A novel vaccine delivery system: biodegradable nanoparticles in thermosensitive hydrogel.
In this work, a novel vaccine delivery system, biodegradable nanoparticles (NPs) in thermosensitive hydrogel, was investigated. Human basic fibroblast growth factor (bFGF)-loaded NPs (bFGF-NPs) were prepared, and then bFGF-NPs were incorporated into thermosensitive hydrogel to form bFGF-NPs in a hydrogel composite (bFGF-NPs/hydrogel). bFGF-NPs/hydrogel was an injectable sol at ambient temperature, but was converted into a non-flowing gel at body temperature. The in vitro release profile showed that bFGF could be released from bFGF-NPs or bFGF-NPs/hydrogel at an extended period, but the release rate of bFGF-NPs/hydrogel was much lower. In vivo experiments suggested that immunogenicity of bFGF improved significantly after being incorporated into the NPs/hydrogel composite, and strong humoral immunity was maintained for longer than 12 weeks. Furthermore, an in vivo protective anti-tumor immunity assay indicated that immunization with bFGF-NPs/hydrogel could induce significant suppression of the growth and metastases of tumors. Thus, the NPs/hydrogel composite may have great potential application as a novel vaccine delivery system.


Effect of cefadroxil on antigen-induced bronchial hyperresponsiveness and eosinophil accumulation in lung from sensitized guinea pigs.
The effect of a semi-synthetic cephalosporin, Cefadroxil, on antigen-induced bronchial hyperresponsiveness and eosinophil accumulation in lungs from sensitized guinea pigs was investigated and compared to the effects of Cetirizine and Ketotifen. When aerosol-sensitized guinea pigs were pretreated 1 h before the antigen challenge with Cefadroxil (100 mg/kg i.p.) a partial but significant inhibition of the bronchial hyperresponsiveness to aerosolized acetylcholine chloride was observed. Furthermore, the treatment of guinea pigs (115 mg/kg, per os) 24 and 1 h before ovalbumin challenge also significantly reduced bronchial hyperresponsiveness. In contrast, no significant inhibition was noted when the guinea pigs were treated by a single dose of Cefadroxil (115 mg/kg per os) 1 h before challenge. Pretreatment of the guinea pigs with Cetirizine (1 mg/kg per os) or Ketotifen (0.1 mg/kg per os) completely inhibited the antigen-induced bronchial hyperresponsiveness. Cefadroxil (100 mg/kg i.p.) slightly inhibited the accumulation of eosinophils in the peribronchial area induced by antigen challenge. In contrast, no significant reduction was noted when the guinea pigs were treated per os with Cefadroxil (115 mg/kg), Cetirizine (1 or 10 mg/kg) or Ketotifen (0.1 mg/kg). These results show that Cefadroxil is effective in reducing antigen-induced bronchial hyperresponsiveness, an effect independent of a reduction in the pulmonary inflammation, namely eosinophil accumulation in lung.


Histone acetyltransferase 1 promotes homologous recombination in DNA repair by facilitating histone turnover.
Faithful repair of DNA double-strand breaks is vital to the maintenance of genome integrity and proper cell functions. Histone modifications, such as reversible acetylation, phosphorylation, methylation, and ubiquitination, which collectively contribute to the establishment of distinct chromatin states, play important roles in the recruitment of repair factors to the sites of double-strand breaks. Here we report that histone acetyltransferase 1 (HAT1), a classical B type histone acetyltransferase responsible for acetylating the N-terminal tail of newly synthesized histone H4 in the cytoplasm, is a key regulator of DNA repair by homologous recombination in the nucleus. We found that HAT1 is required for the incorporation of H4K5/K12-acetylated H3.3 at sites of double-strand breaks through its HIRA-dependent histone turnover activity. Incorporated histones with specific chemical modifications facilitate subsequent recruitment of RAD51, a key repair factor in mammalian cells, to promote efficient homologous recombination. Significantly, depletion of HAT1 sensitized cells to DNA damage compromised the global chromatin structure, inhibited cell proliferation, and induced cell apoptosis. Our experiments uncovered a role for HAT1 in DNA repair in higher eukaryotic organisms and provide a mechanistic insight into the regulation of histone dynamics by HAT1.


