High-affinity binding of peptide agonists to the human B1 bradykinin receptor depends on interaction between the peptide N-terminal L-lysine and the fourth extracellular domain of the receptor.
The aim of this study was to identify the location of the N terminus of peptide agonist ligands when bound to the human B1 bradykinin (BK) receptor. To reach this aim, we exploited the fact that high-affinity binding of kinin peptides to the human B1 receptor subtype requires a peptide N-terminal L-Lys, whereas high-affinity binding to the B2 receptor subtype does not require this residue. This was done by comparing the affinities of BK, a B2 receptor-selective peptide, and kallidin or Lys-BK, a less receptor-selective peptide, for chimeric proteins in which each B1 receptor domain had been substituted in the human B2 receptor and expressed in HEK293 cells. Individual substitution of transmembrane domains 1-7 (TM-I-VII) and extracellular domains 1-4 (EC-I-IV) of the B1 receptor in the B2 receptor influenced the affinities of BK and Lys-BK approximately equally. In contrast, substitution of B1 EC-IV dramatically reduced the affinity and potency of BK, whereas these parameters for Lys-BK were essentially unaltered. Substitution of either the N- or C-terminal half of B1 EC-IV in the B2 receptor only had a limited effect on the peptide binding constants, indicating the involvement of multiple residues throughout this domain. Complementary mutations of the N-terminal residue in Lys-BK revealed that both the positive charge and the proper spatial orientation of this residue were required for interaction with B1 EC-IV. Thus, the N-terminal residue of peptide agonists when bound to the human B1 receptor is positioned extracellularly and interacts with EC-IV.


Inherently Conductive Poly(dimethylsiloxane) Elastomers Synergistically Mediated by Nanocellulose/Carbon Nanotube Nanohybrids toward Highly Sensitive, Stretchable, and Durable Strain Sensors.
With the rapid development of soft electronics, flexible and stretchable strain sensors are highly desirable. However, coupling of high sensitivity and stretchability in a single strain sensor remains a challenge. Herein, a kind of conductive elastomer is constructed with poly(dimethylsiloxane) (PDMS) and silylated cellulose nanocrystal (SCNC)/carbon nanotube (CNT) nanohybrids through a facile one-pot solution-casting method. The hydrophobic SCNCs can effectively facilitate the dispersion of CNTs in PDMS and synergistically improve the interfacial compatibility between CNTs and the PDMS matrix, resulting in favorable stress and electron transfer in the polymer network. Due to the outstanding electrical conductivity of CNTs and the excellent dispersity and high mechanical performance of SCNCs, combined with the good compatibility between SCNC-mediated carbon nanotubes (SCNC-CNTs) and PDMS, the resulting composite elastomer (SCNC-CNT/PDMS) shows high electrical conductivity (∼2.77 S m-1), tensile strength (∼5.72 MPa), and fatigue resistance properties. The strain sensor assembled by SCNC-CNT/PDMS demonstrates a high strain range above 100%, appealing strain sensitivity with a gauge factor of 37.11 at 50-100% strain, and long-term stability and durability, which is capable of monitoring both real-time human motions and acoustic vibrations. This work paves a new way for the design and controllable preparation of flexible and stretchable conductive elastomers, demonstrating promising applications in wearable devices and intelligent electronics.


Involvement of Met receptor pathway in aggressive behavior of colorectal cancer cells induced by parathyroid hormone-related peptide.
Parathyroid hormone-related peptide (PTHrP) plays a key role in the development and progression of many tumors. We found that in colorectal cancer (CRC) HCT116 cells, the binding of PTHrP to its receptor PTHR type 1 (PTHR1) activates events associated with an aggressive phenotype. In HCT116 cell xenografts, PTHrP modulates the expression of molecular markers linked to tumor progression. Empirical evidence suggests that the Met receptor is involved in the development and evolution of CRC. Based on these data, we hypothesized that the signaling pathway trigged by PTHrP could be involved in the transactivation of Met and consequently in the aggressive behavior of CRC cells. To elucidate the relationship among PTHR1, PTHrP, and Met in CRC models. For in vitro assays, HCT116 and Caco-2 cells derived from human CRC were incubated in the absence or presence of PTHrP (1-34) (10-8 M). Where indicated, cells were pre-incubated with specific kinase inhibitors or dimethylsulfoxide, the vehicle of the inhibitors. The protein levels were evaluated by Western blot technique. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the changes in gene expression. Wound healing assay and morphological monitoring were performed to evaluate cell migration and changes related to the epithelial-mesenchymal transition (EMT), respectively. The number of viable HCT116 cells was counted by trypan blue dye exclusion test to evaluate the effects of irinotecan (CPT-11), oxaliplatin (OXA), or doxorubicin (DOXO) with or without PTHrP. For in vivo tests, HCT116 cell xenografts on 6-wk-old male N:NIH (S)_nu mice received daily intratumoral injections of PTHrP (40 μg/kg) in 100 μL phosphate-buffered saline (PBS) or the vehicle (PBS) as a control during 20 d. Humanitarian slaughter was carried out and the tumors were removed, weighed, and fixed in a 4% formaldehyde solution for subsequent treatment by immunoassays. To evaluate the expression of molecular markers in human tumor samples, we studied 23 specimens obtained from CRC patients which were treated at the Hospital Interzonal de Graves y Agudos Dr. José Penna (Bahía Blanca, Buenos Aires, Argentina) and the Hospital Provincial de Neuquén (Neuquén, Neuquén, Argentina) from January 1990 to December 2007. Seven cases with normal colorectal tissues were assigned to the control group. Tumor tissue samples and clinical histories of patients were analyzed. Paraffin-embedded blocks from primary tumors were reviewed by hematoxylin-eosin staining technique; subsequently, representative histological samples were selected from each patient. From each paraffin block, tumor sections were stained for immunohistochemical detection. The statistical significance of differences was analyzed using proper statistical analysis. The results were considered statistically significant at P < 0.05. By Western blot analysis and using total Met antibody, we found that PTHrP regulated Met expression in HCT116 cells but not in Caco-2 cells. In HCT116 cells, Met protein levels increased at 30 min (P < 0.01) and at 20 h (P < 0.01) whereas the levels diminished at 3 min (P < 0.05), 10 min (P < 0.01), and 1 h to 5 h (P < 0.01) of PTHrP treatment. Using an active Met antibody, we found that where the protein levels of total Met decreased (3 min, 10 min, and 60 min of PTHrP exposure), the status of phosphorylated/activated Met increased (P < 0.01) at the same time, suggesting that Met undergoes proteasomal degradation after its phosphorylation/activation by PTHrP. The increment of its protein level after these decreases (at 30 min and 20 h) suggests a modulation of Met expression by PTHrP in order to improve Met levels and this idea is supported by our observation that the cytokine increased Met mRNA levels at least at 15 min in HCT116 cells as revealed by RT-qPCR analysis (P < 0.05). We then proceeded to evaluate the signaling pathways that mediate the phosphorylation/ activation of Met induced by PTHrP in HCT116 cells. By Western blot technique, we observed that PP1, a specific inhibitor of the activation of the proto-oncogene protein tyrosine kinase Src, blocked the effect of PTHrP on Met phosphorylation (P < 0.05). Furthermore, the selective inhibition of the ERK 1/2 mitogen-activated protein kinase (ERK 1/2 MAPK) using PD98059 and the p38 MAPK using SB203580 diminished the effect of PTHrP on Met phosphorylation/activation (P < 0.05). Using SU11274, the specific inhibitor of Met activation, and trypan blue dye exclusion test, Western blot, wound healing assay, and morphological analysis with a microscope, we observed the reversal of cell events induced by PTHrP such as cell proliferation (P < 0.05), migration (P < 0.05), and the EMT program (P < 0.01) in HCT116 cells. Also, PTHrP favored the chemoresistance to CPT-11 (P < 0.001), OXA (P < 0.01), and DOXO (P < 0.01) through the Met pathway. Taken together, these findings suggest that Met activated by PTHrP participates in events associated with the aggressive phenotype of CRC cells. By immunohistochemical analysis, we found that PTHrP in HCT116 cell xenografts enhanced the protein expression of Met (0.190 ± 0.014) compared to tumors from control mice (0.110 ± 0.012; P < 0.05) and of its own receptor (2.27 ± 0.20) compared to tumors from control mice (1.98 ± 0.14; P < 0.01). Finally, assuming that the changes in the expression of PTHrP and its receptor are directly correlated, we investigated the expression of both Met and PTHR1 in biopsies of CRC patients by immunohistochemical analysis. Comparing histologically differentiated tumors with respect to those less differentiated, we found that the labeling intensity for Met and PTHR1 increased and diminished in a gradual manner, respectively (P < 0.05). PTHrP acts through the Met pathway in CRC cells and regulates Met expression in a CRC animal model. More basic and clinical studies are needed to further evaluate the PTHrP/Met relationship.


alpha-Adrenoceptor regulation in vivo and in vitro in the rabbit.
The relationship between alpha-adrenoceptor number and response has been studied in rabbits under a range of physiological and pathological conditions. The effects of irreversible alpha-adrenoceptor blockade, maturation, ageing, oestrogen treatment, adrenaline infusion, perinephritis hypertension and sinoaortic denervation on alpha-adrenoceptor number and response were examined. alpha-Adrenoceptor number was measured by radioligand binding. [3H]Prazosin and [3H]clonidine were used as ligands to measure alpha 1- and alpha 2-adrenoceptor number in spleen and [3H]yohimbine to measure alpha 2-adrenoceptor number on platelets. Responses in vivo were studied by examining the pressor responses to a range of alpha-adrenoceptor agonists. The functional response of platelets was examined in vitro by using the aggregatory response to adrenaline. Reductions in alpha 2-adrenoceptor ligand binding were consistently accompanied by equivalent reductions in alpha 2-adrenoceptor-mediated responses. In contrast large reductions in [3H]prazosin binding were observed with little or no change in alpha 1-adrenoceptor-mediated responses. These results would be consistent with a large receptor reserve for alpha 1-adrenoceptors but few if any spare alpha 2-adrenoceptors in the vasculature or on platelets. Increased responses to both alpha 1- and alpha 2-adrenoceptor agonists were observed in animals with sinoaortic denervation and to alpha 1-adrenoceptor agonists in rabbits with perinephritis hypertension. These increases in response were not accompanied by increases in radioligand binding and may be related to alterations in the coupling of receptor activation to end-organ response.


