[Modern approaches to immunization of patients of rheumatologic profile].
Recently, the importance of comorbid infections in rheumatology has increased significantly, which have a significant impact on morbidity and mortality, especially in immuno-inflammatory rheumatic diseases (IIRD). In this regard, vaccination is becoming increasingly important in the prevention of infections in these patients. This review presents an updated version of the recommendations for vaccination of adult patients with IIRD, prepared by experts of the European Union League against Rheumatism (EULAR). There is a low (suboptimal) vaccination coverage of these patients, partly due to the low frequency of referral by doctors. The role of the rheumatology team in solving the problems associated with immunization of patients with IIRD is emphasized, as well as the importance of joint decision-making taking into account the needs and preferences of patients. The issues concerning the use of vaccines against influenza, pneumococcal infection, hepatitis B.


Cytotoxicity of a series of water-soluble mixed valent diruthenium tetracarboxylates.
Mixed-valent diruthenium tetracarboxylate complexes were shown to have slight antineoplastic activity against P388 leukemia cell lines. However these complexes suffered from poor water-solubility, which may have detrimentally affected their activity. Mixed-valent diruthenium tetracarboxylates of the type [Ru2(O2CR)4(L)2] (PF6) with L = imidazole, 1-methylimidazole and H2O when R = CH3, L = ethanol when R = Fc (ferrocenyl) or Fc-CH=CH- and of the type M3[Ru2(O2CR)4(H2O)2]4H2O, M = Na+ when R = m-C6H4SO3- and M = K+ when R = p-C6H4SO3-, were tested for cytotoxicity against HeLa and multidrug resistant CoLo 320DM human cancer cell lines. Cell survival was measured by means of the colorometric 3-(4,5dimethylthiazol-2-yl)-diphenyltetrazodium bromide assay. The mean drug concentration from 3 experiments causing 50% cell killing, ie, IC50 values, varied between 120 and 950 micromol dm(-3). The antineoplastic activity of the highly water-soluble m-sulpho derivative was the highest, while the poorly water-soluble imidazole derivatives did not exhibit any cytotoxic properties. The CoLo 320DM cancer cells were 5 times more prone to drug-induced cell death than the HeLa cells.


The Use of POSS-Based Nanoadditives for Cable-Grade PVC: Effects on its Thermal Stability.
Plasticized-Poly(vinyl chloride) (P-PVC) for cables and insulation requires performances related to outdoor, indoor and submarine contexts and reduction of noxious release of HCl-containing fumes in case of thermal degradation or fire. Introducing suitable nanomaterials in polymer-based nanocomposites can be an answer to this clue. In this work, an industry-compliant cable-grade P-PVC formulation was added with nanostructured materials belonging to the family of Polyhedral Oligomeric Silsesquioxane (POSS). The effects of the nanomaterials, alone and in synergy with HCl scavenging agents as zeolites and hydrotalcites, on the thermal stability and HCl evolution of P-PVC were deeply investigated by thermogravimetric analysis and reference ASTM methods. Moreover, hardness and mechanical properties were studied in order to highlight the effects of these additives in the perspective of final industrial uses. The data demonstrated relevant improvements in the thermal stability of the samples added with nanomaterials, already with concentrations of POSS down to 0.31 phr and interesting additive effects of POSS with zeolites and hydrotalcites for HCl release reduction without losing mechanical performances.


Cytologic features of sinus histiocytosis with massive lymphadenopathy. A report of three cases.
Sinus histiocytosis with massive lymphadenopathy (SHML) was described over 20 years ago by Rosai and Dorfman. Originally it was described as occurring in young males, predominantly with cervical lymphadenopathy. Since then over 423 histologically documented cases of SHML have been documented, including many extranodal sites. Few studies have characterized the cytologic features of SHML. Three cases of lymph node involvement by SHML occurred, one also with skin involvement. Cytologic findings included numerous histiocytes with phagocytized lymphocytes, atypical forms of histiocytes and a reactive, lymphoid background. Surgical biopsy and immunohistochemical stain for S-100 protein of all three cases confirmed the cytologic impression. Sinus histiocytosis with massive lymphadenopathy can be diagnosed by cytology in conjunction with clinical history and immunohistochemistry.


Distal splenorenal shunt with splenopancreatic disconnection. A 4-year assessment.
The aims of distal splenorenal shunt with splenopancreatic disconnection (DSRS-SPD) were to improve maintenance of portal flow and prevent siphoning of hepatotrophic factors from the pancreas, as occurs after standard DSRS. The main patient population targeted for improvement were alcoholic cirrhotics, who have poorer survival than nonalcoholic cirrhotics and greater loss of portal flow (60%) after standard DSRS. Seventy-eight patients had DSRS-SPD during the study period 1983 to 1987: thirty-two patients were Child's A, 25 were Child's B, and 21 were Child's C. The 35 patients with alcoholic cirrhosis were a significantly poorer risk group by Child's class and galactose elimination capacity (GEC) than the 39 patients with nonalcoholic cirrhosis. Four patients had portal vein thrombosis. At 4-year follow-up, portal perfusion is maintained in 84% alcoholic and 90% nonalcoholic patients, with hepatic and systemic hemodynamics showing identical patterns for both groups. Hepatic function measured by GEC was maintained in alcoholic patients (290 +/- 68 mg/min to 303 +/- 74 mg/min) and nonalcoholics patients (342 +/- 92 to 320 +/- 118 mg/min). Gastric variceal rebleeding occurred in 10 patients--4 early (less than 2 months) and 6 late (18 to 54 months), leading to operation in 4 and transhepatic embolization in 4 patients: 2 of these patients died from this complication. Survival data show an operative mortality rate of 6.4% and overall mortality rate of 30%, with no significant difference between alcoholic and nonalcoholic cirrhotics. DSRS-SPD has significantly improved maintenance of portal perfusion and survival in patients with alcoholic cirrhosis requiring selective shunt for variceal bleeding when compared to standard DSRS. In this population DSRS-SPD is the operation of choice. In patients with nonalcoholic cirrhosis, the current data have not shown DSRS-SPD to have advantage over standard DSRS.


[Synthesis and antinociceptive activity of seselin derivatives].
Natural product seselin and related derivatives with an angular pyranocoumarin skeleton were synthesized from 8-acetyl-7-hydroxycoumarins by condensation with acetone, reduction, and dehydration successively under mild conditions with total yield of > 50%. Twelve seselin derivatives were tested by the writhing response assay induced by acetic acid at a dose of 40 mg x kg(-1). Seselin (4a) and 4,8,8-trimethyl-9,9-dihydro-pyran[2,3-f] chromene-2,10-dione (2b) showed obviously antinociceptive activity with inhibitory effect of 85% and 50%, respectively, more or quite potent than aspirin in the same assay, suggesting that seselin derivatives could be a novel kind of potential antinociceptive agents.


[Fever, headache and paralysis of the left leg].
A 17 year old man was hospitalized because of fever, headache and a paresis of his left leg. Radiologic findings demonstrated a subdural interhemispheric empyema on the right side as a complication of ipsilateral pansinusitis. Streptococcus milleri was cultured as the only pathogen from maxillary sinus suppuration. Pathogenesis and therapy of subdural empyema are discussed. Cure was achieved with ceftriaxone, flucloxacilline and ornidazole during one week followed by ceftriaxone as monotherapy during further five weeks. The importance of streptococcus milleri as causing agent of purulent lesions in internal organs is stressed.


Release of gastrin on vagal stimulation in the cat.
Gastrin released by electrical vagal stimulation was measured in the portal blood of eviscerated cats. Blood flow was recorded by a drop chamber technique and the total gastrin output calculated. Basal peripheral gastrin levels averaged 65 pg/ml and basal portal levels 225 pg/ml. On unilateral vagal stimulation with frequencies above 3-4 Hz gastrin release rapidly increased, reaching a peak within 5-10 min. In spite of continued stimulation and independent of frequency, the gastrin levels declined and returned to basal values after a total of 2-3 000 stimuli. A new maximal response could be induced first after a recovery period of 15-30 min. In the same cat stimulation of either the left or the right vagus released equal maximal amounts of gastrin (average 32 000 pg). The maximal gastrin output on vagal stimulation corresponds to less than 1% of the total content of antral gastrin determined with radioimmunoassay.


The Effect of Insurance Status on Bariatric Surgery Outcomes: A Retrospective Chart Review Study.
Prior studies have shown socioeconomic factors and race to affect weight loss after bariatric surgery, but few have focused on the impact of insurance status. The purpose of this study was to determine if insurance status affects bariatric surgery patients' surgical outcomes and weight loss. A retrospective review was conducted of 408 bariatric patients who underwent laparoscopic Roux-en-Y gastric bypass (LRYGB) or sleeve gastrectomy (SG). Patients were stratified by insurance status and surgery type to evaluate weight loss and surgical outcomes. Overall, patients experienced 71.0% excess weight loss at 1-year postoperatively. Patients undergoing LRYGB had greater percent excess weight loss (%EWL) at 1-year (74.5% vs 63.3%, P < .001) than SG patients. Upon multiple regression analysis, insurance type did not affect %EWL. Instead, younger age, female gender, LRYGB procedure, and lower initial BMI were all associated with greater %EWL. Insurance type is not a useful independent predictor of successful weight loss in bariatric surgery patients.


Primary hepatic neuroendocrine tumor with multiple liver metastases: A case report with literature review.
Primary hepatic neuroendocrine tumors (PHNETs) are a group of extremely rare tumors that are difficult to differentiate from common hepatic malignancies on routine imaging studies. By presenting a case of PHNET, we herein introduce our experience with the diagnosis, differential diagnosis, and management of patients with this rare disease. The patient was preoperatively diagnosed with hepatic hydatidosis but postoperatively diagnosed with a PHNET with multiple liver metastases. He was successfully treated with transcatheter arterial chemoembolization. This case indicates that the clinical diagnosis of PHNET is a medical challenge. Although peptide receptor radionuclide therapy has been suggested as the mainstay of treatment for well-differentiated somatostatin receptor-positive PHNETs, patients with a large tumor burden may also benefit from transcatheter arterial chemoembolization.