Encapsulation of Mentha pulegium Essential Oil in Yeast Cell Microcarriers: An Approach to Environmentally Friendly Pesticides.
A green approach for the encapsulation of Mentha pulegium essential oil in commercial baker's yeast and its evaluation as a pesticide against the insect pest Myzus persicae are presented. Upon treating aqueous yeast cell dispersion with the essential oil, the formation of essential-oil-loaded microparticles of about 9 μm is observed, with a loading capacity ranging from 29 to 36%, depending upon the encapsulation conditions. The thermal properties of the microparticles were characterized using differential scanning calorimetry and thermogravimetric analysis, confirming the protection of the essential oil from the cells. Encapsulation prolonged the insecticidal activity of the essential oil by 3 days.


Importance of administration method in high-dose anticancer chemotherapy from toxicological standpoint in rats.
We examined death rates in Fisher rats when chemotherapeutic drugs were administered in a prescribed amount by either a single or divided dose. Lower death rates were observed when nimustine hydrochloride (ACNU) was given in a divided dose, or when cyclophosphamide (CY), vindesine sulfate (VDS) or vincristine (VCR) was administered as a single dose. Lower hematological toxicity was observed when ACNU was administered in 2 doses and CY in a single dose. With etoposide, we did not observe any significant difference between the two administration methods. In a combination study with ACNU and VDS, we observed lower toxic death rates when the dose of ACNU was split and VDS was given as a single dose. ACNU-induced death was substantially reduced by syngeneic bone marrow support or granulocyte colony-stimulating factor treatment. Our experiments indicate that the toxicity of the administration of chemotherapeutic agents may be significantly modified by altering the time course of administration. This would hopefully result in reducing the chemotherapy-related mortality associated with high-dose anticancer chemotherapy.


Restoration of the rat urothelium after cyclophosphamide treatment.
Processes leading to the recovery of a normal three-layered urothelium from a hyperplastic urothelium induced by cyclophosphamide (CP) treatment in rats have been investigated. A single intraperitoneal (ip) dose of CP caused extensive loss of cells from urothelium, but the remaining cells started to express epidermal growth factor receptor (EGFR) in their plasma membranes. On day 2 after CP injection, proliferating cell nuclear antigen (PCNA) immunohistochemistry showed a rapid increase in positively stained nuclei, from which a hyperplastic urothelium developed, composed of undifferentiated cells expressing EGFR over the entire plasma membrane. Subsequently, EGFR gradually disappeared from the apical plasma membrane but remained in the basolateral membranes. After day 6, PCNA-positive nuclei in all cell layers decreased, except in basal cells. Apoptotic cells were detectable by the TUNEL assay at day 2, and increased in number in all layers of the hyperplastic urothelium until day 10, returning to the control levels by day 14. Electron microscopic evidence showed that apoptotic cells were either pinched off into the bladder lumen or phagocytosed by the neighbouring urothelial cells. Thus, the urothelium responds to the damage by intense proliferation for a week, resulting in an undifferentiated hyperplastic state. Differentiation of superficial cells then begins and damaged cells are gradually removed by apoptosis until the three-layered urothelium is fully restored by two weeks following CP treatment.


Differential characteristics of catalase-positive campylobacters correlated with DNA homology groups.
Eighty-four strains of catalase-positive campylobacters could be placed into seven distinct DNA homology groups (species), corresponding to Campylobacter fetus, "C. hyointestinalis," C. jejuni, C. coli, "C. laridis," "C. fecalis," and aerotolerant campylobacters. The biochemical and physiological characteristics of the strains were examined for their correlation with the homology groups. The characterization tests that provided the most reliable differentiation at the species and subspecies level were growth at 25 and 42 degrees C, sensitivity to cephalothin and nalidixic acid, growth in semisolid media containing 1% glycine and 3.5% NaCl, growth on plates containing 1.5% NaCl, growth in a semisolid minimal medium, anaerobic growth in the presence of 0.1% trimethylamine-N-oxide, hydrogen sulfide production in SIM medium and triple-sugar iron agar, hippurate hydrolysis, nitrite reduction, and growth on plates under an air atmosphere.