Native Competition and Low-Skilled Immigrant Inflows.
This paper demonstrates that immigration decisions depend on local labor market conditions by documenting the change in low-skilled immigrant inflows in response to supply increases among the US-born. Using pre-reform welfare participation rates as an instrument for changes in native labor supply, I find that immigrants competing with native entrants systematically prefer cities with smaller supply shocks. The extent of the response is substantial: for each native woman working due to reform, 0.5 fewer female immigrants enter the local labor force. These results provide direct evidence that international migration flows tend to equilibrate returns across US local labor markets.


Aetiology of hyperkalaemia in hospital inpatients.
Hyperkalaemia is a common metabolic disorder; if left untreated it can lead to life-threatening consequences. We conducted this study to determine the common aetiological factors for hyperkalaemia in hospital inpatients. This prospective cross-sectional study was conducted in a referral teaching hospital in south India. One hundred and forty-three patients with hyperkalaemia (> 5 mEq/L) were selected on 20 random week days over a 3-month period. All the patients were clinically and biochemically evaluated for the aetiology of hyperkalaemia. Hyperkalaemia was twice as common amongst males. Potassium supplementation and drugs were the leading causes for hyperkalaemia, with renal failure being a distant second. Hyperkalaemia developed after admission to hospital in more than 75% of the patients. Severe hyperkalaemia (> 6 mEq/L) was seen in one-third of the patients. Potassium supplementation and other iatrogenic conditions lead to hyperkalaemia in inpatients. Males are at increased risk for hyperkalaemia.


Antihypertensive effects of aerobic exercise in middle-aged normotensive men with exaggerated blood pressure response to exercise.
An exaggerated blood pressure (BP) response to physical exertion among normotensive subjects is considered a significant risk factor for future hypertension. The purpose of this study was to examine whether regular aerobic exercise can lead to a reduction in hypertensive risks in patients with such a high-risk profile. Thirty-five sedentary men (46 +/- 2 years old) with normal BP at rest but an exaggerated BP response during exercise were randomly assigned to an exercise or control group for 12 weeks followed by an 8-week washout period. The subjects were then crossed over to the alternate group for an additional 12-week period. The exercise training consisted of 3 days per week of stationary bicycling for 45 min at 50-60% of the heart rate reserve. The treatment effects were evaluated using the method of Hills and Armitage. The training-induced reduction in resting BP was not statistically significant. In ambulatory BP monitoring, the averages of 24-h and daytime systolic and diastolic BP were significantly lower, but nighttime BP remained unchanged after training. During ergometric exercise, significant decreases were observed in systolic and diastolic BP and plasma norepinephrine concentration measured at the submaximal workloads. M-mode echocardiographic and Doppler-derived left ventricular variables were not significantly affected by training. These findings suggest that regular aerobic exercise attenuates BP elevations during physical exertion and daytime activities mainly as a result of the reduction in enhanced sympathetic nervous tonus, which may in turn play a role in lowering the risk for hypertension in normotensive subjects with an exaggerated BP response to exercise.


Li12Cu16+xAl26-x (x = 3.2): a new intermetallic structure type.
The new ternary lithium copper aluminide, Li(12)Cu(16+x)Al(26-x) (x = 3.2), dodecalithium nonadecacopper tricosaaluminide, crystallizes in a new structure type with space group P4/mbm. Among nine independent atomic positions, two Al (one of which is statistically disordered with Cu) and three Li atoms have point symmetry m.2m, two statistically disordered Al/Cu atoms are in m.. sites, one Al atom is in a 4/m.. site and one Cu atom occupies a general site. The framework of Li(12)Cu(16+x)Al(26-x) consists of pseudo-Frank-Kasper polyhedra enclosing channels of hexagonal prisms occupied by Li atoms. The crystallochemical peculiarity of this new structure type is discussed in relation to the derivatives from Laves phases (LiCuAl(2) and Li(8)Cu(12+x)Al(6-x)) and to the well known CaCu(5) structure.


Ion permeation in the NanC porin from Escherichia coli: free energy calculations along pathways identified by coarse-grain simulations.
Using the X-ray structure of a recently discovered bacterial protein, the N-acetylneuraminic acid-inducible channel (NanC), we investigate computationally K(+) and Cl(-) ions' permeation. We identify ion permeation pathways that are likely to be populated using coarse-grain Monte Carlo simulations. Next, we use these pathways as reaction coordinates for umbrella sampling-based free energy simulations. We find distinct tubelike pathways connecting specific binding sites for K(+) and, more pronounced, for Cl(-) ions. Both ions permeate the porin preserving almost all of their first hydration shell. The calculated free energy barriers are G(#) ≈ 4 kJ/mol and G(#) ≈ 8 kJ/mol for Cl(-) and K(+), respectively. Within the approximations associated with these values, discussed in detail in this work, we suggest that the porin is slightly selective for Cl(-) versus K(+). Our suggestion is consistent with the experimentally observed weak Cl(-) over K(+) selectivity. A rationale for the latter is suggested by a comparison with previous calculations on strongly anion selective porins.


Linkage Analysis of Hydroxyproline-poor Glycoprotein from Phaseolus vulgaris.
Hydroxyproline-poor glycoprotein contains a single polypeptide chain with lysine at the N-terminus. Removal of carbohydrate attached to serine by alkali treatment produces two polypeptide fractions. Labeling with (35)S indicates that most serine residues having a carbohydrate substituent removed by alkali occur on the polypeptide fraction of lower molecular weight. Following alkali treatment, two additional N-terminal amino acids, proline and glycine, were detected suggesting that alkali treatment also cleaves peptide bonds. Methylation analysis of native and degraded glycoproteins, extracted 24, 27, and 36 hours after wounding, demonstrates the following structural features of carbohydrate attached to serine. Arabinose may be (1 --> 2)-, (1 --> 3)-, or (1 --> 5)-linked, glucose occurs as a chain of beta-(1 --> 4)-linked residues, and galactose occurs as a nonreducing terminal unit.


Decrease in mitochondrial function in rat cardiac permeabilized fibers correlates with the aging phenotype.
We measured the loss of cardiac mitochondrial function related to aging in males of three rat strains presenting with different longevity and aging phenotypes: the Fischer 344 (F344), the Brown Norway (BN), and the hybrid F344×BN. The F344 rat has a short life span and a ∼45% decrease in coupled mitochondrial oxidation in the cardiac permeabilized fibers from the old rats compared with the young rats. Citrate synthase activity in the permeabilized fibers (mitochondrial content) did not change significantly with aging. The BN live longer compared with the F344 and have a 15%-18% loss of mitochondrial respiration in the aged rats compared with the young rats. The differences are not significant. In hybrids, more resistant to aging than are the BN and the F344, mitochondrial function is preserved during aging. The difference in longevity of the different strains is correlated with mitochondrial dysfunction in the heart, suggesting the importance of mitochondria in cardiac aging.


Cholesterol metabolism in two strains of rats with high or low response of serum cholesterol to a cholesterol-rich diet.
Transfer from a low cholesterol commercial diet to a high cholesterol diet, containing 2% (wt/wt) cholesterol and 0.5% cholate, caused an increase in serum cholesterol from about 2.5 mmol/L in two inbred rat strains to 5 mmol/L in the hyporesponsive strain and to 20 mmol/L in the hyperresponsive strain. In both strains the excess of cholesterol in the serum was exclusively located in the very low density lipoproteins. Cholesterol feeding caused a sevenfold increase in the amount of cholesterol in the liver, the increase tending to be greater in the hyporesponders. On the commercial diet, the decay of specific radioactivity of serum cholesterol after the intravenous administration of labeled cholesterol was faster in the hyporesponsive rats. The rate of fecal excretion of radioactive bile acids on this diet was higher in the hyporesponders when compared with the hyperresponders, whereas there was no strain difference with regard to the output of fecal neutral steroids. Sterol balance data showed that whole-body cholesterol synthesis on the low cholesterol diet was about twofold higher in the hypo- than in the hyperresponders. When fed the high cholesterol diet the half-life in the serum of injected radioactive cholesterol was about six times shorter in the hyporesponders. In absolute amounts, the hypo- and hyperresponders excreted similar amounts of endogenous (radioactive) bile acids and fecal steroids with the feces on this diet.


Antioxidant, hepatoprotective, and ameliorative effects of methanolic extract of leaves of Grewia mollis Juss. on carbon tetrachloride-treated albino rats.
The methanolic extract of Grewia mollis leaves was evaluated in vivo for its antioxidant and hepatoprotective properties. Oxidative stress was induced in rats by administering carbon tetrachloride (CCl(4)) intraperitoneally at a dose of 0.6 mL/kg, whereas the crude plant extract and standard antioxidant (vitamin E) were administered at a dose of 5 mg/kg and 50 mg/kg, respectively. The effect of G. mollis crude extracts and vitamin E on malondialdehyde (MDA) and liver function parameters such as protein, bilirubin, aspartate aminotransferase, and alanine aminotransferase were measured spectrophotometrically. The methanolic extract of G. mollis leaves and vitamin E showed a significant (P<.05) hepatoprotective potential by lowering the serum levels of bilirubin, aspartate aminotransferase, and alanine aminotransferase and decreasing MDA levels in rats pretreated or post-treated with CCl(4). Based on these results, it is concluded that G. mollis leaves contain potent antioxidant compounds that could offer protection against hepatotoxicity as well as ameliorate preexisting liver damage and oxidative stress conditions.


Bi-parental care contributes to sexually dimorphic neural cell genesis in the adult mammalian brain.
Early life events can modulate brain development to produce persistent physiological and behavioural phenotypes that are transmissible across generations. However, whether neural precursor cells are altered by early life events, to produce persistent and transmissible behavioural changes, is unknown. Here, we show that bi-parental care, in early life, increases neural cell genesis in the adult rodent brain in a sexually dimorphic manner. Bi-parentally raised male mice display enhanced adult dentate gyrus neurogenesis, which improves hippocampal neurogenesis-dependent learning and memory. Female mice display enhanced adult white matter oligodendrocyte production, which increases proficiency in bilateral motor coordination and preference for social investigation. Surprisingly, single parent-raised male and female offspring, whose fathers and mothers received bi-parental care, respectively, display a similar enhancement in adult neural cell genesis and phenotypic behaviour. Therefore, neural plasticity and behavioural effects due to bi-parental care persist throughout life and are transmitted to the next generation.