Prasugrel for the treatment of coronary thrombosis: a review of pharmacological properties, indications for use and future development.
Dual antiplatelet therapy with aspirin and the P2Y(12) receptor antagonist clopidogrel is the cornerstone of treatment for prevention of recurrent ischemic events in high-risk patients. Despite the benefits of this strategy, a number of patients experience recurrent atherothrombotic events. Investigations have shown that this may be in part related to the broad range in pharmacodynamic response to clopidogrel, which includes patients with poor platelet inhibitory effects who have an increased risk of events. Prasugrel (CS-747; LY-640315) is a novel, third-generation oral thienopyridine that is a specific, irreversible antagonist of the platelet P2Y(12) receptor. Laboratory results with prasugrel support more potent antiplatelet effects, a lower incidence of interpatient variability in antiplatelet response, and a reduced time to onset of antiplatelet activity compared with clopidogrel. This manuscript reviews the pharmacological properties, safety and efficacy of prasugrel and provides current indications for its use and future development. Prasugrel exerts more prompt, potent and predictable antiplatelet effects than clopidogrel. These translate into a greater reduction in ischemic events, including stent thrombosis, in acute coronary syndrome patients undergoing percutaneous coronary intervention albeit at the expense of an increased risk of bleeding.


Funnel hopping Monte Carlo: An efficient method to overcome broken ergodicity.
Monte Carlo simulations are a powerful tool to investigate the thermodynamic properties of atomic systems. In practice, however, sampling of the complete configuration space is often hindered by high energy barriers between different regions of configuration space, which can make ergodic sampling completely infeasible within accessible simulation times. Although several extensions to the conventional Monte Carlo scheme have been developed, which enable the treatment of such systems, these extensions often entail substantial computational cost or rely on the harmonic approximation. In this work, we propose an exact method called Funnel Hopping Monte Carlo (FHMC) that is inspired by the ideas of smart darting but is more efficient. Gaussian mixtures are used to approximate the Boltzmann distribution around local energy minima, which are then used to propose high quality Monte Carlo moves that enable the Monte Carlo simulation to directly jump between different funnels. We demonstrate the method's performance on the example of the 38 as well as the 75 atom Lennard-Jones clusters, which are well known for their double funnel energy landscapes that prevent ergodic sampling with conventional Monte Carlo simulations. By integrating FHMC into the parallel tempering scheme, we were able to reduce the number of steps required significantly until convergence of the simulation.


The fine structural localization of endogenous and exogenous peroxidase activity in Kupffer cells of rat liver.
Endogenous peroxidase activity has been demonstrated in sections of rat liver fixed briefly by glutaraldehyde perfusion and incubated in Graham and Karnovsky's medium for cytochemical demonstration of peroxidase activity (29). In 25-40% of sinusoidal cells, an electron-opaque reaction product is localized in segments of the endoplasmic reticulum, including the perinuclear cisternae, a few Golgi vesicles and saccules and in some large membrane-bounded granules. This staining is abolished after prolonged fixation or boiling of tissue sections in glutaraldehyde, and in the absence of H(2)O(2) or DAB from the incubation medium. Furthermore, the reaction is inhibited completely by sodium azide and high concentrations of H(2)O(2), and partially by KCN and aminotriazole. Among the different cells in hepatic sinusoids, the nonphagocytic "fat-storing" cells (39) are always peroxidase negative, whereas the lining cells in process of erythrophagocytosis are consistently peroxidase positive. The possible biological significance of endogenous peroxidase in Kupffer cells is discussed. In addition, the uptake of exogenous horseradish peroxidase by Kupffer cells has been investigated. The exogenous tracer protein, which in contrast to endogenous peroxidase of Kupffer cells is not inhibited by prolonged aldehyde fixation, is taken up by micropinocytosis and remains confined to the lysosomal system of Kupffer cells. The significance of these observations in respect to some recent studies suggesting localization of exogenous peroxidases in the endoplasmic reticulum of Kupffer cells and peritoneal macrophages (22, 23) is briefly discussed.


A dot-ELISA test using a Gnathostoma spinigerum recombinant matrix metalloproteinase protein for the serodiagnosis of human gnathostomiasis.
Gnathostomiasis caused by Gnathostoma spinigerum, is a hazardous food- borne helminthic zoonosis, and is endemic especially in developing countries in Asia. Definitive diagnosis, relying upon identification of worms from human tissues or body, is rarely accomplished. Consequently, sensitive supporting tools such as serological tests have been used widely. But these methods are time con- suming, need sophisticated equipment and are impractical in some settings. In the present study a dot enzyme-linked immunosorbent assay (dot-ELISA), using C. spin igerum recombinant matrix metalloproteinase protein as the antigen, was developed and assessed using sera of gnathostomiasis and other parasitosis pa- tients as well as healthy controls. The accuracy, sensitivity, specificity, positive and negative predictive values were 97.4%, 100%, 96.1%, 92.9%, and 100%, respectively. The dot-ELISA appears to be a suitable rapid test for diagnostic purpose as well as epidemiological studies.


Factors influencing glucose flux and the effect of insulin in cultured human cells.
Uptake of glucose-(3)H into cultured HLM cells was measured. Equilibration of intracellular and extracellular pools occurred after 25 min. Glucose influx was determined subsequently by measuring the glucose-(3)H entering in precisely 1 min. Although saturation kinetics were demonstrated these were not of the simple Michaelis-Menten type. The K(m) of the glucose carrier system is probably about 60 mM glucose. Galactose did not compete with glucose. Insulin stimulated glucose flux without increasing the value of V(max). The stimulation was fully demonstrable after 10 min, could be elicited at concentrations of 10(-4) units/ml, and was absent 2-4 hr after removal. Increasing pH had little or no effect in stimulating glucose flux. Increasing osmotic pressure caused a marked increase and reduced the effect of insulin. Glucose influx was unaffected by anoxia. Glucose influx was increased and the effect of insulin abolished in the absence of K(+). Glucose influx was increased by mercuric chloride, iodoacetate, and fluoride which abolished the effect of insulin. Dinitrophenol decreased the rate of glucose uptake but did not alter the effect of insulin. Phlorizin reduced the rate of glucose uptake and abolished the effect of insulin. ATP and AMP enhanced the rate of glucose uptake. These findings are discussed in relation to the mode of action of insulin.


Assessing cerebrovascular reactivity by the pattern of response to progressive hypercapnia.
Cerebral blood flow responds to a carbon dioxide challenge, and is often assessed as cerebrovascular reactivity, assuming a linear response over a limited stimulus range or a sigmoidal response over a wider range. However, these assumed response patterns may not necessarily apply to regions with pathophysiology. Deviations from sigmoidal responses are hypothesised to result from upstream flow limitations causing competition for blood flow between downstream regions, particularly with vasodilatory stimulation; flow is preferentially distributed to regions with more reactive vessels. Under these conditions, linear or sigmoidal fitting may not fairly describe the relationship between stimulus and flow. To assess the range of response patterns and their prevalence a survey of healthy control subjects and patients with cerebrovascular disease was conducted. We used a ramp carbon dioxide challenge from hypo- to hypercapnia as the stimulus, and magnetic resonance imaging to measure the flow responses. We categorized BOLD response patterns into four types based on the signs of their linear slopes in the hypo- and hypercapnic ranges, color coded and mapped them onto their respective anatomical scans. We suggest that these type maps complement maps of linear cerebrovascular reactivity by providing a better indication of the actual response patterns. Hum Brain Mapp 38:3415-3427, 2017. © 2017 Wiley Periodicals, Inc.


Tissue-specific effect of VDR gene polymorphisms on the response to calcitriol.
In the last decade, the likely role of vitamin D receptor (VDR) polymorphisms in different diseases has been extensively discussed. In this paper we review several studies carried out in this field to investigate the possible influence of VDR polymorphisms on different aspects of bone and parathyroid gland metabolism. On one hand, most of the epidemiological studies showed that the BAt haplotype, from BsmI, ApaI and TaqI polymorphisms in VDR, is associated with a lower bone mineral density (BMD) in women and a higher risk of osteoporotic fractures. On the other hand, experimental studies carried out in both human primary osteoblasts and human parathyroid glands showed that while in osteoblasts the BAt haplotype showed a worse response to calcitriol, in parathyroid glands the results were the opposite, and BAt was the haplotype associated with better responses. Overall, the results reinforce the suggestion that VDR polymorphisms play an important role in bone and parathyroid gland behavior, leading to different response patterns due to a likely tissue-specific effect of the VDR response to calcitriol.


Predicting the Remaining Lifespan and Cultivation-Related Loss of Osteogenic Capacity of Bone Marrow Multipotential Stromal Cells Applicable across a Broad Donor Age Range.
Background and Objectives. Culture expanded multipotential stromal cells (MSCs) have considerable potential for bone regeneration therapy but their wider use is constrained by the lack of simple and predictive assays of functional potency. Extended passaging leads to loss of multipotency but speed of decline depends on MSC donor age. The aim of this study was to develop an assay predictive of MSC culture longevity applicable to a broad donor age range. Materials and Methods. Bone marrow (BM, n = 7) was obtained from a diverse range (2-72 years) of healthy donors. MSCs were culture expanded to senescence and their osteoprogenitor content, gene expression profiles, epigenetic signature, and telomere behaviour were measured throughout. Output data was combined for modelling purposes. Results. Regardless of donor age, cultures' osteoprogenitor content correlated better with remaining lifespan (population doublings before senescence, PD-BS) than proliferative history (accrued PDs). Individual gene's expression or telomere length did not predict PD-BS but methylation of individual CpG islands did, PRAMEF2 in particular (r = 0.775). Coupling the steep relationship of relative SPARC expression with PD-BS (r = -0.753) the formula SPARC × 1/PREMEF2 gave an improved correlation (r = -0.893). Conclusion. A formula based on SPARC mRNA and PRAMEF2 methylation may be used to predict remaining BM-MSC longevity and related loss of multipotentiality independent of donor age.


[Stimulation of labour with oxytocin and ventouse deliveries are inadequately documented].
A retrospective sample of 180 records from four regional hospitals and five university hospitals in Denmark was collected and the documentation for use of oxytocin in augmentation of labour and ventouse deliveries according to the national guidelines was registered. Only approximately half of the elements in the national guidelines were documented. This shows that there is a potential for improvement in the ongoing Danish national quality improvement project Safe Deliveries (Sikre Fødsler).


