Trends in Quit Attempts Among Adult Cigarette Smokers - United States, 2001-2013.
What is already known on this topic? Quitting smoking is beneficial to health at any age, and cigarette smokers who quit before age 35 years have mortality rates similar to those of persons who never smoked. What is added by this report?During 2001–2010, the proportion of adult cigarette smokers who had made a quit attempt in the past year increased significantly in 29 states and the U.S. Virgin Islands. During 2011–2013, the proportion who had made a quit attempt increased in Hawaii and Puerto Rico and decreased in New Mexico. In 2013, the proportion who had made a quit attempt ranged from 56.2% (Kentucky) to 76.4% (Puerto Rico and Guam) with a median of 65.9%, and was generally lower in older age groups. What are the implications for public health practice? Continued implementation of effective evidence-based public health interventions can reduce the health and costs impacts of smoking-related disease and death and accelerate progress toward meeting the Healthy People 2020 target to increase to ≥80% the proportion of U.S. adult cigarette smokers who made a quit attempt in the past year. These interventions include increasing the price of tobacco products, implementing comprehensive smoke-free laws, conducting educational mass media campaigns, and providing insurance coverage for all effective cessation treatments as well as access to quitlines.


Xenotransplantation: state of the art.
Today, at the beginning of the xenogeneic era of transplantation, only simple and single observations about comparative physiology and biochemistry, and even anatomy, are known. Very few data exist which in addition inform about mechanisms after successful xenotransplantation. Nothing is known about phenomena following successfully suppressed hyperacute xenogeneic rejection. Neither the elimination of single factors nor the mitigation of whole systems have led to clinically relevant survival times. Pig organs transplanted into nonhuman primates survived a maximum of 22 days. The hope that transgenic manipulation and modification would be useful to prolong survival times of xenogeneic grafts still waits for evidence. But, within a short time, xenotransplantation could enable patients to receive a life-saving animal organ as an alternative to an allograft. Xenotransplantation would, as a new dimension in medicine, shorten if not eliminate waiting lists. Therefore, scientists must vigorously develop xenografting as a viable alternative for transplantation.


[Intraoperative hemodynamic monitoring using transesophageal echocardiography in orthopedic surgery].
Orthopedic surgery is commonly performed in elderly patients with higher cardiovascular surgical risk. Hemodynamic monitoring in these patients may prevent perioperative complications. To assess the usefulness of transesophageal echocardiography (TEE) for intraoperative cardiovascular monitoring during orthopedic surgery. Patients older than 65 years subjected to orthopedic surgery using general anesthesia and with a high cardiovascular risk were studied. Intraoperative TEE was performed to assess intravascular volume, myocardial contractility and the presence of myocardial ischemia. Fifty three patients aged 72+/-5 years were studied. Hemodynamic stability was detected in 68% of patients, mainly reflected as episodes of hypovolemia. Myocardial ischemia was detected in two patients and embolic episodes in six (11%). Intraoperative TEE was useful for the hemodynamic evaluation of patients with high cardiovascular risk.


Meta-analysis of the role of IL-6 rs1800795 polymorphism in the susceptibility to prostate cancer: Evidence based on 17 studies.
Playing critical roles in immune responses, interleukin-6 (IL-6) has been proposed to be involved in the development of multiple cancers, including prostate cancer. The rs1800795 polymorphism in the promoter of the gene IL-6 can affect the transcription and expression of the gene, becoming a common target in association studies on tumors. We therefore carried out this meta-analysis to further discuss the relationship of this polymorphism with the risk of prostate cancer.Relevant publications were retrieved from the electronic databases. The strength of the correlation between IL-6 rs1800795 polymorphism and prostate cancer risk was evaluated using pooled odds ratios (ORs) with their 95% confidence intervals (95% CIs). Q test was adopted to examine between-study heterogeneity, with P < 0.05 as significant level. Subgroup and meta-regression analyses were conducted to explore potential source of heterogeneity. Sensitivity analysis was implemented to test the statistical stability of the final results. In addition, funnel plot and Egger test were employed to inspect publication bias among included studies.A total of 13 132 cases and 15 282 controls were ultimately incorporated into the present study. Overall estimates revealed no significant relationship between IL-6 rs1800795 polymorphism and prostate cancer risk in total analysis, but a risk-increasing effect of the polymorphism was detected in African-American subgroup under CC versus GG and CC versus GG + GC contrasts (OR 3.43, 95% CI 1.01-11.71; OR 3.51, 95% CI 1.04-11.82) after subgroup analysis by ethnicity.IL-6 rs1800795 polymorphism may enhance the susceptibility to prostate cancer in African-American men.