Starting small: exploring the origins of successor function knowledge.
Although most U. S. children can accurately count sets by 4 years of age, many fail to understand the structural analogy between counting and number - that adding 1 to a set corresponds to counting up 1 word in the count list. While children are theorized to establish this Structure Mapping coincident with learning how counting is used to generate sets, they initially have an item-based understanding of this relationship, and can infer that, e.g, adding 1 to "five" is "six", while failing to infer that, e.g., adding 1 to "twenty-five" is "twenty-six" despite being able to recite these numbers when counting aloud. The item-specific nature of children's successes in reasoning about the relationship between changes in cardinality and the count list raises the possibility that such a Structure Mapping emerges later in development, and that this ability does not initially depend on learning to count. We test this hypothesis in two experiments and find evidence that children can perform item-based addition operations before they become competent counters. Even after children learn to count, we find that their ability to perform addition operations remains item-based and restricted to very small numbers, rather than drawing on generalized knowledge of how the count list represents number. We discuss how these early item-based associations between number words and sets might play a role in constructing a generalized Structure Mapping between counting and quantity.


Evaluating drug safety in children and adolescents with bipolar disorder.
The safety of the use of medications in adolescents and children to treat bipolar disorder has not been extensively studied. The prevalence of bipolar disorder in children and adolescents is unknown due to the lack of completed large-scale epidemiological studies. In addition, the diagnosis of this disorder is still questionable in this age group because the same explicit diagnostic criteria used in adults potentially cannot be applied to children and adolescents since the early-onset symptoms often overlap with other disorders such as attention-deficit disorder. The safety of drugs used to treat bipolar disorder is of growing concern, particularly because this population usually requires more than one psychotropic medication to manage the disease. Common side effects seen with several agents, particularly antipsychotics, are somnolence, weight gain, extrapyramidal symptoms, dyslipidemia, type-2 diabetes, and hyperprolactinemia. This review will discuss the most advanced practice guidelines in assessing and treating bipolar disorder in children and adolescents, the safety and effectiveness of the drugs currently used based on clinical trials and post-marketing surveillance, and the risks versus benefits associated with their use.


Investigation of the Oxidation Behavior of Cr20Mn17Fe18Ta23W22 and Microdefects Evolution Induced by Hydrogen Ions before and after Oxidation.
The oxidation behavior of body-centered cubic (bcc) structure Cr20Mn17Fe18Ta23W22 refractory high-entropy alloy (RHEA) and the microdefects induced by hydrogen ions before and after oxidation were investigated. The results revealed that compared with oxidizing Cr20Mn17Fe18Ta23W22 at 800 °C (6.7 °C/min) for 4 h (ST3, Ar:O2 = 3:1), the heating procedure of oxidizing Cr20Mn17Fe18Ta23W22 at 300 °C (6 °C/min) for 2 h and then increased to 800 °C (5 °C/min) for 4 h is more conducive to the production of oxides without spalling on the surface, i.e., HT1 (Ar:O2 = 1:1), HT2 (Ar:O2 = 2:1) and HT3 (Ar:O2 = 3:1) samples. The oxidation of Cr20Mn17Fe18Ta23W22 RHEA is mainly controlled by the diffusion of cations instead of affinities with O. Additionally, HT1 and HT3 samples irradiated with a fluence of 3.9 × 1022 cm-2 hydrogen ions (60 eV) were found to have a better hydrogen irradiation resistance than Cr20Mn17Fe18Ta23W22 RHEA. The microdefects in irradiated Cr20Mn17Fe18Ta23W22 mainly existed as hydrogen bubbles, hydrogen-vacancy (H-V) complexes and vacancy/vacancy clusters. The microdefects in irradiated HT3 were mainly vacancies and H-V complexes, while the microdefects in irradiated HT1 mainly existed as vacancies and vacancy clusters, as large amounts of hydrogen were consumed to react with oxides on the HT1 surface. The oxides on the surface of the HT3 sample were more stable than those on HT1 under hydrogen irradiation.


Contemporary outcomes of pancreaticoduodenectomy for benign and precancerous cystic lesions.
The decision to undertake pancreaticoduodenectomy for benign and precancerous lesions has historically relied on outcomes data from operations for cancer. We aimed to describe risks for these specific patients and identify the highest risk groups. The ACS-NSQIP pancreatic targeted data was queried for pancreaticoduodenectomies for benign and pre-cancerous neoplasms from 2014 to 2018. Baseline characteristics, operative techniques and outcomes were examined. Multivariate regression was performed to identify predictors of major complications. 748 patients underwent pancreaticoduodenectomy for (n = 541,72.3%) IPMN, (n = 87,11.6%) MCN, (n = 78,10.4%) serous cystadenoma, and (n = 42,5.6%) solid pseudopapillary neoplasm. Median LOS was 8 days. Major complications (n = 135,18.0%), non-home discharges (n = 83,11.1%) and readmissions (n = 153,20.5%) occurred frequently. In patients ≥ 80 years of age (n = 37), major complications (n = 11,29.7%) and non-home discharge (n = 9,24.3%) were quite common. 5-item modified frailty index ≥ 0.4 (OR 1.84,95%CI 1.06-3.19,p = 0.030), Male sex (OR 1.729,95%CI 1.152-2.595,p = 0.008), Age ≥ 65 (OR 1.63,95%CI 1.05-2.54,p = 0.29) and African-American race (OR 2.50,95%CI 1.22-5.16,p = 0.013) were independent predictors of major morbidity. Pancreaticoduodenectomies in this setting have high rates of major complications. Morbidity extends beyond the index hospitalization, with frequent readmission and non-home discharge. Patient specific factors, rather than technical or disease factors predicted outcomes. In certain patients, particularly those older than 80, the morbidity of this operation may exceed the cancer prevention benefits.


Training in Paediatric Clinical Nutrition Across Europe: A Survey of the National Societies Network (2016-2019) of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition.
Disease-related malnutrition is common in patients with chronic diseases and has detrimental effects, therefore, skills in nutrition care are essential core competencies for paediatric digestive medicine. The aim of this survey, conducted as part of a global survey of paediatric gastroenterology, hepatology and nutrition (PGHN) training in Europe, was to assess nutrition care-related infrastructure, staff, and patient volumes in European PGHN training centres. Standardized questionnaires related to clinical nutrition (CN) care were completed by representatives of European PGHN training centres between June 2016 and December 2019. One hundred training centres from 17 European countries, Turkey, and Israel participated in the survey. Dedicated CN clinics exist in 66% of the centres, with fulltime and part-time CN specialists in 66% and 42%, respectively. Home tube feeding (HTF) andhome parenteral nutrition (HPN) programmes are in place in 95% and 77% of centres, respectively. Twenty-four percent of centres do not have a dedicated dietitian and 55% do not have a dedicated pharmacist attached to the training centre. Even the largest centres with >5000 outpatients reported that 25% and 50%, respectively do not have a dedicated dietitian or pharmacist. Low patient numbers on HTF and HPN of <5 annually are reported by 13% and 43% of centres, respectively. The survey shows clear differences and deficits in Clinical Nutrition training infrastructure, including staff and patient volumes, in European PGHN training centres, leading to large differences and limitations in training opportunities in Clinical Nutrition.


Signal-to-noise-ratio equations for a heterodyne laser radar.
We analyze the signal-to-noise-ratio equations for a heterodyne laser radar with identical transmit and receive optics. We defines the beam-profile efficiency, a quantity that must be maximized to optimize a system design. This calculation can be used to evaluate a system in both near and far fields for focused and nonfocused systems. The beam-profile efficiency can be evaluated in many ways, and we describe one possible solution. Using this solution, we present the results of an actual system evaluation.


Epstein-Barr virus-associated gastric carcinoma in Papua New Guinea.
Using in situ hybridization assay, we examined Epstein-Barr virus (EBV) encoded RNA (EBER) expression in 66 cases of oral cancer, 40 esophageal cancer cases, 150 stomach cancer cases, and 46 colorectal cancer cases diagnosed in the Pathology Department of Port Moresby General Hospital, University of Papua New Guinea during the period between 1986-2002. There were no malignancies with positive EBER expression except for the following two male stomach cancer cases: a male case with a gastric carcinoma in pylorus whose age was unknown; and a male case aged 55 years without information on location of tumor. Both cases were histologically classified as non-solid poorly differentiated adenocarcinoma of the Japanese histological classification. The frequency of EBV-associated gastric carcinomas was 1.3% (2/150), and was the lowest ever reported in the world. We examined genotypes of two EBV strains detected from gastric carcinomas. Four different regions of EBV genome were examined by PCR-RFLP, coupled with Southern blot hybridization. The EBV genotype of the first case were type A, wild-type F at BamHI-F region, type D of BamHI-I region and the kept type of the XhoI cleavage site in LMP1. The second case had EBV whose genotypes were type A, wild-type F at BamHI-F region, and the kept type of the XhoI cleavage site in LMP1. The BamHI-I region of this case could not be analyzed.


Impact of radiotherapy with and without concurrent cisplatin on lymphocyte subpopulations in cervical cancer patients.
The impact of radiotherapy alone (RT-alone) and radiotherapy plus concurrent chemotherapy with cisplatin (RT-CHT) was determined for lymphocyte subpopulations in cervical cancer patients. Thirty-four women were treated either with RT-alone (n=14) or RT-CHT (n=20). Peripheral lymphocytes were collected before, immediately after and 6, 12 and 24 weeks after completion of treatment. Flow cytometric analysis included total T-cells, T-helper-cells, T-suppressor-cells, T-cytotoxic-cells, NK-cells, B-cells and the CD4+/CD8+ratio. Twenty-four weeks after treatment, B-cells had recovered to pretreatment levels whereas total lymphocyte counts, T-helper and T-cytotoxic-cells were still significantly reduced in both groups. In contrast, T-suppressor-cells and NK-cells had recovered to pretreatment levels only in patients who received RT-alone and were still significantly reduced in patients who received RT-CHT. RT-alone and RT-CHT induce a significant and prolonged suppression of all lymphocyte subpopulations. RT-CHT, but not RT-alone, causes a prolonged suppression of NK-cells and T-suppressor cells.


Nutritional aspects to prevent heart diseases in traditional Persian medicine.
Cardiovascular diseases are major health complications currently in various societies. Management of heart diseases as a prevention step or as treatment with low-cost procedures like lifestyle modifications including nutrition are important current trends. Although the term nutrition dates back to 2 past centuries, Persian physicians contributed to this term at least from 1000 years ago. Rhazes (865-925 AD) was one of the pioneers in this field. He preferred using foods in treating illnesses. "Foods and drinks" were 1 subject from 6 principles (Setteh Zarorieh) that Persian physicians believed can affect human health. In this review, we described some medieval Persian views on the role of nutrition in heart diseases and compare their prescriptions with current findings. Interestingly, current investigations mostly support Persian medicine principles. Historically, this work shows that the concept of nutrition in heart diseases has had a successful background at least from 1000 years ago in Persia.