Guidelines on replacement therapy for haemophilia and inherited coagulation disorders in Italy.
In the last years, the availability in Italy of technologically advanced products for replacement therapy has produced significant changes in the management of haemophilia and of hereditary bleeding disorders in general. With the aim of a uniform approach to treatment, the Italian Association of Haemophilia Centres express in these guidelines a consensus on therapeutic strategies designed to ensure the highest degree of safety and efficacy for the treatment of inherited coagulopathies. The guidelines provide specific recommendations for the choice of the product according to updated scientific evidence, and advice on optimal dosages for the treatment of rare bleeding disorders. The system for haemophilia care and funding in Italy is briefly described.


Primary angiitis of central nervous system: The story of a great masquerader.
Primary angiitis of central nervous system (PACNS) is characterized by non-caseating granulomatous angiitis restricted to CNS. The condition often masquerades as migraine, stroke, epilepsy, dementia, demyelinating disorder and CNS infection. The protean manifestations frequently lead to misdiagnoses. We present a case of a young male from rural background that remained undiagnosed for years as the possibility of PACNS was not considered. He had history suggestive of migraine-like headaches followed by seizures. Subsequently, he developed rapidly progressive dementia and two episodes of hemorrhagic strokes over a short period. The diagnosis was finally clinched by the absence of evidence of systemic vasculitis and the presence of characteristic non-caseating granuloma around vessels of duramater and cerebral parenchyma on brain biopsy. He was started on pulse therapy with intravenous cyclophosphamide and methylprednisolone. The current literature about the condition and its management is reviewed in this report.


Nurses' knowledge of the code for nurses.
"Investigation of Professionalism in Nursing Behaviors" was funded by the Beta Upsilon Chapter of Sigma Theta Tau International and the College of Nursing, Arizona State University. Researchers asked 514 nurses in eight western states if they had a copy of the Code For Nurses. Most respondents did not have a copy of the Code; however, they indicated that adherence to the Code was essential to the professional nurse. Years of practice, educational background, participation in autonomous activities, and present position were variables used to determine those respondents most likely to possess a copy of the Code. Implications for continuing educators are discussed.


A Rare Presentation of Coinfection: Dengue Virus and Hepatitis A Virus.
Dengue fever caused by dengue virus is a common tropical infection transmitted by the mosquitos Aedes aegypti and Aedes albopictus. Four strains of the genus flavivirus is responsible for the epidemics of varying severity. Hepatitis A caused by hepatitis A virus is spread by faecal-oral route. The culprit virus is a hepatovirus. Coinfection with dengue virus and hepatitis A virus is rare and is a diagnostic as well as management challenge to the medical professional. We report a patient who presented to us with dengue virus and hepatitis A virus coinfection.


Elucidating light-induced charge accumulation in an artificial analogue of methane monooxygenase enzymes using time-resolved X-ray absorption spectroscopy.
We report the use of time-resolved X-ray absorption spectroscopy in the ns-μs time scale to track the light induced two electron transfer processes in a multi-component photocatalytic system, consisting of [Ru(bpy)3]2+/ a diiron(iii,iii) model/triethylamine. EXAFS analysis with DFT calculations confirms the structural configurations of the diiron(iii,iii) and reduced diiron(ii,ii) states.


Rectal prolapse in children.
Some of the factors thought to be responsible for rectal prolapse in children are reviewed. In the United Kingdom management has in the past been conservative. It is suggested that children should be treated at an early stage by means of an injection of phenol in almond oil, in order to reduce the discomfort of recurrent manipulative reductions of the prolapse in the child and alleviate the anxiety of the parents. In 18 cases treated during the past 3 years a single injection performed under general anaesthesia, as a day case, was successful in preventing further prolapse of the rectum.


Thermodynamics of nano- and macrocrystalline anatase using cell voltage measurements.
In view of increasing scientific and technological interest in nanomaterials, it is important to examine whether or, more exactly, to what extent the thermodynamic parameters change with size. Electrochemical e.m.f. measurements which provide a direct and elegant access to these thermodynamic data have been used in this study to investigate the excess contributions of anatase due to nano-size. The e.m.f. measurements are carried out (250-450 degrees C) on different particle sizes (1.2 microm-5 nm) using the cell: Au, O(2), Na(2)Ti(6)O(13), TiO(2) (anatase) |Na-beta'' alumina |TiO(2) (rutile), Na(2)Ti(6)O(13), O(2), Au. The e.m.f. observed is closely related to the difference of the Gibbs energies of formation (Delta(f)G degrees) of the titania crystals on both sides. Such cell voltage measurements with various sizes of anatase (1200, 100, 15, and 5 nm) as working electrodes enable us to calculate the excess enthalpy and entropy due to surface contributions and to provide refined data for the macroscopic anatase. No electrochemical Ostwald ripening or chemical Ostwald ripening was observed in the case of anatase nanoparticles up to 500 degrees C.