Correlation of CT indicators of NSCLC and pathological features and the expression level of p53 and c-myc.
To investigate the correlations of the computed tomography (CT) signs of non-small cell lung cancer (NSCLC) with pathological features and the expression levels of phosphoprotein 53 (p53) and c-Myc in patients. 87 patients with NSCLC admitted to the Department of Oncology in our hospital from July 2014 to March 2017 were randomly selected. Morphologies of NSCLC and cancer-adjacent tissues were detected by hematoxylin and eosin (H&E) staining; messenger ribonucleic acid (mRNA) and protein levels of p53 and c-Myc in cancer and cancer-adjacent tissues were detected using real-time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC); spiral CT (SCT) was conducted for exploring imaging signs of patients with NSCLC; the correlation of CT signs with pathology and the expressions of p53 and c-Myc was analyzed. H&E staining showed that NSCLC tissues had a larger nucleus, a larger nucleus-cytoplasm ratio, and a more evident histopathological atypia, with no clear histological structure compared with cancer-adjacent normal tissues; RT-PCR and IHC results revealed that the mRNA and protein expression levels of p53 and c-Myc in NSCLC tissues were significantly higher than those in cancer-adjacent tissues, in which differences in mRNA levels were 1.75 folds and 1.84 folds, respectively (p<0.05). SCT signs indicated that swollen lymph nodes and spiculation, spinous process and deep lobulation signs often occurred in the chest of NSCLC patients, and pleural indentation appeared in the majority of patients; the chi-square test results showed that the positive rates of p53 and c-Myc proteins were not related to pathological types of NSCLC, but significantly correlated with tumor differentiation (p<0.05); the positive rates of p53 and c-Myc proteins were correlated with tumor diameter, spiculation and deep lobulation signs and lymph node metastasis (p<0.05), but not associated with spinous process, vacuole and pleural indentation signs (p>0.05). CT scan combined with the detection of p53 and c-Myc expressions can improve the diagnosis of lymph node metastasis and clinical staging for patients with NSCLC, which is conducive to the clinical treatment and prognosis analysis of NSCLC.


The cellular immune mechanism after transfer of chemically extracted acellular nerve xenografts.
Severe peripheral nerve defect by injuries causing functional loss require nerve grafting. Autograft has limitations for clinical use because it results in the creation of a new nerve injury and the generation of donor site morbidity. Based on these limitations, nerve allografts and xenografts provide a readily accessible alternative strategy. The aim of the present study was to observe the immune mechanism underlying the rejection of chemically extracted acellular nerve xenografts, and further evaluate immunogenicity of chemically treated acellular nerve grafts for clinical applications. A total of 160 BALB/c mice were randomly divided into a negative contrast group (NC, 40 mice), a fresh autograft group (AG, 40 mice), a fresh xenogeneic nerve group (FXN, 40 mice) and a chemically extracted acellular xenogeneic nerve group (CEXN, 40 mice). Various types of nerve grafts were implanted into the thigh muscle of BALB/C mice in the corresponding groups. At 3, 7, 14 and 28 days post-operation, the mice (10 mice from each group) were sacrificed and their spleens were extracted. The spleens were ground into paste. The erythrocytes and other cells were lysed using distilled water and the T lymphocytes were collected. Fluorescein isothiocyanate (FITC) -labeled monoclonal antibodies (CD3, CD4, CD8, CD25, IL-2, IFN-γ and TNF-α) were then added to the solution. The Fluorescence Activated Cell Sorting (FACS) was used to determine the positivity rate of the cells combined with the monoclonal antibodies above. No significant statistical differences were observed between the CEXN, NC and AG groups, so that no obvious immune rejections were observed among the chemically extracted acellular nerve xenografts.