[Atrial fibrillation and cerebral infarct].
The importance of atrial fibrillation (AF) as a risk factor (RF) for cerebral infarction (CI) is well-known. It is probably caused by cardiac embolism but other explanations can also justify this association. Our aim was to analyse the features of the patients with CI and AF and sinus rhythm (SR), as well as to form hypotheses as regards the pathogenesis. 250 patients with CI, 204 in RS and 46 in AF (31 non-valvular and 15 associated to a valvular disease) were studied, analysing the prevalence of RF and initial blood tests. The group of patients with valvular AF of probably embolic mechanism had a minor prevalence of RF (hypertension, diabetes, smoking, alcoholism) but higher mortality. The group with non-valvular AF, had a lower RF prevalence compared to the SR group (non-embolic mechanism), without statistical significance and with a similar mortality rate. We concluded that the atherothrombotic mechanism can be the cause of a considerable proportion of CI in patients with non-valvular AF.


Famotidine in the management of duodenal ulcer: experience in Italy.
A multicenter study that involved 15 Italian institutions was carried out to compare the efficacy and safety of famotidine 40 mg at bedtime, famotidine 20 mg b.i.d., famotidine 40 mg b.i.d., and ranitidine 150 mg b.i.d. in promoting the healing of acute duodenal ulcer. Two hundred and twenty-four patients with endoscopically proven duodenal ulcer were randomly allocated into four treatment groups. Efficacy results for the four groups were similar at weeks 2, 4, and 8 of therapy. At week 8, the percentage of patients healed in each group was as follows: 92% in the famotidine 40-mg bedtime group, 97% with 20 mg b.i.d., 93% with 40 mg b.i.d., and 90% with ranitidine 150 mg b.i.d. Day pain and night pain were markedly reduced in all four groups, antacid consumption fell considerably, and therapy was generally well tolerated. The adverse experiences evaluated by the investigator as possibly, probably, or definitely related to test medication were rare and moderate.


Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion.
Anti-epidermal growth factor receptor treatment strategies, i.e. monoclonal antibodies such as cetuximab and panitumumab, or epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitors, such as erlotinib and gefitinib, have expanded the treatment options for different tumor types. Dermatologic toxic effects are the most common side-effects of EGFR inhibitor therapy. They can profoundly affect the patient's quality of life. The aim of this study was to provide interdisciplinary expert recommendations on how to treat patients with skin reactions undergoing anti-EGFR treatment. An expert panel from Germany with expertise in medical oncology, dermatology or clinical pharmacology was convened to develop expert recommendations based on published peer-reviewed literature. The expert recommendations for the state-of-the-art treatment of skin reactions induced by EGFR inhibitor therapy include recommendations for diagnostics and grading as well as grade-specific and stage-adapted treatment approaches and preventive measures. It was concluded that EGFR-inhibitor-related dermatologic reactions should always be treated combining basic care of the skin and a specific therapy adapted to stage and grade of skin reaction. For grade 2 and above, specific treatment recommendations for early- and later-stage skin reactions induced by EGFR-inhibitor therapy were proposed. This paper presents a German national expert opinion for the treatment of skin reactions in patients receiving EGFR inhibitor therapy.


Explant culture of sarcoma patients' tissue.
Human sarcomas comprise a heterogeneous group of rare tumors that affect soft tissues and bone. Due to the scarcity and heterogeneity of these diseases, patient-derived cells that can be used for preclinical research are limited. In this study, we investigated whether the tissue explant technique can be used to obtain sarcoma cell lines from fresh as well as viable frozen tissue obtained from 8 out of 12 soft tissue and 9 out of 13 bone tumor entities as defined by the World Health Organization. The success rate, defined as the percent of samples that yielded sufficient numbers of outgrowing cells to be frozen, and the time to freeze were determined for a total of 734 sarcoma tissue specimens. In 552 cases (75%) enough cells were obtained to be frozen at early passage. Success rates were higher in bone tumors (82%) compared with soft tissue tumors (68%), and the mean time to freezing was lower in bone tumors (65 days) compared with soft tissue tumors (84 days). Overall, from 40% of the tissues cells could be frozen at early passage within <2 month after tissue removal. Comparable results as with fresh tissue were obtained after explant of viable frozen patient-derived material. In a selected number of bone and soft tissue sarcoma entities, conventional karyotyping and/or FISH (fluorescence in situ hybridization) analysis revealed a high amount (>60%) of abnormal cells in 41% of analyzed samples, especially in bone sarcomas (osteosarcoma and Ewing sarcoma). In conclusion, the explant technique is well suited to establish patient-derived cell lines for a large majority of bone and soft tissue sarcoma entities with adequate speed. This procedure thus opens the possibility for molecular analysis and drug testing for therapeutic decision making even during patient treatment.


[Evaluation of diagnostic imagings of liver metastases].
With the advent of various therapeutic modalities for the management of metastatic liver tumor, the task of pretreatment imaging has become more demanding. US and CT are non-invasive, and the most widely used techniques for pretreatment imaging, but they are far from optimal. Recently, the most sensitive pretreatment imaging modality for the depiction of focal liver lesions is CT during arterial portography (CTAP); however, it is an invasive procedure with an established risk of false-positive results. CT and MRI are the sensitivities of these techniques have recently been improved with the development of multidetector CT, contrast agents for MRI that specifically accumulate in the liver, and other advances. Superparamagnetic iron oxide (Feridex) has been developed as a liver-specific particulate MRI contrast agent that is taken up by the Kupffer cells of the liver. Rational selection of appropriate modalities for a given purpose requires familiarity with the characteristics of each modality. The aim of the present study was to evaluate the sensitivities of diagnostic modalities in the pre- and post-treatment periods of metastatic liver tumor. Feridex-enhanced MRI (Ferumoxide MRI) is more sensitive than enhanced CT and MRI in the depiction of metastatic liver tumor. In terms of the ability to visualize residual tumor after MCT, dynamic MRI was superior to enhanced CT and Ferumoxide MRI. In conclusion, combined Ferumoxide MRI and dynamic MRI is a noninvasive method and clinically useful since it can change the therapeutic approach.


Polyclonal cell activity of a repeat peptide derived from the sequence of an 85-kilodalton surface protein of Trypanosoma cruzi trypomastigotes.
Some in vitro and in vivo biological activities of an octadecapeptide derived from an 85-kDa surface protein of Trypanosoma cruzi trypomastigote were studied. The peptide coupled to a carrier protein induced the proliferative response of lymph node cells from mice immunized with various antigens. Moreover, sera from mice immunized with the coupled peptide were found to contain antibodies against a number of self and nonself antigens: fibronectin, bovine serum albumin, myosin, tetanus toxoid, ovalbumin, keyhole limpet hemocyanin, and DNA. These results are discussed in the context of Chagas' disease immunopathology.


Expression, purification, and characterization of a novel acid phosphatase that displays protein tyrosine phosphatases activity from Metarhizium anisopliae strain CQMa102.
The protein tyrosine phosphatase (PTPase) plays an important role in insect immune system. Our group has purified a type of acid phosphatase that could specifically dephosphorylate trans-Golgi p230 in vitro. In order to study this phosphatase further, we have identified and cloned the phosphatase gene from a locust specific Metarhizium anisopliae Strain CQMa102. The CQMa102 phosphatase was expressed in Pichia pastoris to verify its protease activity. The molecular weight (MW) and the isoelectric point (pI) of the phosphatase were about 85 kDa and 6.15, respectively. Substrate specificity evaluation showed that the purified enzyme exhibited high activity on O-phospho-L-tyrosine. At its optimal pH of 6.5 and optimum temperature of 70 °C, the protein showed the highest activity respectively. It can be activated by Ca2+, Mg2+, Mn2+, Ba2+, Co2+ and phosphate analogs, but inhibited by Zn2+, Cu2+, fluoride, dithiothreitol, β-mercaptoethanol and N-ethylmaleimide.


Comprehensive review on patulin and Alternaria toxins in fruit and derived products.
Mycotoxins are toxic secondary metabolites produced by certain fungi, which can contaminate various food commodities, including fruits and their derived products. Patulin and Alternaria toxins are among the most commonly encountered mycotoxins in fruit and their derived products. In this review, the sources, toxicity, and regulations related to these mycotoxins, as well as their detection and mitigation strategies are widely discussed. Patulin is a mycotoxin produced mainly by the fungal genera Penicillium, Aspergillus, and Byssochlamys. Alternaria toxins, produced by fungi in the Alternaria genus, are another common group of mycotoxins found in fruits and fruit products. The most prevalent Alternaria toxins are alternariol (AOH) and alternariol monomethyl ether (AME). These mycotoxins are of concern due to their potential negative effects on human health. Ingesting fruits contaminated with these mycotoxins can cause acute and chronic health problems. Detection of patulin and Alternaria toxins in fruit and their derived products can be challenging due to their low concentrations and the complexity of the food matrices. Common analytical methods, good agricultural practices, and contamination monitoring of these mycotoxins are important for safe consumption of fruits and derived products. And Future research will continue to explore new methods for detecting and managing these mycotoxins, with the ultimate goal of ensuring the safety and quality of fruits and derived product supply.


Role of asparagine in the photorespiratory nitrogen metabolism of pea leaves.
In pea leaves, much of the metabolism of imported asparagine is by transamination. This activity was previously shown to be localized in the peroxisomes, suggesting a possible connection between asparagine and photorespiratory nitrogen metabolism. This was investigated by examination of the transfer of (15)N from the amino group of asparagine, supplied via the transpiration stream, in fully expanded pea leaves. Label was transferred to aspartate, glutamate, alanine, glycine, serine, ammonia, and glutamine (amide group). Under low oxygen (1.8%), or in the presence of alpha-hydroxy-2-pyridine methanesulfonic acid (an inhibitor of glycolate oxidase, a step in the photorespiratory formation of glyoxylate), there was a substantial (60-80%) decrease in transfer of label to glycine, serine, ammonia, and glutamine. Addition of isonicotinyl hydrazide (an inhibitor of formation of serine from glycine) caused a 70% decrease in transfer of asparagine amino nitrogen to serine, ammonia, and glutamine, while a 4-fold increase in labeling of glycine was observed. The results demonstrate the involvement of asparagine in photorespiration, and show that photorespiratory nitrogen metabolism is not a closed cyclic process.