Prostate high dose rate brachytherapy in a free-standing cancer center setting.
To determine the safety and acute tolerance of performing prostate high dose rate (HDR) brachytherapy in a free-standing cancer center setting, and to report our approach in delivering such treatment. Patients treated with prostate HDR from the inception of our program through December 2004 were included. Disease- and treatment-related information was gathered from chart review. Acute side effects were obtained from both chart review and questioning the patient at follow-up visits. A total of 234 patients were treated with 459 HDR needle insertions. Nearly all patients were treated with external beam irradiation, and the majority also received adjuvant hormonal manipulation. There were no adverse events related to transport to the free-standing cancer center. Treatment was well tolerated, with only 3.7% of procedures developing retention requiring catheter placement; 20% of patients reported significant postimplant dysuria, mean duration of any dysuria being 7.5 days. Postimplant retention and length of any dysuria were not found to be related to any of the analyzed factors. Severity of dysuria was found to be related only to timing of external beam. Postimplant retention was more frequent for some physicians, but this finding was not statistically significant. Prostate HDR brachytherapy can be delivered safely and effectively in an ambulatory free-standing cancer center setting when done by a urology and radiation oncology team working in close conjunction. Treatment combining HDR brachytherapy as described with external beam radiation, with or without androgen manipulation, is well tolerated by the patient.


Differential expression of the Chlamydomonas [FeFe]-hydrogenase-encoding HYDA1 gene is regulated by the copper response regulator1.
The unicellular green alga Chlamydomonas reinhardtii adapts to anaerobic or hypoxic conditions by developing a complex fermentative metabolism including the production of molecular hydrogen by [FeFe]-hydrogenase isoform1 (HYDA1). HYDA1 transcript and hydrogenase protein accumulate in the absence of oxygen or copper (Cu). Factors regulating this differential gene expression have been unknown so far. In this study, we report on the isolation of a Chlamydomonas mutant strain impaired in HYDA1 gene expression by screening an insertional mutagenesis library for HYDA1 promoter activity using the arylsulfatase-encoding ARYLSULFATASE2 gene as a selection marker. The mutant strain has a deletion of the COPPER RESPONSE REGULATOR1 (CRR1) gene encoding for CRR1, indicating that this SQUAMOSA-PROMOTER BINDING PROTEIN (SBP) domain transcription factor is involved in the regulation of HYDA1 transcription. Treating the C. reinhardtii wild type with mercuric ions, which were shown to inhibit the binding of the SBP domain to DNA, prevented or deactivated HYDA1 gene expression. Reporter gene analyses of the HYDA1 promoter revealed that two GTAC motifs, which are known to be the cores of CRR1 binding sites, are necessary for full promoter activity in hypoxic conditions or upon Cu starvation. However, mutations of the GTAC sites had a much stronger impact on reporter gene expression in Cu-deficient cells. Electrophoretic mobility shift assays showed that the CRR1 SBP domain binds to one of the GTAC cores in vitro. These combined results prove that CRR1 is involved in HYDA1 promoter activation.


Characterization of a New Silk Sericin-Based Hydrogel for Water Retention in Soil.
Hydrogel-type absorbent materials are currently a technological alternative for improving water retention in the soil and reducing nutrient loss by leaching and evaporation. This study aimed to evaluate the application of a new hydrogel based on silk sericin (SS) as a water retention material in soil. The morphology of the hydrogel was characterized using Scanning Electron Microscopy (SEM), and its impact on moisture retention in sandy loam soil (SLS) under different levels of matric pressure (MP) was evaluated. Additionally, water content data were collected over time for both SLS and SLS with hydrogel (SLS + H), and the data were used to fit predictive models. The results indicate that the hydrogel had a porous morphology that promoted water retention and soil release. Under a MP of 0.3 bar, the use of the hydrogel increased water retention by 44.70% with respect to that of SLS. The predictive models developed were adequately adjusted to the behavior of the moisture data over time and evidenced the incidence of the absorbent material on the dynamics of the moisture content in the soil. Therefore, these models could be useful for facilitating subsequent simulations or for designing automatic soil moisture control systems oriented to smart farming.


In vitro motility analysis of thin filaments from failing and non-failing human heart: troponin from failing human hearts induces slower filament sliding and higher Ca(2+) sensitivity.
Contractility of the myocardium is altered in end-stage heart failure. We investigated whether this was related to functional changes in troponin. We isolated troponin from 1 g samples of end-stage failing, non-failing and foetal human heart and studied its regulation of actin-tropomyosin movement over immobilised HMM by in vitro motility assay. At pCa5.4 the sliding velocity of thin filaments reconstituted with non-failing heart troponin was 52+/-4% more than actin-tropomyosin, with failing heart troponin velocity increased by 35+/-2% and with foetal heart troponin velocity increased by 11+/-4%. Thin filaments containing troponin from failing hearts were more Ca(2+)-sensitive than non-failing heart troponin. EC(50) for the fraction of filaments motile and filament velocity decreased 1.76+/-0.20 and 1.89+/-0.62-fold respectively relative to non-failing heart troponin. With foetal heart troponin the EC(50) decreased 2.16+/-0.23 and 3.50+/-1.73-fold for fraction and velocity respectively. Western blots revealed no difference in troponin T or troponin I isoform expression in troponin from failing and non-failing adult hearts but foetal isoforms of troponin I and T were observed in troponin from foetal heart. The level of PKA phosphorylation of troponin from failing and non-failing heart was not significantly different, however, complete non-specific dephosphorylation of troponin abolished most of the difference between failing and non-failing heart troponin. These findings show functional alterations in troponin in failing hearts which could account for the reduced contractile function but there is no change in troponin isoform expression or PKA phosphorylation. Differential phosphorylation by other kinases may account for altered troponin function.


Obsidian hydration rate for the klamath basin of california and Oregon.
A hydration rate for obsidian of 3.5(4) microns squared per 1000 radio-carbon years has been established at the Nightfire Island archeological site in northern California and provides a means to date other prehistoric Klamath Basin sites. The new rate follows the form of the hydration equation formulated by Friedman and helps to refute claims made for other hydration equations.


Photoinduced Electron Transfer-based Halogen-free Photosensitizers: Covalent meso-Aryl (Phenyl, Naphthyl, Anthryl, and Pyrenyl) as Electron Donors to Effectively Induce the Formation of the Excited Triplet State and Singlet Oxygen for BODIPY Compounds.
Pristine BODIPY compounds have negligible efficiency to generate the excited triplet state and singlet oxygen. In this report, we show that attaching a good electron donor to the BODIPY core can lead to singlet oxygen formation with up to 58 % quantum efficiency. For this purpose, BODIPYs with meso-aryl groups (phenyl, naphthyl, anthryl, and pyrenyl) were synthesized and characterized. The fluorescence, excited triplet state, and singlet oxygen formation properties for these compounds were measured in various solvents by UV/Vis absorption, steady-state and time-resolved fluorescence methods, as well as laser flash photolysis technique. In particular, the presence of anthryl and pyrenyl showed substantial enhancement on the singlet oxygen formation ability of BODIPY with up to 58 % and 34 % quantum efficiency, respectively, owing to their stronger electron-donating ability. Upon the increase in singlet oxygen formation, the fluorescence quantum yield and lifetime values of the aryl-BODIPY showed a concomitant decrease. The increase in solvent polarity enhances the singlet oxygen generation but decreases the fluorescence quantum yield. The results are explained by the presence of intramolecular photoinduced electron transfer from the aryl moiety to BODIPY core. This method of promoting T1 formation is very different from the traditional heavy atom effect by I, Br, or transition metal atoms. This type of novel photosensitizers may find important applications in organic oxygenation reactions and photodynamic therapy of tumors.


Expression of sulfotransferase SULT1A1 in cancer cells predicts susceptibility to the novel anticancer agent NSC-743380.
The small molecule anticancer agent NSC-743380 modulates functions of multiple cancer-related pathways and is highly active in a subset of cancer cell lines in the NCI-60 cell line panel. It also has promising in vivo anticancer activity. However, the mechanisms underlying NSC-743380's selective anticancer activity remain uncharacterized. To determine biomarkers that may be used to identify responders to this novel anticancer agent, we performed correlation analysis on NSC-743380's anticancer activity and the gene expression levels in NCI-60 cell lines and characterized the functions of the top associated genes in NSC-743380-mediated anticancer activity. We found sulfotransferase SULT1A1 is causally associated with NSC-743380's anticancer activity. SULT1A1 was expressed in NSC-743380-sensitive cell lines but was undetectable in resistant cancer cells. Ectopic expression of SULT1A1 in NSC743380 resistant cancer cells dramatically sensitized the resistant cells to NSC-743380. Knockdown of the SULT1A1 in the NSC-743380 sensitive cancer cell line rendered it resistance to NSC-743380. The SULT1A1 protein levels in cell lysates from 18 leukemia cell lines reliably predicted the susceptibility of the cell lines to NSC-743380. Thus, expression of SULT1A1 in cancer cells is required for NSC-743380's anticancer activity and can be used as a biomarker for identification of NSC-743380 responders.


An easy-to-use artificial intelligence preoperative lymph node metastasis predictor (LN-MASTER) in rectal cancer based on a privacy-preserving computing platform: multicenter retrospective cohort study.
Although the surgical treatment strategy for rectal cancer (RC) is usually based on the preoperative diagnosis of lymph node metastasis (LNM), the accurate diagnosis of LNM has been a clinical challenge. In this study, we developed machine learning (ML) models to predict the LNM status before surgery based on a privacy-preserving computing platform (PPCP) and created a web tool to help clinicians with treatment-based decision-making in RC patients. A total of 6578 RC patients were enrolled in this study. ML models, including logistic regression, support vector machine, extreme gradient boosting (XGB), and random forest, were used to establish the prediction models. The areas under the receiver operating characteristic curves (AUCs) were calculated to compare the accuracy of the ML models with the US guidelines and clinical diagnosis of LNM. Last, model establishment and validation were performed in the PPCP without the exchange of raw data among different institutions. LNM was detected in 1006 (35.3%), 252 (35.3%), 581 (32.9%), and 342 (27.4%) RC patients in the training, test, and external validation sets 1 and 2, respectively. The XGB model identified the optimal model with an AUC of 0.84 [95% confidence interval (CI), 0.83-0.86] compared with the logistic regression model (AUC, 0.76; 95% CI, 0.74-0.78), random forest model (AUC, 0.82; 95% CI, 0.81-0.84), and support vector machine model (AUC, 0.79; 95% CI, 0.78-0.81). Furthermore, the XGB model showed higher accuracy than the predictive factors of the US guidelines and clinical diagnosis. The predictive XGB model was embedded in a web tool (named LN-MASTER) to predict the LNM status for RC. The proposed easy-to-use model showed good performance for LNM prediction, and the web tool can help clinicians make treatment-based decisions for patients with RC. Furthermore, PPCP enables state-of-the-art model development despite the limited local data availability.