Investigating mechanical properties of a fabric-based affective haptic display through electrodermal activity analysis.
The aim of this study is the development of a classification system able to discern between two levels of velocity of a caress-like haptic stimulus, through information gathered from the analysis of the Electrodermal Activity (EDA) dynamics. We designed and performed an experiment where EDA signals were acquired during caress-like stimuli conveyed to 32 healthy volunteers (16 females) by means of four different fabrics (hemp, burlap, velvet and silk) and at two velocity levels (9.4 mm/s and 65 mm/s). CvxEDA model was used to process the EDA signal and extract features from both tonic and phasic components. The feature set was used as an input to a K-NN classifier implementing a leave-one-subject-out procedure. Considering all fabrics, results show an accuracy of velocity recognition between 91.07% and 96.43%. Conversely, poor accuracy was achieved considering the fabric classification. Results also suggest that caress velocity significantly affects EDA dynamics regardless of the typology of fabrics. This is probably due to the fact that velocity is strictly related to the valence of the affective stimuli.


Herbert Remmer during the early fifties, as seen by a doctoral fellow.
Herbert Remmer is remembered by his first Ph.D. student as a demanding mentor with high standards in scientific matters. Remmer was always ready to discuss and question his student's findings, and in this way, served as a lifetime model. Remmer was always generous with the multitude of scientific ideas he generated and he was ready to share these new ideas with others. Remmer is characterized as a person with universal interests possessing a curiosity in philosophy, religion and in all other unanswered questions of the universe.


Catalytic enantioselective alkenylation-heteroarylation of olefins: stereoselective syntheses of 5-7 membered azacycles and oxacycles.
Catalytic enantioselective domino alkenylation-heteroarylation of nonconjugated iododienes proceeded with excellent stereoselectivity and broad scope of substrates. The reaction enables stereoselective syntheses of substituted azacycles such as piperidine, pyrrolidine azepine and dihydropyrans carrying new quaternary stereocenters. Mechanistically, C-H bonds of heterocycles were activated by lithium alkoxides via reversible deprotonation, rather than conventional palladium(ii)-assisted metalation processes. Many types of heteroarenes can be used, including not only azoles (such as thiazoles, oxazoles, imidazoles and oxadiazoles), but also nonazoles (thiophene, furan and azine N-oxides).


Association of impaired left ventricular twisting-untwisting with vascular dysfunction, neurohumoral activation and impaired exercise capacity in hypertensive heart disease.
We investigated the association between left ventricular (LV) torsional deformation and vascular dysfunction, fibrosis, neurohumoral activation, and exercise capacity in patients with normal ejection fraction In 320 newly-diagnosed untreated hypertensive patients and 160 controls, we measured: pulse wave velocity (PWV); coronary flow reserve (CFR) by Doppler echocardiography; global longitudinal strain and strain rate, peak twisting, the percentage changes between peak twisting, and untwisting at mitral valve opening (%dpTw - UtwMVO ), at peak (%dpTw - UtwPEF ), and the end of early LV diastolic filling (%dpTw - UtwEDF ) by speckle tracking imaging; transforming growth factor (TGFb-1), metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloptoteinase-1(TIMP-1), markers of collagen synthesis, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Oxygen consumption (VO2 ), measured by means of cardiopulmonary exercise test, was assessed in a subset of 80 patients. The PWV, CFR, longitudinal strain and strain rate, %dpTw-UtwMVO , %dpTw-UtwPEF , and %dpTw-UtwEDF were impaired in hypertensive patients compared with controls. In multivariable analysis, CFR, PWV, LV mass, and systolic blood pressure were independent determinants of longitudinal strain, strain rate, and untwisting markers (P < 0.05). Increased TGFb-1 was related with increased collagen synthesis markers, TIMP-1 and MMP-9 and these biomarkers were associated with impaired longitudinal systolic strain rate, untwisting markers, CFR and PWV (P < 0.05). Delayed untwisting as assessed by reduced %dpTw - UtwEDF was related with increased NT-proBNP and reduced VO2 (P < 0.05). Impaired LV untwisting is associated with increased arterial stiffness and coronary microcirculatory dysfunction, and is linked to reduced exercise capacity and neurohumoral activation in hypertensive heart disease. A fibrotic process may be the common link between vascular dysfunction and abnormal myocardial deformation.