The influence of carbohydrate ingestion on peripheral and central fatigue during exercise in hypoxia: A narrative review.
Hypoxia impairs aerobic performance by accelerating fatiguing processes. These processes may originate from sites either distal (peripheral) or proximal (central) to the neuromuscular junction, though these are not mutually exclusive. Peripheral mechanisms include decrements in muscle glycogen or fluctuations in intramuscular metabolites, whereas central responses commonly refer to reductions in central motor drive elicited by alterations in blood glucose and neurotransmitter concentrations as well as arterial hypoxemia. Hypoxia may accelerate both peripheral and central pathways of fatigue, with the level of hypoxia strongly dictating the degree and primary locus of impairment. As more people journey to hypoxic settings for work and recreation, developing strategies to improve work capacity in these environments becomes increasingly relevant. Given that sea level performance improves with nutritional interventions such as carbohydrate (CHO) ingestion, a similar strategy may prove effective in delaying fatigue in hypoxia, particularly considering how the metabolic pathways enhanced with CHO supplementation overlap the fatiguing pathways upregulated in hypoxia. Many questions regarding the relationship between CHO, hypoxia, and fatigue remain unanswered, including specifics on when to ingest, what to ingest, and how varying altitudes influence supplementation effectiveness. Therefore, the purpose of this narrative review is to examine the peripheral and central mechanisms contributing to fatigue during aerobic exercise at varying degrees of hypoxia and to assess the role of CHO ingestion in attenuating fatigue onset.


Skincare Products as Sources of Mutagenic Exposure to Infants: An Imperative Study Using a Battery of Microbial Bioassays.
Infant skin is highly absorptive and sensitive to exposure from external agents (microbes, toxicants, heat, cold, etc.). Many specialized infant skincare products are currently commercially available. Although the manufacturers claim that their products are mild enough to suit the infant skin, these products need to be studied for their safety. Using animal models to examine the safety of the ever-increasing number of skincare products is not economically or logistically feasible. To overcome this problem, we suggest using a battery of microbial bioassays as a robust system for monitoring the mutagenic potential of skincare products. We picked popular infant skincare products from the Indian market and assessed them by using a battery of three microbial mutagenicity bioassays. Most of them showed significant and reproducible mutagenic potential. Our study results raise concerns about regular use of infant products and emphasize the need to enforce strict regulations for the manufacturing and safety assessment of infant products.


Crowd Characterization in Surveillance Videos Using Deep-Graph Convolutional Neural Network.
Crowd behavior is a natural phenomenon that can provide valuable insight into the crowd characterization process. Modeling the visual appearance of a large crowd gathering can reveal meaningful information about its dynamics. Parametric modeling can be used to develop efficient and robust crowd monitoring systems. A crowd can be structured or unstructured based on the organization. In this article, crowd characterization has been mapped to a graph classification problem to classify movements based on order parameter ( ϕ ), active force components, and steadiness (Reynolds number). The graphs are constructed from the motion groups obtained using an active Langevin framework. These graphs are processed using a deep graph convolutional neural network for crowd characterization. For experimentation, we have prepared a dataset comprising of videos from popular publicly available datasets and our own recorded videos. The proposed framework has been compared with the latest deep learning-based frameworks in terms of accuracy and area under the curve (AUC). We have obtained a 4%-5% improvement in accuracy and AUC values over the existing frameworks. The insights obtained from the proposed framework can be used for better crowd monitoring and management.


Palliative care considerations and practices for adolescents and young adults with cancer.
The definition of adolescents and young adults (AYAs) in oncology varies with upper limits up to age 39. Younger AYAs, ages 12-24 years, are often cared for within pediatrics. In caring for AYAs with cancer, there are unique considerations that become even more important to recognize, acknowledge, and address in AYAs with life-threatening cancer receiving palliative care. This review highlights important factors such as psychosocial development, cultural considerations, and support structure, which should be considered when providing palliative care to AYAs with cancer during the various stages of care: introduction of palliative care; symptom management; advanced care planning (ACP); end-of-life (EOL) care; and bereavement.


Literacy, education and adherence to antiretroviral therapy in The Gambia.
We examined the relationship of patients' literacy and education to antiretroviral therapy (ART) adherence in an urban treatment centre in The Gambia. Information on education and literacy systematically collected before ART initiation was compared against selected adherence outcomes. Formally educated patients were significantly more likely to achieve virological suppression at both six and 12 months (87% vs. 67%, OR=3.13, P=0.03; 88% vs. 63%, OR=4.49, P=0.007, respectively). Literate patients had similar benefit at 12 months (OR=3.39 P=0.03), with improved virological outcomes associated with degree of literacy (P=0.003). A trend towards similar results was seen at 6 months for Koranically educated patients; however, this was no longer apparent at 12 months. No significant correlation was seen between socio-demographic characteristics and missed appointments. Our study suggests that literacy, formal education and possibly Koranic education may impact favourably on adherence to ART.


A cross-cultural study of oral health values.
The Oral Health Impact Profile (OHIP) is a measure of oral-health-related quality of life developed in Australia but being used increasingly in other populations. In view of the culturally specific nature of peoples' perceptions of health, if we are to make between-population comparisons of oral-health-related quality of life, cross-cultural equivalency of the relevant instruments needs to be verified. A study was therefore undertaken to compare item weights generated by an Australian sample with those generated by a sample of English-speaking Canadians and another of French-speaking Canadians. In addition, within-group comparisons by age were performed. The items and subscales used for the 2 Canadian samples were identical to those developed in Australia, although a formal French translation was used for the French-speaking sample. The method used for the generation of weights was Thurstone's paired-comparison technique, based on the judgments of convenience samples of subjects drawn from each of the three cultural settings. Comparisons were made by means of intra-subscale weight rankings and magnitude. Spearman's rank correlations of r> or =0.6 were found for 16/21 between-group comparisons and for 12/21, 19/21, and 8/21 within-group comparisons made by age in Australia, Ontario, and Quebec, respectively. Comparisons of the magnitudes of weights found that, even when items were ranked similarly, magnitudes could be quite different. These results suggest a reasonable degree of cross-cultural consistency, and hence validity, for the OHIP.


Drug metabolism in the horse: a review.
A detailed understanding of equine drug metabolism is important for detection of drug abuse in horseracing and also in veterinary drug development and practice. To date, however, no comprehensive review of equine drug metabolism has been published. The majority of literature regarding equine drug metabolite profiles is derived from sports drug detection research and is generally targeted at detecting marker metabolites of drug abuse. However, the bulk of the literature on equine drug metabolism enzymology is derived from veterinary studies aimed at determining the molecular basis of metabolism. In this article, the phase 1 and 2 metabolisms of seven of the most important classes of drugs monitored in horseracing are reviewed, including: anabolic-androgenic steroids (AAS), β₂ -agonists, stimulants, sedatives/tranquilizers, local anesthetics, non-steroidal anti-inflammatory analgesics (NSAIDS)/cyclooxygenase-2 (COX-2) inhibitors, and opioid analgesics. A summary of the literature relating to the enzymology of drug metabolism in this species is also be presented. The future of equine drug metabolism in the area of doping research will be influenced by several factors, including: a possible move towards the increased use of blood and other alternative testing matrices; the development of assays based on intact drug conjugates; the increasing threat of 'designer' and herbal- based products; advances in the use of in vitro technologies; the increased use of liquid-chromatography/high-resolution mass spectrometry; and the possibility of screening using 'omics' approaches. Also, the recent cloning of a range of equine cytochrome P450 (CYP) enzymes opens up the potential for carrying out more detailed mechanistic pharmacological and toxicological veterinary studies.


Purification of the putative alpha-latrotoxin receptor from bovine synaptosomal membranes in an active binding form.
alpha-Latrotoxin (alpha-LTx, apparent mol. wt. 130 000) is a presynaptically active neurotoxin purified from the venom of the black widow spider that causes massive exocytotic release of neurotransmitters, presumably via binding to presynaptic membrane protein(s). Solubilization and purification experiments were undertaken to identify and characterize this membrane component. An immunoaffinity matrix was prepared by sequentially binding anti-alpha-LTx antibodies and alpha-LTx to Protein A-Sepharose CL-4B. Beads were irreversibly cross-linked with dimethyl pimelimidate. These beads were capable of extracting alpha-LTx binding activity from Triton X-100 solubilized bovine synaptosomal membranes. Following extensive washing, bound material was eluted with 6 M urea. Analysis of silver stained and radiolabel-containing gels revealed one major band (apparent mol. wt. 200 000) under non-reducing conditions and two major bands (apparent mol. wts. 66 000 and 54 000) under reducing conditions. The purified material was still capable of specifically binding alpha-LTx as determined by solid phase assays on microtiter plates. The affinity for alpha-LTx of the purified preparation was similar to that of the native membrane (KA approximately 10(10) M). It is concluded that a putative alpha-LTx receptor protein can be purified from synaptosomal membranes using an immunoaffinity matrix in a form that retains its defined biological property (alpha-LTx binding).


The growth and nutritional status of healthy Asian children aged 4-40 months living in Sheffield.
Detailed anthropometric measurements were made on 169 healthy children aged between 4 and 40 months during a comprehensive study of the diet and nutritional status of Asian children (of Pakistani and Bangladeshi origin) living in Sheffield. These measurements were used to describe the growth profile of these apparently healthy children and to compare this with both international and UK reference data. The distribution of values for most anthropometric measurements was close to the UK reference data although both boys and girls tended to be slight of build, and girls tended to have relatively smaller head circumferences. Nevertheless, it was concluded that their growth and nutritional status over this age range can be evaluated using standard (UK) growth charts.


Mycoplasma bovis outbreak in a herd of North American bison (Bison bison).
A disease outbreak of high morbidity and high mortality in bison (Bison bison) was investigated. Clinical signs included lameness, swollen joints, respiratory distress, and lethargy. Fifty-three of 194 animals died. Cows between 5 and 10 years of age were the most affected group, in which 40 of 88 animals died. Necropsies were performed on several animals. There were abscesses in the lung and liver, as well as fibrinosuppurative pleuritis, polyarthritis, and disseminated microabscesses in various organs. No significant bacteria were isolated by routine aerobic cultures of lung and liver from 2 representative cases. However, Mycoplasma cultures were positive. Polymerase chain reaction tests on the isolated bacteria were positive for Mycoplasma bovis. Histologically, the abscesses were characterized by areas of necrosis with variable mineralization rimmed by granulomatous inflammation and fibrous tissue. No new animals had been introduced into the herd, but a cattle herd was present adjacent to the affected bison herd. Two restriction fragment length polymorphism techniques were used to compare the bison isolate and another bison isolate from an outbreak in North Dakota with a field isolate of M. bovis from cattle and with a laboratory control strain of M. bovis; the isolates and control strain were found to be similar. The isolates and the control were sequenced and compared with sequences in GenBank. Bison isolates were more than 99% homologous to M. bovis sequences in GenBank. It was concluded that M. bovis in bison can cause disseminated infection with a high morbidity and mortality and that bison isolates are similar to bovine M. bovis isolates.