Effects of stimulus salience and methamphetamine on choice reaction time in the rat: central tendency versus distribution skew.
Stimulants decrease reaction time in humans as well as laboratory rats. This effect is seen as a decrease in average reaction time or a shift in the distribution peak towards shorter reaction times. However, response-time distributions are typically skewed, exhibiting a positive tail. Our goal for this project was to develop a method of analyzing reaction-time distributions in the rat which will allow us to study systematically measures of central tendency and distribution skew. This analysis subdivided reaction time into initiation time and movement time, and also subdivided the response time distributions into distribution mode and distribution skew. Rats were trained on a two-choice visual reaction-time task. We then evaluated the effects of stimulus salience and methamphetamine (METH) treatment (vehicle, 0.25, 0.5, 1.0, and 1.5 mg/kg) on measures of distribution mode and skew. Stimulus salience decreased initiation time mode, initiation time skew and movement time skew, but had no effect on movement time mode. METH had a greater effect on skew for the initiation time distribution and a greater effect on mode for the movement time distribution. This analysis will serve as a useful method of determining whether initiation time and movement time, as well as distribution mode and distribution skew, represent different behavioral processes in the rat.


The Impact of Patient Preference on Attendance and Completion Rates at Centre-Based and mHealth Pulmonary Rehabilitation: A Non-Inferiority Pragmatic Clinical Trial.
Pulmonary rehabilitation (PR) is vital in the management of chronic respiratory disorders (CRDs) although uptake, attendance and completion are poor. Differing models of delivering PR are emerging in an attempt to increase the uptake and completion of this intervention. This study aimed to evaluate participant rate of attendance and completion of PR when given a preference regarding model of delivery (centre-based and mPR). Secondary aims were to evaluate the factors affecting patient preference for model of delivery and determine whether mPR is non-inferior to centre-based PR in health outcomes. A multi-centre non-inferiority preference based clinical trial in Auckland, New Zealand. Participants with a CRD referred for PR were offered the choice of centre-based or mHealth PR (mPR). The primary outcome was completion rate of chosen intervention. A total of 105 participants were recruited to the study with 67 (64%) preferring centre-based and 38 (36%) mPR. The odds of completing the PR programme were higher in the centre-based group compared to mPR (odds ratio 1.90 95% CI [0.83-4.35]). Participants opting for mPR were significantly younger (p = 0.002) and significantly more likely to be working (p = 0.0001). Results showed that mPR was not inferior to centre-based regarding changes in symptom scores (CAT) or time spent in sedentary behaviour (SBQ). When services were forced to transition to telehealth services during COVID-19 restrictions, the attendance and completion rates were higher with telephone calls and video conferencing compared to mPR - suggesting that synchronous interpersonal interactions with clinicians may facilitate the best attendance and completion rates. When offered the choice of PR delivery method, the majority of participants preferred centre-based PR and this facilitated the best completion rates. mPR was the preferred choice for younger, working participants suggesting that mPR may offer a viable alternative to centre-based PR for some participants, especially younger, employed participants.


A shell-resolved analysis of preferential solvation of coffee ingredients in aqueous mixtures of the ionic liquid 1-ethyl-3-methylimidazolium acetate.
Ionic liquids increase the solubility of various coffee ingredients in aqueous solution but little is known about the underlying mechanism. Kirkwood-Buff integrals as well as the potential of mean force indicate that the imidazolium cations are accumulated at the surface of the solutes, removing water molecules from the solute surface. Although hydrogen bonding of the anions to hydroxy groups of the solutes can be detected, their concentration at the surface is less enhanced compared to the cations. The decomposition into solvation shells by Voronoi tessellation reveals that structural features are only observed in the first solvation shell. Nevertheless, the depletion of water and the excess concentration of the ions and, in particular, of the cations are visible in the next solvation shells as well. Therefore, classical arguments of hydrotropic theory fail to explain this behavior.


Nonpharmacologic treatment of hypertension in the United States.
Although efficacious pharmacologic approaches to the control of high blood pressure are available, concern about risk versus benefit in the use of antihypertensive drug therapy for patients with mild hypertension has led to renewed interest in nonpharmacologic interventions. In the United States, the National High Blood Pressure Education Program, an organization comprised of research scientists and a variety of other professionals concerned with the control of high blood pressure has, through a consensus process, recommended some nonpharmacologic approaches to the treatment of hypertension. These include weight reduction for the obese, moderate sodium restriction (although this is controversial), and restriction of alcohol consumption to less than 1 oz of ethanol daily.


Genetic mechanisms and correlational selection structure trait variation in a coral snake mimic.
Covariation among traits shapes both phenotypic evolution and ecological interactions across space and time. However, rampant geographical variation in the strength and direction of such correlations can be particularly difficult to explain through generalized mechanisms. By integrating population genomics, surveys of natural history collections and spatially explicit analyses, we tested multiple drivers of trait correlations in a coral snake mimic that exhibits remarkable polymorphism in mimetic and non-mimetic colour traits. We found that although such traits co-occur extensively across space, correlations were best explained by a mixture of genetic architecture and correlational selection, rather than by any single mechanism. Our findings suggest that spatially complex trait distributions may be driven more by the simple interaction between multiple processes than by complex variation in one mechanism alone. These interactions are particularly important in mimicry systems, which frequently generate striking geographical variation and genetic correlations among colour pattern traits.


Use of cone beam computed tomography in endodontics.
Cone Beam Computed Tomography (CBCT) is a diagnostic imaging modality that provides high-quality, accurate three-dimensional (3D) representations of the osseous elements of the maxillofacial skeleton. CBCT systems are available that provide small field of view images at low dose with sufficient spatial resolution for applications in endodontic diagnosis, treatment guidance, and posttreatment evaluation. This article provides a literature review and pictorial demonstration of CBCT as an imaging adjunct for endodontics.


Defining control of HIV epidemics.
Although the HIV pandemic remains a global crisis, much progress has been made in implementing programmes to treat and prevent HIV infection. To guide prioritisation of efforts, the metric by which a country can declare its HIV epidemic as controlled has become increasingly relevant. Herein, we evaluate the merits of the four control criteria proposed by UNAIDS: percentage reduction in incidence over time; ratio of incidence to mortality; ratio of incidence to prevalence; and annual incidence. Using a transmission model to generate projections of demography, incidence, and mortality, we highlight potential pitfalls associated with each of the first three criteria. A definition of control based on annual incidence would provide clarity and consistency across settings.


Posterior epidural disc fragment masquerading as spinal tumor: Review of the literature.
Posterior epidural lumbar disc fragment is infrequent because of anatomical barriers, and it is difficult to diagnose posterior epidural lumbar disc fragment because of its rare incidence and the ambiguity of radiologic evaluations. And it is difficult to differentiate it from other diseases such as spinal tumors. Differential diagnosis of posterior epidural lumbar disc fragment is clinically important because its diagnosis can affect treatment and prognosis. To investigate the incidence, anatomical concern, etiology, symptom, diagnostic tool, management and prognosis of posterior epidural lumbar disc fragment, we reviewed articles including case report. We performed a search of all clinical studies of posterior epidural lumbar disc fragment published to date. The following keywords were searched: Posterior epidural lumbar disc fragment, disc migration, posterior epidural disc, extradural migration, dorsal epidural migration, sequestrated disc, and disc fragment. We identified 40 patients of posterior epidural lumbar disc fragment from 28 studies. The most common presentation of posterior epidural lumbar disc fragment was sudden onset radiculopathy (70.0%), followed by cauda equina syndrome (27.5%). The most frequently used diagnostic modality was magnetic resonance imaging (MRI), conducted in 36 cases (90.0%), and followed by computed tomography in 14 cases (35.0%). After the imaging studies, the preoperative diagnoses were 45.0% masses, 20.0% lesions, and 12.5% tumors. Characteristic MRI findings in posterior epidural lumbar disc fragment are helpful for diagnosis; it typically displays low signals on T1-weighted images and high signals on T2-weighted images with respect to the parent disc. In addition, most of the disc fragments show peripheral rim enhancement on MRI with gadolinium administration. Electrodiagnostic testing is useful for verifying nerve damage. Surgical treatment was performed in all cases, and neurologic complications were observed in 12.5%. As posterior epidural lumbar disc fragment could be masqueraded as spinal tumor, if rim enhancement is observed in MRI scans with sudden symptoms of radiculopathy or cauda equina syndrome, it should be taken into consideration. Early diagnosis can lead to early surgery, which can reduce complications.


[The reviewers' review].
Peer review is a process designed to ensure quality, integrity and novelty of scientific or medical studies, published in scientific journals. This process accompanies scientific publication since it began and is the cornerstone of scientific appreciation and acceptance. Since peer review is a non-transparent process and lacks standardized criteria for evaluation, it thereby attracts extensive criticism, as discussed in this article. Editors and reviewers of this journal have a special responsibility when discussing a submitted article, since this journal is the only scientific-medical platform in the Hebrew language.


Is There Any Age Cutoff to Treat Elderly Patients with Head and Neck Cancer? Comparing with Septuagenarians and Octogenarians.
With the increase in life expectancy, age is no longer considered as a limitation for treatment. Nevertheless, the treatment of elderly patients with head and neck cancer (HNC) remains controversial. Here, we aimed to review our experience with the treatment for elderly patients, while particularly focusing on the differences among older old patients (septuagenarians vs. octogenarians). We retrospectively reviewed the records of 260 elderly patients who were assigned to 3 groups according to age: 70 years old ≤ group 1 < 75 years old, 75 years old ≤ group 2 < 80 years old, and group 3 ≥ 80 years old. The patients were assessed for comorbidities using the Adult Comorbidity Evaluation (ACE)-27, and the American Society of Anesthesia (ASA) physical status was also compared. Group 1, 2, and 3, consisted of 97, 102, and 61 patients, respectively. No significant difference in demographic data was noted among the groups. However, group 3 showed more comorbidities than groups 1 and 2. With regard to the initial treatment for HNC, radiation therapy (RT) was more frequently performed in group 3 than in groups 1 and 2. Among 7 patients of non-compliant to treatment in group 3, 6 patients had have performed RT. In group 3, a total of 18 patients underwent surgery, including microvascular free flap reconstruction and no significant difference in complications was observed postoperatively compared with group 1 and 2. Moreover, no significant difference was noted in overall survival between the groups, regardless of the treatment modality chosen. In conclusion, octogenarians with HNC should be more carefully managed than septuagenarians with HNC. Surgical treatment can be considered in octogenarians with HNC, if it can be tolerated.