The Korea Cancer Big Data Platform (K-CBP) for Cancer Research.
Data warehousing is the most important technology to address recent advances in precision medicine. However, a generic clinical data warehouse does not address unstructured and insufficient data. In precision medicine, it is essential to develop a platform that can collect and utilize data. Data were collected from electronic medical records, genomic sequences, tumor biopsy specimens, and national cancer control initiative databases in the National Cancer Center (NCC), Korea. Data were de-identified and stored in a safe and independent space. Unstructured clinical data were standardized and incorporated into cancer registries and linked to cancer genome sequences and tumor biopsy specimens. Finally, national cancer control initiative data from the public domain were independently organized and linked to cancer registries. We constructed a system for integrating and providing various cancer data called the Korea Cancer Big Data Platform (K-CBP). Although the K-CBP could be used for cancer research, the legal and regulatory aspects of data distribution and usage need to be addressed first. Nonetheless, the system will continue collecting data from cancer-related resources that will hopefully facilitate precision-based research.


Sydowia polyspora is both a Foliar Endophyte and a Preemergent Seed Pathogen in Pinus ponderosa.
Poor seedling performance and reduced seed emergence are often ascribed to known pathogens that cause low seedling recruitment and poor seed emergence in forest nurseries and regeneration plantings. On the other hand, foliar endophytes are often overlooked as a source of poor emergence or tree seedling disease. Here, we show that an endophytic fungus common to the foliar microbiome of Pinus ponderosa acts as a cryptic pathogen in delaying emergence. In a series of experiments, we inoculated seed of P. ponderosa with a suspension of Sydowia polyspora 12 h prior to sowing. S. polyspora reduced seed emergence of its host, P. ponderosa, by as much as 30%. A tetrazolium chloride viability assay showed that S. polyspora reduces emergence by preventing germination; seed remained viable. In sum, pathogens affecting tree seed emergence and seedling recruitment may be endophytic as well as in seed and soil and deserve greater attention in studies of natural regeneration.


A novel constructed SPT15 mutagenesis library of Saccharomyces cerevisiae by using gTME technique for enhanced ethanol production.
During the last few years, the global transcription machinery engineering (gTME) technique has gained more attention as an effective approach for the construction of novel mutants. Genetic strategies (molecular biology methods) were utilized to get mutational for both genes (SPT15 and TAF23) basically existed in the Saccharomyces cerevisiae genome via screening the gTME approach in order to obtain a new mutant S. cerevisiae diploid strain. The vector pYX212 was utilized to transform these genes into the control diploid strain S. cerevisiae through the process of mating between haploids control strains S. cerevisiae (MAT-a [CICC 1374]) and (MAT-α [CICC 31144]), by using the oligonucleotide primers SPT15-EcoRI-FW/SPT15-SalI-RV and TAF23-SalI-FW/TAF23-NheI-RV, respectively. The resultant mutants were examined for a series of stability tests. This study showed how strong the effect of using strategic gTME with the importance of the modification we conducted in Error Prone PCR protocol by increasing MnCl2 concentration instead of MgCl2. More than ninety mutants we obtained in this study were distinguished by a high level production of bio-ethanol as compared to the diploid control strain.