Torsed ectopic intra-abdominal liver rest within an adolescent female.
Extrahepatic liver (EL) rests are rare, with a reported annual incidence of 0.24-0.47. While reports often note EL incidentally found on pathologic specimens of aberrant tissue, there has been a case report of hepatocellular carcinoma arising from one of these rests, highlighting the importance of surgical resection. EL has been reported to cause symptoms such as abdominal pain, intraperitoneal bleeding and compression of adjacent organs. Most commonly, it has been identified in the gallbladder, likely due to proximity of the gallbladder to the native liver. The paucity of diagnostic tests makes the preoperative diagnosis challenging. We present a case of a 12-year-old female presenting with severe epigastric pain secondary to incapsulated EL tissue attached to the stomach via a narrow stalk. By describing this case, we hope to improve the diagnosis and management of abdominal masses with unclear etiology.


Oral Metformin for Treating Dermatological Diseases: A Systematic Review.
Introduction:Metformin is an antihyperglycemic medication most commonly used to treat Type II Diabetes Mellitus with promising off-label application for the treatment of hidradenitis suppurativa, psoriasis, acne, acanthosis nigricans, and hirsutism. Objective: To comprehensively assess evidence regarding the use of metformin for treating primary cutaneous disorders. Materials and Methods: A systematic literature search was conducted through PubMed, Cochrane, Web of Science, and CINAHL to identify the role of metformin in primary skin disease. Results: Sixty-four studies met inclusion criteria. Metformin demonstrates promising clinical response and favorable safety profile for treatment of HS, with most patients experiencing a decrease in frequency or severity of HS flares, and some experiencing full resolution of HS lesions. Patients with psoriasis treated with metformin experienced quantifiable clinical responses. Application of metformin on polycystic ovarian disease (PCOS) related acne, acanthosis nigricans, and hirsutism yielded mixed clinical results. No serious adverse effects were reported. Conclusion: Metformin is safe and efficacious and may be considered as an adjunctive therapy for the treatment of psoriasis and hidradenitis suppurativa in addition to first line therapies as well as PCOS related acne, acanthosis nigricans, and hirsutism. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.4874.


Stenting and abciximab in primary angioplasty: a review of current status.
Improvement of stent deployment techniques and advances in antiplatelet therapy have shown that stenting in the setting of ST-elevation myocardial infarction (STEMI) is safe and effective. Randomized trials have found that as compared to balloon angioplasty, coronary stenting does not reduce mortality and reinfarction, despite the reduction in target vessel revascularization. Furthermore, these benefits seem to be reduced when applied to unselected patients with STEMI. Direct stenting represents an attractive strategy with potential benefits in terms of myocardial perfusion. Future randomized trials are needed to evaluate if this strategy is associated with a significant impact on outcome, and to provide cost-benefit analysis of an unrestricted use of drug-eluting stent in this high-risk subset of patients. Data from randomized trials have shown that the additional use of abciximab reduces mortality in primary angioplasty. Since the feasibility of long-distance transportation has been shown in several randomized trials, early pharmacological pretreatment may confer further advantages by early recanalization and shorter ischemic time, particularly in high-risk patients. Further large randomized trials are needed to clarify the potential role of small molecules in primary angioplasty for STEMI.


Facial aesthetic correction with injectable poly-L-lactic Acid following removal of malar cheek implants.
Cheek implants may need to be removed from some patients due to pathologic conditions, such as infection, or patient dissatisfaction with cosmetic results. In these cases, correction of implant-associated facial volume loss may be achieved by using injectable poly-L-lactic acid. Injectable poly-L-lactic acid has been used successfully and safely for restoration and/or correction of the signs of facial fat loss (lipoatrophy) in people with human immunodeficiency virus. Here, the author reports the off-label use of injectable poly-L-lactic acid for the correction of facial volume loss following removal of malar cheek implants to yield a cheek lift and correction of prominent nasolabial fold wrinkles in a man with no significant medical problems. A total of three treatments using two vials of injectable poly-L-lactic acid per treatment were administered over the course of 16 weeks. Photographs were taken at baseline, during the 16-week injection period, and at a post-treatment evaluation visit 35 days after the final treatment (21 weeks after the initial injection). Although the patient has since been lost to follow up, he was very satisfied with the aesthetic results at the evaluation visit five weeks after the last treatment and expressed a desire to be treated with poly-L-lactic acid in the future. Injectable poly-L-lactic acid may be a good option for the correction of facial volume loss due to reasons other than human immunodeficiency virus-related lipoatrophy.


Fluticasone Induces Epithelial Injury and Alters Barrier Function in Normal Subjects.
The airway epithelium has a number of roles pivotal to the pathogenesis of asthma, including provision of a physical and immune barrier to the inhaled environment. Dysregulated injury and repair responses in asthma result in loss of airway epithelial integrity. Inhaled corticosteroids are a corner stone of asthma treatment. While effective in controlling asthma symptoms, they fail to prevent airway remodeling. Direct cytopathic effects on the airway epithelium may contribute to this. This study examined the effects of a 4-week treatment regimen of inhaled fluticasone 500 μg twice daily in healthy human subjects. Induced sputum was collected for cell counts and markers of inflammation. Barrier function was examined by diethylenetriaminepentacetic acid (DTPA) clearance measured by nuclear scintillation scan, and albumin concentration in induced sputum. Steroid exposure resulted in epithelial injury as measured by a significant increase in the number of airway epithelial cells in induced sputum. There was no change in airway inflammation by induced sputum inflammatory cell counts or cytokine levels. Epithelial shedding was associated with an increase in barrier function, as measured by both a decrease in DTPA clearance and decreased albumin in induced sputum. This likely reflects the normal repair response. Inhaled corticosteroids cause injury to normal airway epithelium. These effects warrant further evaluation in asthma, where the dysregulated repair response may contribute to airway remodeling.


Hemodynamic measurements in the evaluation and follow-up of transluminal angioplasty of the iliac and femoral arteries.
Intra-arterial pressure measurements and ankle pressure indices (determined by Doppler ultrasound) were used to evaluate the hemodynamic response after transluminal angioplasty of the iliac and superficial femoral arteries. Intra-arterial pressure was the best determinant of the end point and technical success of the procedure, while improvement in the ankle pressure index was a good predictor of clinical success. Patients with clinical improvement had a significant increase in ankle pressure regardless of the status of peripheral runoff, while those without improvement did not; they demonstrated impaired distal runoff and required further surgical intervention. Peripheral Doppler pressures also provided a convenient noninvasive method of long-term follow-up.


Distribution of schistosome infections in molluscan hosts at different levels of parasite prevalence.
Biomphalaria glabrata snails infected with Schistosoma mansoni were collected during consecutive seasons from a site in Brazil known to have a very high percentage of infected snails. Schistosoma mansoni cercariae from single snails were used to infect individual mice, and the recovered adult worms were genetically assessed using a mtVNTR marker. The number of unique parasite genotypes found per snail was compared to expected abundance values, based on the infection prevalence at the site, to determine the distribution of S. mansoni infections within the snail population. The observed distributions and those from previous studies were used to examine the relationship between schistosome prevalence and aggregation across a wide range of prevalence values. Our analysis showed that prevalence was inversely related to the degree of parasite overdispersion, and at high prevalence, S. mansoni infections were randomly distributed among snails.


Transitional cell carcinoma of ureteral stump after radical nephrectomy for renal cell carcinoma.
A 68-year-old male presented with microscopic hematuria during a routine checkup after undergoing a radical nephrectomy for renal cell carcinoma. Retrograde ureterography demonstrated a ureteral stump tumor. The ureteral stump was completely resected with a bladder cuff and histologic diagnosis was grade 2 to 3 transitional cell carcinoma of the ureteral stump. He is doing well and has been tumor-free for 2 years. The ureteral stump must be correctly evaluated using retrograde ureterography in any patient with a prior history of bladder cancer. Even if a patient had no history of ureterial cancer, whenever hematuria is present in the follow-up period after nephrectomy for renal cell carcinoma, a retrograde pyelogram should be performed.


Spatial Pattern of Verticillium dahliae Microsclerotia and Cotton Plants with Wilt Symptoms in Commercial Plantations.
Spatial patterns of pathogen inoculum in field soils and the resulting patterns of disease may reflect the underlying mechanisms of pathogen dispersal. This knowledge can be used to design more efficient sampling schemes for assessing diseases. Spatial patterns of Verticillium dahliae microsclerotia were characterized in commercial cotton fields through quadrat and point sampling in 1994 and 2013, respectively. Furthermore, cotton plants with wilt symptoms, caused by V. dahliae, were assessed in six commercial cotton fields in 2013. Soil samples were assayed for the density of microsclerotia (expressed as CFU g-1 of soil) using a wet-sieving plating method and a real-time quantitative PCR method for the 1994 and 2013 study, respectively. The estimated inoculum threshold for causing wilt development on individual plants varied with the three fields: ca. 1.6 CFU g-1 of soil for one field, and 7.2 CFU g-1 of soil for the other two. Both quadrat and point sampling spatial analyses showed that aggregation of V. dahliae inoculum in soils was usually not detected beyond 1.0 m. Similarly, the spatial patterns of wilted cotton plants indicated that spatial aggregation of diseased plants were only observed below the scale of 1.0 m in six commercial cotton plantations. Therefore, spatial aggregation of both V. dahliae inoculum and cotton plants with wilt symptoms is not likely to be detected above the scale of 1.0 m for most commercial cotton plantations. When designing schemes for assessing wilt inoculum and wilt development, this scale needs to be taken into consideration.


Regulation of endothelin-1 gene expression by cell shape and the microfilament network in vascular endothelium.
Endothelial synthesis and release of endothelin-1 (ET-1) are exquisitely regulated by external shear and strain. We tested the hypothesis that manipulation of endothelial cell shape can regulate ET-1 gene expression. Treatment of bovine aortic endothelial cell (BAEC) monolayers with cytochalasin D disrupted F-actin and induced cell retraction and rounding, in parallel with time- and dose-dependent specific decreases in ET-1 mRNA levels. Treatments with forskolin, phorbol 12-myristate 13-acetate, staurosporine, and genistein also induced cell shape change and decreased F-actin staining and ET-1 mRNA levels. BAEC plated onto nonadhesive petri dishes coated with decreasing concentrations of synthetic RGD polymer showed RGD dose-dependent decreases in cell spreading and in F-actin microfilament elaboration. These changes were specifically accompanied by decreases in ET-1 peptide secretion (60%) and, via posttranscriptional mechanisms, ET-1 mRNA (94%) and were not due to decreased cell-cell contact. We conclude that the shape and microfilament network of endothelial cells are potent posttranscriptional regulators of ET-1 gene expression.