Safety of contrast administration for endocardial enhancement during stress echocardiography compared with noncontrast stress.
The aim was to evaluate the safety of stress echocardiography using contrast (CE) for endocardial enhancement compared with a noncontrast (NCE) cohort in a large nonselect population. The recent Food and Drug Administration warning cited lack of data for safety regarding the use of contrast in conjunction with stress echocardiography. A detailed record review was performed for 5,069 consecutive patients who underwent stress echocardiography (58% pharmacologic, 42% exercise) during an 8-year period. Contrast use, hemodynamics, and adverse clinical and electrocardiographic events were evaluated until time of discharge from the laboratory. Contrast was administered to 2,914 patients (58%) and was higher in in-patients (66%) and during dobutamine stress (67%). Compared with the NCE group, the CE group was older (median age 61 vs 58 years) and had more depressed left ventricular ejection fraction <50% (14% vs 11%; all p <0.001). The CE group experienced more chest pain (11% vs 8%; p = 0.001), back pain (0.6% vs 0.05%; p <0.001), and premature ventricular contractions (odds ratio 1.42, 95% confidence interval 1.19 to 1.69, p <0.001). There was no sustained ventricular tachycardia, ventricular fibrillation, cardiac arrest, or death in either group. One uncomplicated acute myocardial infarction and 1 anaphylactoid reaction occurred in the CE group, and none occurred in the NCE group (p = 0.51). Rates of clinically significant arrhythmias were similar in both groups (CE 2.1% vs NCE 1.9%; p = 0.8). In conclusion, although CE of echocardiographic images was used more often in patients with a higher cardiac risk profile, the risk of major adverse events was very small in both the CE and NCE stress echocardiography cohorts.


Implantable atrial flow regulator for severe, irreversible pulmonary arterial hypertension.
Pulmonary arterial hypertension (PAH) is a severe, progressive and fatal disease. The creation of an interatrial right-to-left shunt in patients with PAH may enhance systemic ventricular output at the expense of desaturation. However, creating sustainable restricted interatrial communication is challenging. We describe the successful use of an atrial flow regulator, a novel implantable atrial communication device, in a 54-year-old female with severe irreversible PAH.


Cytohistomorphological grading of breast carcinoma with special reference to apoptotic rates and lymph node metastasis.
To analyze the significance of comparative evaluation of cytohistomorphological grading of infiltrating ductal carcinoma with specific reference to lymphnode metastasis status and apoptotic index. 50 patients who underwent FNAC and mastectomy for infiltrating ductal carcinoma were included in the study. Concordance between cytological and histological grades was calculated. Cytological smears were also evaluated for apoptotic rates and lymph node metastasis and then compared with the histological grades using regression analysis. Histological and cytological grades were comparable and statistically significant difference was found in the lymphnode metastasis rate and apoptotic index in the three cytological grades of the tumor. Moreover, by considering the apoptotic rates, the sensitivity of cytological grading significantly rose in relation to histological grade. With histological grade taken as the standard, cytology was found to be comparable but less sensitive for grading infiltrating ductal carcinoma. However, by considering lymphnode status and apoptotic rates as calculated on cytology, the sensitivity of cytological grading rose significantly in relation to histological grade. Therefore, apoptotic index incorporated with cytological grade may provide relevant information on the aggressiveness of invasive ductal carcinoma of breast and could be a useful parameter to take into consideration when selecting neo-adjuvant therapy.


Papilloedema and Autoimmune Retinopathy from Systemic Lupus Erythematosus.
A 33-year-old female presented with bilateral papilloedema and constricted visual fields from autoimmune retinopathy. She then developed a painful peripheral neuropathy that led to further work-up and the diagnosis of systemic lupus erythematosus. Papilloedema and autoimmune retinopathy from systemic lupus erythematosus is a unique presentation.


Asymptotic correction of the exchange-correlation kernel of time-dependent density functional theory for long-range charge-transfer excitations.
Time-dependent density functional theory (TDDFT) calculations of charge-transfer excitation energies omegaCT are significantly in error when the adiabatic local density approximation (ALDA) is employed for the exchange-correlation kernel fxc. We relate the error to the physical meaning of the orbital energy of the Kohn-Sham lowest unoccupied molecular orbital (LUMO). The LUMO orbital energy in Kohn-Sham DFT--in contrast to the Hartree-Fock model--approximates an excited electron, which is correct for excitations in compact molecules. In CT transitions the energy of the LUMO of the acceptor molecule should instead describe an added electron, i.e., approximate the electron affinity. To obtain a contribution that compensates for the difference, a specific divergence of fxc is required in rigorous TDDFT, and a suitable asymptotically correct form of the kernel fxc(asymp) is proposed. The importance of the asymptotic correction of fxc is demonstrated with the calculation of omegaCT(R) for the prototype diatomic system HeBe at various separations R(He-Be). The TDDFT-ALDA curve omegaCT(R) roughly resembles the benchmark ab initio curve omegaCT CISD(R) of a configuration interaction calculation with single and double excitations in the region R=1-1.5 A, where a sizable He-Be interaction exists, but exhibits the wrong behavior omegaCT(R)<<omegaCT CISD(R) at large R. The TDDFT curve obtained with fxc (asymp) however approaches omegaCT CISD(R) closely in the region R=3-10 A. Then, the adequate rigorous TDDFT approach should interpolate between the LDA/GGA ALDA xc kernel for excitations in compact systems and fxc(asymp) for weakly interacting fragments and suitable interpolation expressions are considered.


[Area postrema lesion as a cause of intractable nausea, vomiting and hiccups in neuromyelitis optica spectrum disorders].
Neuromyelitis optica (Devic's disease) is a chronic autoimmune disease associated with the production of anti-bodies to aquaporin-4 (AQP4). Area postrema lesions is the third, after optic neuritis and myelitis, syndrome of opticomyelitis-related disorders. Clinical symptoms of this disorder include intractable nausea, vomiting and hiccups. In many cases, area postrema syndrome manifests as the first clinical symptom of a neuromyelitis optica spectrum disorder that hampers the diagnosis. The authors present a case report of a female patient with area postrema lesions developed several months before the first disabling attack of myelitis.


A diet containing chickpeas and wheat offers less protection against colon tumors than a casein and wheat diet in dimethylhydrazine-treated rats.
We examined the influence of extruded chickpeas and wheat relative to casein and wheat in a dimethylhydrazine (DMH)-induced colon tumor study in male Sprague-Dawley rats. The three diets, based on a modified AIN76 rodent diet with fat present at 10 g/100 g dry matter (DM), were as follows: casein with wheat starch (Cas/S) as control, casein with wheat (Cas/W) and chickpeas with wheat (CP/W). All diets were fed from 5 wk of age throughout the 28-wk study. At 28 wk, there was a significantly lower incidence of large intestinal tumors in rats fed Cas/W relative to those fed CP/W ( 11 vs. 56%, chi-square test, P = 0.018). The colonic tumor burden (tumors/tumor-bearing animal) was not different in Cas/W-fed and CP/W-fed rats (1 vs. 1.7), but the tumor mass index was significantly lower in the former group (0.22 vs. 1.21, P = 0.026). Rats fed the CP/W diet had significantly lower plasma cholesterol concentration (P < 0.01) than rats fed the other two diets. The cecal contents of rats fed the CP/W diet had significantly greater relative weights (46%, P < 0.05) than those of the Cas/W-fed rats; this was associated with higher concentrations of all short-chain fatty acids. Fecal analyses showed significantly (P < 0.05) higher concentrations of total fat (54%), total steroids (83%) and secondary bile acids (179%) in the CP/W-fed rats relative those fed Cas/W. There were higher concentrations of nitrogen in the feces of CP/W rats relative to the Cas/W-fed rats (84%, P < 0.05), associated with greater fecal weights (67%, P < 0.05). Although wheat and its fibers have been shown to be protective against DMH-induced cancers in rats, this was not the case in this study in which chickpeas (45 g/100 g diet) provided the protein and were an important source of soluble fiber. Elevated fat, secondary bile acid concentrations and/or nitrogenous compounds could be responsible for the increased colon tumorigenesis seen and may reflect a legume effect.


Induction of extrahepatic biliary carcinoma by N-nitrosobis(2-oxopropyl)amine in hamsters given cholecystoduodenostomy with dissection of the common duct.
The methods we used to produce a carcinoma in the extrahepatic bile duct and gallbladder in hamsters are described along with the characteristics of the induced tumors. Female Syrian golden hamsters were first subjected to cholecystoduodenostomy with dissection of the extrahepatic bile duct on the distal end of the common duct (CDDB) and were, 4 weeks later, treated with weekly subcutaneous injections of N-nitrosobis(2-oxopropyl)amine (BOP) at a dose of 10 mg/kg body weight for 9 weeks. The animals were killed at the 12th, 16th and 20th week after the initiation of BOP treatment. Extrahepatic bile duct carcinoma developed in 16%, 24% and 41% and gallbladder carcinoma occurred in 58%, 81% and 82% of the hamsters, respectively, at the corresponding times of killing. The incidences were significantly higher than those in sham-operated controls (P < 0.01). The induced extrahepatic bile duct carcinomas were predominantly of the polypoid type and gallbladder carcinomas were of the papillary type in growth form, being morphologically similar to early stage biliary carcinoma in humans. Immunohistochemical staining using bromodeoxyuridine and anti-bromodeoxyuridine monoclonal antibody demonstrated that the CDDB procedure greatly accelerated the cell kinetic activity of the biliary epithelium, and this was considered to be a major factor promoting the development of biliary carcinomas in this hamster model. In conclusion, this new model provides a high incidence of tumor development at the extrahepatic biliary tract and is expected to be useful for clarifying the characteristics of this highly malignant tumor.


Characteristics of Transcriptome and Metabolome Concerning Intramuscular Fat Content in Beijing Black Pigs.
To study the characteristics of genes and metabolites related to intramuscular fat (IMF) content with less influence by breed background and individual differences, the skeletal muscle samples from 40 Beijing black pigs with either high or low IMF content were used to perform transcriptome and metabolome analyses. About 99 genes (twofold-change) were differentially expressed. Up-regulated genes in the high IMF pigs were mainly related to fat metabolism. The key genes in charge of IMF deposition are ADIPOQ, CIDEC, CYP4B1, DGAT2, LEP, OPRL1, PLIN1, SCD, and THRSP. KLHL40, TRAFD1, and HSPA6 were novel candidate genes for the IMF trait due to their high abundances. In the low IMF pigs, the differentially expressed genes involved in virus resistance were up-regulated. About 16 and 18 differential metabolites (1.5 fold-change) were obtained in the positive and negative modes, respectively. Pigs with low IMF had weaker fatty acid oxidation due to the down-regulation of various carnitines. Differentially expressed genes were more important in determining IMF deposition than differential metabolites because relatively few differential metabolites were obtained, and they were merely the products under the physiological status of diverged IMF content. This study provided valuable information for further studies on IMF deposition.