The use of immortalized cell lines in GPCR screening: the good, bad and ugly.
For most membrane-bound molecular targets, including G protein linked receptors (GPCRs), the optimal approach in drug discovery involves the use of cell based high throughput screening (HTS) technologies to identify compounds that modulate target activity. Most GPCRs have been cloned and can therefore be routinely expressed in immortalized cell lines. These cells can be easily and rapidly grown in unlimited quantities making them ideal for use in current HTS technologies. A significant advantage of this approach is that immortalized recombinant cells provide a homogenous background for expression of the target which greatly facilitates consistency in screening, thus allowing for a better understanding of the mechanism of action of the interacting compound or drug. Nonetheless, it is now evident that numerous disparities exist between the physiological environment of screening systems using recombinant cells and natural tissues. This has lead to a problem in the validity of the pharmacological data obtained using immortalized cells in as much as such cells do not always reflect the desired clinical efficacy and safety of the compounds under examination. This brief review discusses these issues and describes how they influence the discovery of drugs using modern HTS.


Paget's disease of the breast areola mimicking cutaneous melanoma.
Paget's disease of the breast nipple and areola complex represents a cutaneous manifestation of an underlying breast malignancy. The typical skin changes characteristic of breast Paget's disease are usually easily distinguished from those found of malignant melanoma. The rare finding of a pigmented cutaneous breast lesion mimicking melanoma presents a diagnostic dilemma. This case presentation describes a pigmented mammary lesion involving the areola that had undergone changes in diameter and pigmentation. The lesion was not associated with nipple drainage, nipple excoriation, dermal ulceration, or a palpable breast mass. The areola lesion was highly suggestive of a dermatologic malignancy such as malignant melanoma. As such, a biopsy was performed with initial findings suggestive of cutaneous melanoma. Upon more detailed analysis of a larger excision specimen, immunohistochemical staining was highly supportive of the diagnosis of breast Paget's disease. A total mastectomy with sentinel lymph node evaluation was performed along with immediate reconstruction. The final pathology revealed a small focus of ductal carcinoma in situ of the breast associated with the areola changes. Histologic and immunohistochemical analysis of a biopsy specimen were paramount in differentiating these two lesions.


Telomere maintenance genes SIRT1 and XRCC6 impact age-related decline in telomere length but only SIRT1 is associated with human longevity.
Leukocyte telomere length is widely considered a biomarker of human age and in many studies indicative of health or disease. We have obtained quantitative estimates of telomere length from blood leukocytes in a population sample, confirming results of previous studies that telomere length significantly decreases with age. Telomere length was also positively associated with several measures of healthy aging, but this relationship was dependent on age. We screened two genes known to be involved in telomere maintenance for association with the age-related decline in telomere length observed in our population to identify candidate longevity-associated genes. A single-nucleotide polymorphism located in the SIRT1 gene and another in the 3' flanking region of XRCC6 had significant effects on telomere length. At each bi-allelic locus, the minor variant was associated with longer telomeres, though the mode of inheritance fitting best differed between the two genes. No statistical interaction was detected for telomere length between the SIRT1 and XRCC6 variants or between these polymorphisms and age. The SIRT1 locus was significantly associated with longevity (P < 0.003). The frequency of the minor allele was higher in long-lived cases than in young controls, which coincides with the protective role of the minor variant for telomere length. In contrast, the XRCC6 variant was not associated with longevity. Furthermore, it did not affect the association of SIRT1 with exceptional survival. The association of the same variant of SIRT1 with longevity was near significant (P < 0.07) in a second population. These results suggest a potential role of SIRT1 in linking telomere length and longevity. Given the differences between this gene and XRCC6, they point to the distinct impact that alternate pathways of telomere maintenance may have on aging and exceptional survival.


Tertiary Amine Pyrazolones and Their Salts as Inhibitors of Mutant Superoxide Dismutase 1-Dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis.
Pyrazolone derivatives have previously been found to be inhibitors of Cu/Zn superoxide dismutase 1 (SOD1)-dependent protein aggregation, which extended survival of an amyotrophic lateral sclerosis (ALS) mouse model. On the basis of ADME analysis, we describe herein a new series of tertiary amine-containing pyrazolones and their structure-activity relationships. Further conversion to the conjugate salts greatly improved their solubility. Phosphate compound 17 exhibited numerous benefits both to cellular activity and to CNS-related drug-like properties in vitro and in vivo, including microsomal stability, tolerated toxicity, and blood-brain barrier permeation. These results indicate that tertiary amine pyrazolones comprise a valuable class of ALS drug candidates.


Subarachnoid pleural fistula due to penetrating trauma: case report and review of the literature.
We describe a case of a 30-year-old man who developed a recurrent pleural effusion after sustaining a gunshot wound to the left side of his chest with subsequent complete paralysis at the T2 level. Subarachnoid-pleural fistulas have rarely been reported as complications of penetrating and blunt trauma, thoracic surgery, as well as spinal surgery. Concomitant injuries may overshadow or complicate the diagnosis of subarachnoid-pleural fistulas. The diagnosis should be considered in any patient with a pleural effusion that is associated with severe neurologic injury, as the fistula rarely heals without surgical intervention and may lead to CNS infection or pneumocephalus.


Ensemble Neuron Tracer for 3D Neuron Reconstruction.
Tracing of neuron paths is important in neuroscience. Recent studies have shown that it is possible to segment and reconstruct three-dimensional morphology of axons and dendrites using fully automatic neuron tracing methods. A specific tracer may be better than others for a specific dataset, but another tracer could perform better for some other datasets. Ensemble of learners is an effective way to improve learning accuracy in machine learning. We developed automatic ensemble neuron tracers, which consistently perform well on 57 datasets of 5 species collected from 7 laboratories worldwide. Quantitative evaluation based on the data generated by human annotators shows that the proposed ensemble tracers are valuable for 3D neuron tracing and can be widely applied to different datasets.


Prevalence of metabolic syndrome in Qazvin Metabolic Diseases Study (QMDS), Iran: a comparative analysis of six definitions.
The aim of the present study was to compare the prevalence of metabolic syndrome (MS) according to six definitions and evaluate the agreement between them in an urban sample in Qazvin, Iran. In a cross sectional study, 529 men and 578 women in age of 20-78 years were attended from September 2010 to April 2011 in Qazvin, Iran. Standardized measurements were available for waist circumference, blood pressure, fasting serum high-density lipoprotein cholesterol, triglycerides, glucose, and insulin. The diagnostic criteria proposed by World Health Organization (WHO), National cholesterol education program third Adult Treatment Panel (ATPIII 2001, 2004), International Diabetes Federation (IDF), American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI), and new Joint Interim Societies (JIS) were applied. The degree of agreement between different definitions was assessed by kappa statistic. The prevalence of MS was found to be 28% (WHO), 26.2% (ATPIII 2001), 30.6% (ATPIII 2004), 34.2% (IDF), 33% (AHA/NHLBI), and 39.3% (JIS). With regards to the gender, the prevalence of MS according to ATPIII 2001 and IDF was significantly greater in women than men. However, using other definitions, the prevalence of MS was similar in both genders. The agreement of JIS criteria with IDF and AHA/NHLBI definitions was excellent (IDF: 0.902; AHA/NHLBI: 0.862), while the agreement of IDF criteria with ATPIII 2004 and AHA/NHLBI was good (ATPIII 2004:0.719; AHA/NHLBI: 0.756). Although JIS definition resulted in a higher prevalence of MS than other definitions, an excellent agreement has been seen between these criteria. Widespread acceptance of JIS definition may lead to management and therapy in a greater part of the population.


Metabolic effects of omega-3 fatty acids in type 2 (non-insulin-dependent) diabetic patients.
The metabolic effects of a 3-week dietary supplement of a fish oil concentrate was examined in mildly obese, normotriglyceridemic men with non-insulin-dependent diabetes mellitus (NIDDM) treated with hypoglycemic agents (n = 20). Patients were randomized into two groups, receiving 15 ml per day of fish oil (Martens Oil, Norway) containing 3.1 g of omega-3 fatty acids (FA) (n = 10) or placebo (n = 10). Whereas fish oil led to the expected increase in the ratio of omega-3 to omega-6 FA in serum phospholipids, reflecting the increase in omega-3 FA intake, it did not alter fasting or mixed meal stimulated blood glucose, plasma insulin, and C-peptide concentrations. No changes in insulin action were noted, estimated by the metabolic clearance rates of glucose at plasma insulin levels of approximately 100 microU/ml and 1,400 microU/ml during a hyperinsulinemic, isoglycemic clamp; no changes were seen in insulin binding to erythrocytes. We conclude that during short-term administration, no adverse effects of low dose fish oil on glucose homeostasis were found in mildly obese NIDDM patients treated with oral hypoglycemic agents.


Transverse spin dynamics in structured electromagnetic guided waves.
Spin-momentum locking, a manifestation of topological properties that governs the behavior of surface states, was studied intensively in condensed-matter physics and optics, resulting in the discovery of topological insulators and related effects and their photonic counterparts. In addition to spin, optical waves may have complex structure of vector fields associated with orbital angular momentum or nonuniform intensity variations. Here, we derive a set of spin-momentum equations which describes the relationship between the spin and orbital properties of arbitrary complex electromagnetic guided modes. The predicted photonic spin dynamics is experimentally verified with four kinds of nondiffracting surface structured waves. In contrast to the one-dimensional uniform spin of a guided plane wave, a two-dimensional chiral spin swirl is observed for structured guided modes. The proposed framework opens up opportunities for designing the spin structure and topological properties of electromagnetic waves with practical importance in spin optics, topological photonics, metrology and quantum technologies and may be used to extend the spin-dynamics concepts to fluid, acoustic, and gravitational waves.