Sphingosine kinase 2 inhibitor ABC294640 suppresses neuronal excitability and inhibits multiple endogenously and exogenously expressed voltage-gated ion channels in cultured cells.
Sphingolipids regulate multiple cellular processes, including proliferation, autophagy, and apoptosis. Sphingosine kinases, the key enzymes in the metabolism of sphingolipids, are overexpressed in many cancers, making them important targets for the development of antitumor drugs. ABC294640 is a selective sphingosine kinase 2 (SK2) inhibitor that shows good antitumor activity in vitro. One phase I clinical study of ABC294640 reported that ABC294640 caused a variety of neurological disorders. The mechanism of these phenomena, however, remains unclear. In the present study, we used in vitro cell experiments to test the effects of ABC294640 on the nervous system. We found that ABC294640 suppressed the firing of action potentials in cultured hippocampal neurons from neonatal mice and inhibited endogenous sodium, potassium, and calcium currents in both cultured neurons and SH-SY5Y cells. In addition, we tested four types of human voltage-gated potassium channels transiently expressed in HEK293T cells. All were inhibited by ABC294640, of which KV4.2 and KV1.4 were more sensitive than BK and K2P2.1. The effect of ABC294640 on ion channels was different from another SK2 inhibitor K145 and was not affected by S1P. The fast onset and recovery of the inhibition indicated that ABC294640 was likely to inhibit ion channels by acting directly on channel proteins, rather than by inhibiting SK2. These results revealed the mechanism by which ABC294640 interferes with the nervous system. To develop future antitumor drugs, researchers should modify the structure of ABC294640 to avoid its effects on ion channels or should develop compounds that target SK2 or downstream molecules.


Substitution of the selective serotonin reuptake inhibitors fluoxetine and paroxetine for the discriminative stimulus effects of ethanol in rats.
Rats trained to discriminate ethanol (EtOH, 1 g/kg IP) from saline in a two-lever procedure completely generalized to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and paroxetine. Substitution of fluoxetine was completely blocked by the selective 5-HT2A receptor antagonist MDL 100,907 and not affected by the selective 5-HT1A receptor antagonist WAY-100635. It is suggested that the previously reported effectiveness of SSRIs in reducing EtOH consumption could be based on similarities in discriminative stimulus effects of SSRIs and EtOH. Stimulation of 5-HT2A receptors may underlie these stimulus similarities and contribute to the EtOH intake-reducing effects of SSRIs.


Cellulase and hemicellulase genes of Clostridium thermocellum from five independent collections contain few overlaps and are widely scattered across the chromosome.
Five independent collections, comprising a total of 34 clones encoding cellulases, hemicellulases and cell surface proteins of Clostridium thermocellum, were searched for overlapping or contiguous DNA fragments. The clones were hybridized to large genomic restriction fragments separated by pulse-field electrophoresis. Clones hybridizing to the same fragment were further compared by hybridization to smaller fragments, by cross-hybridization and by restriction mapping. The probes hybridized to loci which were usually not clustered and were scattered over at least one third of the chromosome. Besides previously identified clusters, only two clones were found to be adjacent. Two pairs of clones appeared to contain the same genes cloned in duplicate, and one of the genes was shown to be cloned in triplicate.


PON1 polymorphisms can predict generalized anxiety and depressed mood in patients with multiple chemical sensitivity.
Background: Multiple chemical sensitivity (MCS) is a chronic condition with somatic, cognitive and affective symptoms that follow contact with chemical agents at usually non toxic concentrations. We aimed to assess the role of genetic polymorphisms involved in oxidative stress on anxiety and depression in MCS. Materials & methods: Our study investigated the CAT rs1001179, MPO rs2333227, PON1 rs662 and PON1 rs705379 polymorphisms in MCS. Results: The AG genotype of the PON1 rs662 and the TT and CT genotypes of the PON1 rs705379 were involved in anxiety and depression. Discussion: These results are in line with existing evidence of PON1 involvement in MCS and suggest a further role of this gene in the exhibition of anxiety and depression in this disease.


Pelvic lymphangioleiomyomatosis treated successfully with everolimus: Two case reports with literature review.
Lymphangioleiomyomatosis (LAM) is a rare disease affecting young women caused by abnormal proliferation of smooth muscle-like cells (LAM cells) in the lungs and extrapulmonary sites (extrapulmonary LAM). The objective of this case series is to demonstrate marked regression in 2 cases of retroperitoneal LAM after treatment with everolimus, an mTOR inhibitor. We enrolled 2 cases with large volume, extrapulmonary pelvic LAM, and evaluated them with contrast-enhanced abdominal computed tomographic (CT) scans at presentation and serially during treatment with everolimus. Results were objectively quantified using the Response Evaluation Criteria in Solid Tumors, RECIST, Version 1.1. After 12 to 18 months of treatment with everolimus, both patients showed substantial reduction in the volume of their tumors. The first had about 50% regression of the pelvic LAM and renal angiomyolipoma (AML). The second patient had extensive abdomino-pelvic LAM which after treatment showed complete remission. Both patients have not demonstrated disease progression after nearly 4 and 2 years of follow-up, respectively. This case series demonstrates the enormous value of mTOR inhibitors (specifically everolimus) in the management of extrapulmonary pelvic LAM, of which there is no effective treatment currently available.


Blunt injuries of the cervical trachea: review of 51 patients.
The low incidence of blunt trauma to the cervical portion of the trachea limits management experience in most centers. Hence, we combined our patients with those in published reports containing essential information on injury, treatment, and results. Among 51 patients (93% male), ages ranged from 3 to 65 years. There were 32 complete transections, 15 partial transections, and four tears. There were associated injuries of the recurrent laryngeal nerve (49%), esophagus (21%), larynx (14%), and cervical spine (9%). Presenting signs and symptoms included subcutaneous emphysema in 84%, respiratory distress in 76%, hoarseness/dysphonia in 46%, and hemoptysis in 21%. Tracheostomy was the best means of airway control; 13 of 17 (76%) attempted oral/nasotracheal intubations failed, necessitating emergency tracheostomy. Five patients with no respiratory distress and minimal tissue injury were successfully managed without tracheal repair. Ten patients had tracheal repair without tracheostomy. The only poor result occurred in a patient with a treatment delay of several days. Tracheal repair with tracheostomy was used in 27 patients, with good results in 19. Two patients died of other injuries, and six patients (four with delayed repair) required subsequent tracheal reconstruction. Repair over a stent was used in seven patients, four of whom had satisfactory results. From this review we conclude that (1) the diagnosis of blunt trauma to the cervical trachea requires a high index of suspicion, since this injury can easily be overlooked; (2) tracheostomy (vs intubation or cricothyroidotomy) is the preferred means of airway control; (3) preoperative laryngoscopy/bronchoscopy should be done to assess vocal cord function, possible laryngeal damage, and level of tracheal injury; (4) good long-term results, measured by voice and airway quality, are best obtained by immediate repair of significant injuries.


Compound heterozygous complement C3 deficiency.
Complete deficiency of the third component of the complement system is a result of defects in the two alleles of the C3 gene. In this study a family with C3 deficiency is reported; the parents expressed a distinct abnormality of the C3 gene and their two children had compound heterozygous C3 deficiency. These are the first reported cases of compound heterozygous complement deficiency. Our results indicate that the maternal abnormality leads to synthesis of an abnormal proC3 protein which is not secreted from the cells. The paternal abnormality results in ablation of synthesis of the proC3 protein.


Genetically switched D-lactate production in Escherichia coli.
During a fermentation process, the formation of the desired product during the cell growth phase competes with the biomass for substrates or inhibits cell growth directly, which results in a decrease in production efficiency. A genetic switch is required to precisely separate growth from production and to simplify the fermentation process. The ldhA promoter, which encodes the fermentative D-lactate dehydrogenase (LDH) in the lactate producer Escherichia coli CICIM B0013-070 (ack-pta pps pflB dld poxB adhE frdA), was replaced with the λ p(R) and p(L) promoters (as a genetic switch) using genomic recombination and the thermo-controllable strain B0013-070B (B0013-070, ldhAp::kan-cI(ts)857-p(R)-p(L)), which could produce two-fold higher LDH activity at 42°C than the B0013-070 strain, was created. When the genetic switch was turned off at 33°C, strain B0013-070B produced 10% more biomass aerobically than strain B0013-070 and produced only trace levels of lactate which could reduce the growth inhibition caused by oxygen insufficiency in large scale fermentation. However, 42°C is the most efficient temperature for switching on lactate production. The volumetric productivity of B0013-070B improved by 9% compared to that of strain B0013-070 when it was grown aerobically at 33°C with a short thermo-induction at 42°C and then switched to the production phase at 42°C. In a bioreactor experiment using scaled-up conditions that were optimized in a shake flask experiment, strain B0013-070B produced 122.8 g/l D-lactate with an increased oxygen-limited productivity of 0.89 g/g·h. The results revealed the effectiveness of using a genetic switch to regulate cell growth and the production of a metabolic compound.


Relationship between operating room nursing staff expertise and patient outcomes.
This secondary analysis evaluated the association of operating room scrub staff expertise, based on frequency of working on a specific surgical procedure, with the development of surgical site infections. The odds of developing surgical site infections decreased by 5.7% (odds ratio = 0.943; 95% confidence interval, 0.834-1.067) with increased expertise, although a statistically significant association was not established (P = .354). The relationship between operating room scrub staff expertise and patient outcomes is important to understand.


Heavy metal toxicity in poultry: a comprehensive review.
Arsenic (As), lead (Pb), cadmium (Cd), and mercury (Hg) have been recognized as most toxic heavy metals that are continuously released into the environment, both from natural sources and from anthropogenic production of fertilizers, industrial activities, and waste disposal. Therefore, As, Cd, Hg, and Pb are found in increasing concentrations in bodies of water, fodder, feed, and in the tissues of livestock, including poultry, in the surroundings of industrial areas, leading to metabolic, structural, and functional abnormalities in various organs in all animals. In poultry, bioaccumulation of As, Pb, Cd, and Hg occurs in many organs (mainly in the kidneys, liver, reproductive organs, and lungs) as a result of continuous exposure to heavy metals. Consumption of Cd lowers the efficiency of feed conversion, egg production, and growth in poultry. Chronic exposure to As, Pb, Cd, and Hg at low doses can change the microscopic structure of tissues (mainly in the brain, liver, kidneys, and reproductive organs) as a result of the increased content of these heavy metals in these tissues. Histopathological changes occurring in the kidneys, liver, and reproductive organs are reflected in their negative impact on enzyme activity and serum biochemical parameters. Metal toxicity is determined by route of exposure, length of exposure, and absorbed dosage, whether chronic and acute. This review presents a discussion of bioaccumulation of As, Cd, Pb, and Hg in poultry and the associated histopathological changes and toxic concentrations in different tissues.


Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration.
Most information about pharmacokinetics of antimicrobial agents is obtained from studies in healthy volunteers. However, antibiotics are therapeutically used in infected patients with very different pharmacokinetic properties compared with healthy individuals. In a single-centre, prospective, open-label study, 17 adult critically ill patients with early-onset ventilator-associated pneumonia (VAP) were treated with 1 g of ertapenem infusion once a day. Blood and urine samples were collected before and at different time-points up to 24 h after medication on day 1. Concentrations of ertapenem in plasma were determined with a validated HPLC method. Free-drug concentrations were estimated using a two-class binding site equation. The overall clinical success rate of the assessable cases was 66.7% (12/16). Pharmacokinetic parameters of ertapenem in our critically ill patients were clearly different when compared to those reported in the literature for healthy volunteers. The enhanced V(z) (17 vs. 8 L) and CL(TOT) (43 vs. 20 mL/min) with resulting lower C(max) (90 vs. 253 mg/L) and AUC(0-infinity) (418 vs. 817 mg x h/L) values were mainly related to hypoalbuminaemia (range 9.2-25.6 g/L) in our patient population. A population pharmacokinetic analysis using the NONMEM program indicated creatinine clearance as a significant covariate for explaining the between-subject variability of ertapenem in the patient population. Estimated free plasma concentrations of ertapenem exceeded a MIC(90) of 2 mg/L only for 6 h (25%) after infusion. For an adequate dose adjustment of highly protein-bound drugs like ertapenem, knowledge of actual albumin concentrations is necessary. A shortening of the dosage interval or continuous infusion of ertapenem should be considered to ensure optimal free concentrations in critically ill patients with severe hypoalbuminaemia and normal renal function.


Diversity and characterization of mercury-resistant bacteria in snow, freshwater and sea-ice brine from the High Arctic.
It is well-established that atmospheric deposition transports mercury from lower latitudes to the Arctic. The role of bacteria in the dynamics of the deposited mercury, however, is unknown. We characterized mercury-resistant bacteria from High Arctic snow, freshwater and sea-ice brine. Bacterial densities were 9.4 × 10(5), 5 × 10(5) and 0.9-3.1 × 10(3) cells mL(-1) in freshwater, brine and snow, respectively. Highest cultivability was observed in snow (11.9%), followed by freshwater (0.3%) and brine (0.03%). In snow, the mercury-resistant bacteria accounted for up to 31% of the culturable bacteria, but <2% in freshwater and brine. The resistant bacteria belonged to the Alpha-, Beta- and Gammaproteobacteria, Firmicutes, Actinobacteria, and Bacteriodetes. Resistance levels of most isolates were not temperature dependent. Of the resistant isolates, 25% reduced Hg(II) to Hg(0). No relation between resistance level, ability to reduce Hg(II) and phylogenetic group was observed. An estimation of the potential bacterial reduction of Hg(II) in snow suggested that it was important in the deeper snow layers where light attenuation inhibited photoreduction. Thus, by reducing Hg(II) to Hg(0), mercury-resistant bacteria may limit the supply of substrate for methylation processes and, hence, contribute to lowering the risk that methylmercury is being incorporated into the Arctic food chains.


The representation of the visual field in parvicellular and magnocellular layers of the lateral geniculate nucleus in the macaque monkey.
Two-dimensional maps of individual layers of the dorsal lateral geniculate nucleus (LGN) in the macaque monkey were constructed and used as a basis for comparing laminar size, shape, and topographic organization. Topographical data from the electrophysiological investigation of the LGN by Malpeli and Baker ('75) were displayed on maps of all six layers. As known from previous studies, there is a significant over-representation of central vision in the LGN. Unexpectedly, though, the visual representation is anisotropic over portions of most LGN layers. That is, the linear magnification factor (millimeters along the laminar surface per degree of visual field) is not equal for all directions from a given point in the visual field. Moreover, the visual representations in the parvicellular and magnocellular divisions of the LGN differ both in their emphasis on central vision and in their anisotropies. To determine the degree of individual variability, laminar maps were prepared from the LGN of seven other hemispheres. The shapes of laminar maps varied considerably between LGNs, from nearly circular to highly elliptical, but the surface area was relatively constant for each layer. Topographical organization, determined by mapping the optic disc representation on the LGN laminae and by labeling from anterograde and retrograde tracer injections in striate cortex, showed significant individual variability. Interestingly, the visual representations in the LGN and striate cortex are topologically inverted with respect to one another. This indicates that the establishment of geniculocortical connections involves a systematic crossing-over of fibers. Information on cell densities and magnification factors in striate cortex obtained from other studies was compared to the results of the present study in order to estimate ratios of cortical neurons to LGN neurons at different eccentricities. The total number of cortical neurons per LGN neuron is about 130 on average, but it extends over approximately a tenfold range, from less than 100 in the far periphery to nearly 1,000 in the fovea. The estimated number of cells in layers 4A and 4C beta per parvicellular layer neuron is smaller and extends over a slightly narrower range, from 30 to 240, whereas the number of layer 4C alpha neurons per magnocellular neuron varies more widely, from about 45 to 7,000.


Alcohol Consumption and Risk of Common Autoimmune Inflammatory Diseases-Evidence From a Large-Scale Genetic Analysis Totaling 1 Million Individuals.
Purpose: Observational studies have suggested a protective effect of alcohol intake with autoimmune disorders, which was not supported by Mendelian randomization (MR) analyses that used only a few (<20) instrumental variables. Methods: We systemically interrogated a putative causal relationship between alcohol consumption and four common autoimmune disorders, using summary-level data from the largest genome-wide association study (GWAS) conducted on inflammatory bowel disease (IBD), rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). We quantified the genetic correlation to examine a shared genetic similarity. We constructed a strong instrument using 99 genetic variants associated with drinks per week and applied several two-sample MR methods. We additionally incorporated excessive drinking as reflected by alcohol use disorder identification test score. Results: We observed a negatively shared genetic basis between alcohol intake and autoimmune disorders, although none was significant (r g = -0.07 to -0.02). For most disorders, genetically predicted alcohol consumption was associated with a slightly (10-25%) decreased risk of onset, yet these associations were not significant. Meta-analyzing across RA, MS, and IBD, the three Th1-related disorders yielded to a marginally significantly reduced effect [OR = 0.70 (0.51-0.95), P = 0.02]. Excessive drinking did not appear to reduce the risk of autoimmune disorders. Conclusions: With its greatly augmented sample size and substantially improved statistical power, our MR study does not convincingly support a beneficial role of alcohol consumption in each individual autoimmune disorder. Future studies may be designed to replicate our findings and to understand a causal effect on disease prognosis.


A Novel Peptide Hydrogel for an Antimicrobial Bandage Contact Lens.
A peptide hydrogel with an antimicrobial activity is developed as a bandage contact lens. The antimicrobial activity is enhanced with the addition of the biomolecules penicillin G or poly-ε-lysine and is positive against Staphylococcus aureus and Escherichia coli. The lens is also noncytotoxic toward a human corneal epithelial cell line and as a consequence is of great potential as a drug-eluting bandage lens replacing conventional corneal ulcer treatment.


Effect of Fish Oil and Linseed Oil on Intake, Milk Yield and Milk Fatty Acid Profile in Goats.
This study aimed to evaluate the effect of incorporating linseed oil and fish oil in the diet on intake, ruminal fermentation, milk yield, and milk fatty acid profiles in dairy goats. Four crossbred Saanen lactating goats in mid-lactation and milking 1.30 ± 0.28 g/day were used in a 4 × 4 Latin square design. The basal diet contained concentrate and Para grass (C:F 40:60). Treatments included a basal diet without oil supplementation (Ctrl) or with 2.5% linseed oil (LO2.5), 2.5% linseed oil and fish oil (3:2, w/w, LFO2.5), and 4.16% linseed oil and fish oil (3:2, w/w, LFO4.16). Diets had no effect on intake, milk yield, milk composition, or ruminal fermentation (p > 0.05). Compared with Ctrl, lower (p < 0.05) proportions of C10:0-C14:0 in milk fat were observed with LFO4.16. Compared with the Ctrl and linseed oil added alone, feeding LFO4.16 led to a greater (p < 0.01) concentration of C18:1 t11. Compared with both the Ctrl and LO2.5 diets, milk c9,t11 CLA was 4.53 and 2.94 times greater with the LFO4.16 diet. Compared with Ctrl and LO2.5 diets (0.06% and 0.08%), goats fed LFO2.5, and LFO4.16 had greater (p < 0.001) concentrations of C22:6n-3 (0.63% and 0.87%). Overall, the combined data suggested that including 4.16% linseed oil and fish oil in the diet of dairy goats was effective in improving the concentrations of health-promoting fatty acids in milk without affecting milk production.


Editorial: The right to know. On the freedom of medical information.
Information about health and disease has high social value and is, thus, subject to a variety of controls. These influence the freedom of investigators to generate it; of editors and publishers to transmit it; and of professionals and the public to have access to it. Unconstrained research may threaten the social order and evoke legal or political limit setting. Prominent in the present era are the possibilities of dangerous ethical and biological consequences of new knowledge or, perhaps more important, of procedures for obtaining it. Medical information is transmitted through both the mass media and professional journals. Access to both by potential authors is limited by institutionalized mechanisms of social control and the academic-research subculture. An emerging factor is the editor's possible ethical responsibility for material which he accepts for publication. Access to information is determined by what finally is published, as well as membership in informal communication networks. It is also influenced by dependence, due to cost, time limitation and information overload, on prepackaged material presented in texts, anthologies, busy clinician-oriented journals, or commercial, e.g., pharmaceutical firms. The possibility that governments will, in time, become the major distributors as well as generators of medical information raises new questions as to its eventual freedom and control.