Primary vitreoretinal involvement and immunopositivity for BRAFV600E help distinguish metastatic from primary intraocular melanoma: a detailed histopathologic study of metastatic cutaneous melanoma to the eye.
To evaluate the clinicopathologic characteristics of metastatic cutaneous melanoma to the eye and identify potential distinguishing characteristics from the more common primary uveal melanoma; particularly, tumour location within the eye, cytomorphology and immunohistochemical/specific molecular genetic features. A retrospective observational case series using surgical enucleation and diagnostic vitrectomy cytologic specimens from seven patients with suspected intraocular melanoma, eventually diagnosed as metastatic melanoma, was conducted. Haematoxylin and eosin-stained sections of tumour and immunohistochemical (IHC) stains for BRAFV600E and Ki-67 were critically reviewed; BAP1 IHC was also evaluated in cases where additional tissue was available. Clinical imaging studies and medical records were reviewed. The majority of patients (86%) with metastatic melanoma have primary vitreoretinal (not uveal) involvement and epithelioid, highly malignant cytomorphology (100%); many (50%) harbour BRAFV600E mutations, a finding not seen in large cohorts of primary uveal melanoma. Characteristics favouring or defining metastatic intraocular melanoma over primary uveal melanoma include high-grade epithelioid cytology, predominant involvement of the vitreous cavity and/or retina, and presence of positive immunostaining for BRAFV600E.


Prediction of atomic force microscope probe dynamics through the receptance coupling method.
The increased growth in the use of tip-based sensing, manipulations, and fabrication of devices in atomic force microscopy (AFM) necessitates the accurate prediction of the dynamic behavior of the AFM probe. The chip holder, to which the micro-sensing device is attached, and the rest of the AFM system can affect the overall dynamics of the probe. In order to consider these boundary effects, we propose a novel receptance coupling method to mathematically combine the dynamics of the AFM setup and probe, based on the equilibrium and compatibility conditions at the joint. Once the frequency response functions of displacement over force at the tool tip are obtained, the dynamic interaction forces between the tip and the sample in nanoscale can be determined by measuring the probe tip displacement.


Secrets of management success.
Research has shown that certain characteristics set successful managers apart from their less successful colleagues. Research that is just beginning shows that most of those characteristics also set successful physician executives apart. This article is based on presentations at the College's 1989 National Conference in Washington, D.C., and introduces concepts that will be reported on in more detail in upcoming issues of Physician Executive.


Muscle-targeted interleukin-12 gene therapy of orthotopic hepatocellular carcinoma in mice using in vivo electrosonoporation.
We developed a new potent nonviral gene transfer method into mouse muscles in vivo named "electrosonoporation." We tried in this report to treat murine orthotopic hepatocellular carcinoma (HCC) by muscle-targeted mouse interleukin-12 (mIL-12) gene transfer using in vivo electrosonoporation. I.m. administration of the mIL-12 gene with electrosonoporation elevated serum IL-12 and IFN-gamma and significantly prolonged the survival periods with both growth inhibition of orthotopic HCC and inhibition of spontaneous lung metastasis. The IL-12 gene therapy reduced the number of microvessels and induced more Mac-1-positive cells into HCC. These results show that muscle-targeted mIL-12 gene therapy for orthotopic HCC using in vivo electrosonoporation is very efficient and is thus promising for further clinical trial.


Anxa2- and Ctsd-knockout CHO cell lines to diminish the risk of contamination with host cell proteins.
Chinese hamster ovary (CHO) cells have been used as host cells in the production of a range of recombinant therapeutic proteins, including monoclonal antibodies and Fc-fusion proteins. Host cell proteins (HCP) represent impurities that must be removed from therapeutic formulations because of their potential risks for immunogenicity. While the majority of HCP impurities are effectively removed in typical downstream purification processes, clearance of a small population of HCP remains challenging. In this study, we knocked out the Anxa2 and Ctsd genes to assess the feasibility of knockout approaches for diminishing the risk of contamination with HCP. Using the CRISPR/Cas9 system, Anxa2-, and Ctsd-knockout CHO cell lines were successfully established, and we confirmed the complete elimination of the corresponding HCP in cell lysates. Importantly, all knockout cell lines showed similar growth and viability to those of the wild-type control during 8 days of cultivation. Thus, knockout of unrequired genes can reduce contamination with HCP in the production of recombinant therapeutic proteins.


Bridging team faultlines by combining task role assignment and goal structure strategies.
This study tests whether the detrimental effects of strong diversity faultlines on team performance can be counteracted by combining 2 managerial strategies: task role crosscutting and superordinate goals. We conducted a 2 (crosscut vs. aligned roles) × 2 (superordinate vs. subgroup goals) experimental study. Seventy-two 4-person teams with faultlines stemming from gender and educational major performed a complex decision-making task. The results show that teams with crosscut roles perform better when they are assigned a superordinate goal than a subgroup goal, whereas teams with aligned roles are not affected by goal manipulations. This effect is mediated by elaboration of task-relevant information. Implications for theory and management of team faultlines are discussed.


Iodide transport in primary cultured thyroid follicle cells: evidence of a TSH-regulated channel mediating iodide efflux selectively across the apical domain of the plasma membrane.
The transport of iodide was studied in porcine thyroid follicle cells cultured in bicameral chambers. The continuous layer of polarized follicle cells, joined by tight junctions, formed a diffusion barrier between the two compartments (apical and basal) of the culture chamber. Uptake and efflux of 125I- at either surface (apical and basolateral) of the cells were thus possible to determine. Protein binding of iodide was inhibited by methimazole (10(-3) M) in all experiments. Radioiodide was taken up by the cells from the basal medium in a thyroid-stimulating hormone (TSH)-dose dependent manner with a maximal cell/medium ratio of 125I- of about 50 in cultures prestimulated with 0.1 to 1 mU/ml for 2 days. This uptake was inhibited by perchlorate and ouabain. In contrast, 125I- was not taken up from the apical medium. In preloaded cells, iodide efflux was rapidly (within 1-2 min) and dose-dependently (0.1-10 mU/ml) stimulated by TSH. Bidirectional measurements revealed that TSH stimulated iodide efflux in apical direction, leaving efflux in basal direction unchanged. In experiments with continuous uptake of label from the basal compartment, the TSH-stimulated efflux in apical direction had a duration of 4 to 6 min and resulted in a reduction in the cellular content of radioiodide by up to 80%. Decreased levels of cellular 125I- remained for at least 15 min after TSH addition. From our observations we conclude that the TSH-regulated uptake and efflux of iodide take place at opposite surfaces of the porcine thyroid follicle cell. Acutely stimulated iodide efflux is not the result of an increased permeability for iodide in the entire plasma membrane but only in the apical domain of this membrane. This implicates the presence of an iodide channel mediating TSH-stimulated efflux across the apical plasma membrane of the follicle cell. The mechanism is suggested to facilitate a vectorial transport of iodide in apical direction, i.e., to the lumen of the intact follicle.


Phylodynamics and Codon Usage Pattern Analysis of Broad Bean Wilt Virus 2.
Broad bean wilt virus 2 (BBWV-2), which belongs to the genus Fabavirus of the family Secoviridae, is an important pathogen that causes damage to broad bean, pepper, yam, spinach and other economically important ornamental and horticultural crops worldwide. Previously, only limited reports have shown the genetic variation of BBWV2. Meanwhile, the detailed evolutionary changes, synonymous codon usage bias and host adaptation of this virus are largely unclear. Here, we performed comprehensive analyses of the phylodynamics, reassortment, composition bias and codon usage pattern of BBWV2 using forty-two complete genome sequences of BBWV-2 isolates together with two other full-length RNA1 sequences and six full-length RNA2 sequences. Both recombination and reassortment had a significant influence on the genomic evolution of BBWV2. Through phylogenetic analysis we detected three and four lineages based on the ORF1 and ORF2 nonrecombinant sequences, respectively. The evolutionary rates of the two BBWV2 ORF coding sequences were 8.895 × 10-4 and 4.560 × 10-4 subs/site/year, respectively. We found a relatively conserved and stable genomic composition with a lower codon usage choice in the two BBWV2 protein coding sequences. ENC-plot and neutrality plot analyses showed that natural selection is the key factor shaping the codon usage pattern of BBWV2. Strong correlations between BBWV2 and broad bean and pepper were observed from similarity index (SiD), codon adaptation index (CAI) and relative codon deoptimization index (RCDI) analyses. Our study is the first to evaluate the phylodynamics, codon usage patterns and adaptive evolution of a fabavirus, and our results may be useful for the understanding of the origin of this virus.


Actinic keratoses: Natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial.
Actinic keratoses (AKs) are established as direct precursors of squamous cell carcinoma (SCC), but there is significant controversy regarding the rate at which AKs progress to SCC. The authors of this report studied a high-risk population to estimate the risk of progression of AK to SCC and to basal cell carcinoma (BCC) and the risk of spontaneous regression of untreated AKs. Data were obtained from participants in the Department of Veterans Affairs Topical Tretinoin Chemoprevention Trial. Participants were examined every 6 months for up to 6 years. At each examination, the locations on the face and ears of clinically diagnosed AKs and lesions scheduled for biopsy were marked, and high-resolution digital photographs were taken. These photographs were used later to map and track the presence, absence, or biopsy of each AK across visits. In total, 7784 AKs were identified on the face and ears of 169 participants. The risk of progression of AK to primary SCC (invasive or in situ) was 0.60% at 1 year and 2.57% at 4 years. Approximately 65% of all primary SCCs and 36% of all primary BCCs diagnosed in the study cohort arose in lesions that previously were diagnosed clinically as AKs. The majority of AKs (55%) that were followed clinically were not present at the 1-year follow-up, and the majority (70%) were not present at the 5-year follow-up. In the current study, the authors quantified the malignant potential of clinically diagnosed AKs for both SCC and BCC, although many did not persist, and the results suggested that AKs may play a greater role in the overall burden of keratinocyte carcinomas than previously documented.


Recent developments of sonodynamic therapy in antibacterial application.
The rapid emergence of pathogenic bacteria poses a serious threat to global health. Notably, traditional antibiotic therapies suffer from the risk of strengthening bacterial drug resistance. Sonodynamic therapy (SDT) combining sonosensitizers and low-intensity ultrasound (US) has broadened the way towards treating drug-resistant bacteria. The allure of this therapy emerges from the capacity to focus the US energy on bacterial infection sites buried deep in tissues, locally activating the sonosensitizers to produce cytotoxic reactive oxygen species (ROS) with the ability to induce bacterial death. The past decade has witnessed the rapid development of antibacterial SDT owing to their excellent penetration, favorable biocompatibility and specific targeting ability. This review summarizes available sonosensitizers for antibacterial SDT, and digs into innovative biotechnologies to improve SDT efficiency, such as enhancing the targeting ability of sonosensitizers, image-guided assisted SDT, improvement of hypoxia and combination of SDT with other therapies. Finally, we conclude with the present challenges and provide insights into the future research of antibacterial SDT.