Satellite DNA as a driver of population divergence in the red flour beetle Tribolium castaneum.
Tandemly repeated satellite DNAs are among most rapidly evolving sequences in eukaryotic genome, usually differing significantly among closely related species. By inducing changes in heterochromatin and/or centromere, satellite DNAs are expected to drive population and species divergence. However, despite high evolutionary dynamics, divergence of satellite DNA profiles at the level of natural population which precedes and possibly triggers speciation process is not readily detected. Here, we characterize minor TCAST2 satellite DNA of the red flour beetle Tribolium castaneum and follow its dynamics among wild-type strains originating from diverse geographic locations. The investigation revealed presence of three distinct subfamilies of TCAST2 satellite DNA which differ in monomer size, genome organization, and subfamily specific mutations. Subfamilies Tcast2a and Tcast2b are tandemly arranged within pericentromeric heterochromatin whereas Tcast2c is preferentially dispersed within euchromatin of all chromosomes. Among strains, TCAST2 subfamilies are conserved in sequence but exhibit a significant content variability. This results in overrepresentation or almost complete absence of particular subfamily in some strains and enables discrimination between strains. It is proposed that homologous recombination, probably stimulated by environmental stress, is responsible for the emergence of TCAST2 satellite subfamilies, their copy number variation and dispersion within genome. The results represent the first evidence for the existence of population-specific satellite DNA profiles. Partial organization of TCAST2 satellite DNA in the form of single repeats dispersed within euchromatin additionally contributes to the genome divergence at the population level.


Physicochemical properties and bioactivity of nisin-containing cross-linked hydroxypropylmethylcellulose films.
Cross-linked hydroxypropylmethylcellulose (HPMC) cast films with citric acid as polycarboxylic cross-linker were elaborated to study the effect of cross-linking level on various properties. Increased amounts of cross-linking agent were not connected to statistically different tensile strength and Young's modulus. Whatever the cross-linking level of the film was, the ultimate elongation parameter decreased by approximately 60% compared to the HMPC control film. Moisture sorption isotherms and water contact angle meter showed that the effect of cross-linking degree tends to reduce the hygroscopic and hydrophilic characteristics of films. In addition, to control bacteria growth on food surfaces, the antimicrobial activity of both 98% cross-linked HPMC-nisin and control HPMC-nisin films was tested on Micrococcus luteus. Despite the incorporation of a significant content of nisin, cross-linked HPMC-nisin films were completely inactive on the microbial strain compared to the HPMC-nisin control films. Cross-linking conditions likely either denatured the nisin or irreversibly bound nisin to the cross-linked HPMC. However, nisin adsorbed into films made from previously cross-linked HPMC maintained its activity.


Intelligent Method to Optimize the Frequency Modulation for Beam Pumping System Based on Deep Reinforcement Learning.
A mathematical simulation model of a beam pumping system with frequency conversion control is established, considering the influence of the real-time frequency variation on the motion law of a pumping unit, the longitudinal vibration of a sucker rod string, the crankshaft torque, and the motor power. On this basis, the key links such as state space, action space, and reward function are defined by using deep reinforcement learning theory, and an intelligent model to optimize the frequency modulation for a beam pumping system based on deep reinforcement learning is constructed. The simulation and field application results show that the frequency optimization model can significantly reduce the fluctuation amplitude of the polished rod load, crankshaft torque, motor power, and input power of the system, making the operation of the pumping system more stable and energy-saving. More importantly, the model can realize the independent learning and control of the corresponding parameters without manual intervention to ensure the normal operation of the system and improve the level of information and intelligent management of oil wells.


Enthalpic homogeneous pair interaction coefficients of L-alpha-amino acids as a hydrophobicity parameter of amino acid side chains.
Enthalpies of dilution of aqueous solutions of L-alpha-cysteine, L-alpha-histidine, L-alpha-asparagine, L-alpha-glutamine, L-alpha-arginine, L-alpha-tryptophan, and L-alpha-glutamic acid in water at a temperature of 298.15 K have been measured. The values of dilution enthaply were used to determine enthalpic homogeneous pair interaction coefficients which characterize the interactions between zwitterions of the examined L-alpha-amino acids in water. Approachable literature data of hydrophobic scales have been analyzed to obtain average values. The obtained values of enthalpic pair interaction coefficients have been put together with an average hydrophobic scale.


Role of the IFNG +874T/A polymorphism in Chagas disease in a Colombian population.
Genetic susceptibility to Trypanosoma cruzi infection and the development of cardiomyopathy is complex, heterogeneous, and likely involves several genes. Previous studies have implicated cytokine and chemokine genes in susceptibility to Chagas disease. Here we investigated the association between the interferon-gamma gene (IFNG) +874T/A polymorphism and Chagas disease, focusing on susceptibility and severity. This study included 236 chagasic patients (asymptomatic, n=116; cardiomyopathic, n=120) and 282 healthy controls from a Colombian population where T. cruzi is highly endemic. Individuals were genotyped for functional single nucleotide polymorphism (SNP; rs2430561; A/T) of the IFNG gene by amplification refractory mutational system PCR (ARMS-PCR). Moreover, clinical manifestations of Chagas in patients were analyzed. We found a significant difference in the distribution of the IFNG +874 "A" allele between patients and healthy controls (P=0.003; OR=1.46, 95% CI, 1.13-1.89). The frequency of the IFNG +874 genotype A/A, which is associated with reduced production of interferon-gamma, was increased in the patients relative to controls (38.1% vs. 26.6%). We compared the frequencies of IFNG alleles and genotypes between asymptomatic patients and those with chagasic cardiomyopathy and found no significant difference. Our data suggest that the IFNG +874T/A genetic polymorphism may be involved in susceptibility but not in the progression of Chagas disease in this Colombian population.


Detection of Adulteration and Pesticide Residues in Chinese Patent Medicine Qipi Pill Using KASP Technology and GC-MS/MS.
Chinese patent medicines (CPMs) are of great value for the prevention and treatment of diseases. However, adulterants and pesticide residues in CPMs have become the "bottleneck" impeding the globalization of traditional Chinese medicine. In this study, 12 batches of commercially available Qipi pill (a famous CPM recorded in Chinese Pharmacopeia) from different manufacturers were investigated to evaluate their authenticity and quality safety. Considering the severely degraded DNA in CPMs, kompetitive allele specific PCR (KASP) technology combined with DNA mini-barcodes was proposed for the quality regulation of a large number of products in CPM market. The residues of four kinds of pesticides including pentachloronitrobenzene (PCNB), hexachlorocyclohexane (HCH), aldrin, and dichlorodiphenyltrichloroethane (DDT) were quantified using gas chromatography and tandem mass spectrometry (GC-MS/MS). The results indicated that in two of the 12 batches of Qipi pill, the main herbal ingredient Panax ginseng was completely substituted by P. quinquefolius, and one sample was partially adulterated with P. quinquefolius. The PCNB residue was detected in 11 batches of Qipi pill, ranging from 0.11 to 0.46 mg/kg, and the prohibited pesticide HCH was present in four samples. Both adulteration and banned pesticides were found in two CPMs. This study suggests that KASP technology combined with DNA mini-barcodes can be used for the quality supervision of large sample size CPMs with higher efficiency but lower cost. Our findings also provide the insight that pesticide residues in CPMs should be paid more attention in the future.


Repetitive and non-repetitive violent offending behaviour in male patients in a maximum security mental hospital--clinical and neuroimaging findings.
To examine if different violent offending behaviours are associated with different clinical and neuroimaging profiles. Thirty-nine schizophrenic and schizoaffective offenders from a maximum security mental hospital-20 repetitive violent offenders (RVOs) and 19 non-repetitive violent offenders (NRVOs)-were selected for clinical and neuroimaging assessments. Both groups had positive family history of mental illness and violence. Age, diagnosis, duration of illness, victim profiles and use of weapons at the time of the index offence were similar. RVOs had a higher prevalence of early parental separation, juvenile conduct problem, previous convictions of crimes not involving violence, impulsive suicide attempts, delusion of their lives being threatened at the time of the index offence and electroencephalographic (EEG) abnormalities localized to temporal lobes. NRVOs had a higher prevalence of sexual inexperience and command hallucinations to kill at the time of the index offence. Asymmetric gyral patterns at the temporo-parietal region were particularly common in RVOs and absent in NRVOs. Non-specific white matter changes in magnetic resonance imaging (MRI) and generalized cortical hypometabolism in positron emission tomography (PET) were present in both groups. Different structural and metabolic changes in the brain were associated with different violent offending behaviours. The complex interaction between violent behaviour, clinical features and neuroimaging findings in schizophrenia requires further studies.


[Determination of digoxin-like immunoreactive substances in sera of 15 elder patients with cardiac insufficiency].
The presence of a higher concentration of digoxin-like immunoreactive substances (DLIS) in human serum have been reported in a number of pathophysiological conditions. DLIS can react with anti-digoxin antibodies when determination of serum digoxin was performed with immunoassay. It may falsely elevate the serum digoxin concentration and is troublesome in the therapeutic monitoring of digoxin. The apparent digoxin concentrations (DLIS) in serum were determined in 15 elder patients with cardiac insufficiency by fluorescence polarization immunoassay (FPIA). The lowest measurable concentration, defined as the concentration that could be distinguished from zero with 95% confidence, was 0.256 nmol.L-1. Steroids and drugs commonly administered with digoxin showed no significant cross-reactivity. In these patients, the positive ratio for determination of DLIS was 46.7% (7 in 15 cases), and its mean serum concentration was 0.55 +/- 0.44 nmol.L-1 (range 0.26-1.52 nmol.L-1). The results were well consistent with that obtained by Dasgupta et al. In conclusion, there are certain increased concentrations of DLIS in the sera of elder patients with cardiac insufficiency, suggesting that digoxin levels measured by immunoassay method must be interpreted carefully in these patients after treatment with digoxin or other digitalis preparations.


PatchSearch: A Fast Computational Method for Off-Target Detection.
Many therapeutic molecules are known to bind several proteins, which can be different from the initially targeted one. Such unexpected interactions with proteins called off-targets can lead to adverse effects. Potential off-target identification is important to predict to avoid drug side effects or to discover new targets for existing drugs. We propose a new program named PatchSearch that implements local nonsequential searching for similar binding sites on protein surfaces with a controlled amount of flexibility. It is based on detection of quasi-cliques in product graphs representing all the possible matchings between two compared structures. This method has been benchmarked on a large diversity of ligands and on five data sets ranging from 12 to more than 7000 protein structures. The experiments conducted in this study show that the PatchSearch method could be useful in the early identification of off-targets. The program and the benchmarks presented in this paper are available as an R package at https://github.com/MTiPatchSearch .