Spatial and temporal analysis of sheep scab notifications in Scotland, 2014-2019.
Sheep scab is considered an endemic disease of great welfare and economic significance in the UK. This paper provides an up-to-date assessment of the impact of Sheep Scab (Scotland) Order 2010 on sheep scab notifications in Scotland between 1 January 2014 and 31 December 2019, using data collected by the APHA. In total, 564 sheep scab notifications were reported from 503 unique holdings, of which 44 holdings (8.7%) reported more than one incident. The number of notifications did not differ between years, with 81, 84, 93, 101, 109 and 97 notifications recorded in 2014, 2015, 2016, 2017, 2018 and 2019, respectively: representing an average annual notification prevalence of 0.63% (1/159 flocks/year). A total of 413/564 records documented how notifications were resolved, with macrocyclic lactone and organophosphate treatments accounting for 79.6% and 20.4% of resolutions, respectively. Our results suggest that the Order has facilitated the notification of sheep scab in Scotland (including trends and preferred methods of resolution), allowed industry and government to identify previously unidentified potentially free areas as well as recurrent incidents on sheep farms, and start to understand better the geographical and temporal nature of scab outbreaks. However, concerns remain about a potential lack of engagement, evidenced by the low notification prevalence and stagnant annual notification rates.


The Monolayer Behavior of Amphiphilic Polymer and Heterostructure of Polymer LB Film/CdS Clusters.
In this paper we report the behavior of an amphiphilic polymer monolayer on pure water and Cd2+ subphase. This polymer was composed of hydrophilic ethylene diamine epichlorohydrin slightly crosslinked microgel and hydrophobic stearic chains, noted as ES-1. The introduction of Cd2+ ions in subphase had a marked effect on the process of the organization of the amphiphilic polymer at the air/water interface due to the association of Cd2+ ions with the hydrophilic network, which could be indicated by the pressure-area isotherms and Brewster Angle Microscopy. Ordered ES-1/Cd2+ LB multilayers were fabricated. After the multilayers reacted with H2S gas, CdS clusters were synthesized within the film, which was characterized by X-ray diffraction and UV-visible spectroscopy. Copyright 1999 Academic Press.


[Intellectual and psychosocial functions in children treated with radiation for brain tumor].
Modern treatment has increased the survival rate for children with brain tumour, but treatment with radiation may lead to late adverse neuropsychologic effects. Also, peer problems may follow long periods away from school, and painful treatment and anxiety about the disease may mobilize emotional stress reactions. 16 brain tumour children with a mean age of 11 years (range 6-16 years), all of them treated with radiation, were tested with WISC-R. The mean time between diagnosis and study was five years (range 2-11 years). Parents and teachers completed the Achenbach check lists CBCL and TRF. Children below age four years at diagnosis achieved the lowest WISC-R IQs, the highest problem scores and the lowest social adaptive scores on CBCL and TRF. More problems were reported among the youth group aged 12-16 years than among the child group aged 6-11 years. Hypoactivity and low psychomotor speed seemed to have an adverse effect on both intellectual and psychosocial functioning. An almost normal communicative and reasoning ability was a resource for most of the children.


Balloon Versus Computed Tomography Sizing of the Aortic Annulus for Transcatheter Aortic Valve Replacement and the Impact of Left Ventricular Outflow Tract Calcification and Morphology on Sizing.
To evaluate the role of balloon annular sizing in transcatheter aortic valve replacement (TAVR). Multidetector cardiac computed tomography (MDCT) is the gold standard for aortic annular sizing in TAVR. Balloon sizing is increasingly used in patients with borderline annular size and severe calcification. A comparison between these two techniques is needed. We retrospectively compared baseline characteristics and 30-day outcomes of patients undergoing balloon-expandable TAVR using annular MDCT or balloon sizing. Paravalvular leak (PVL) rates were compared adjusting for access site, valve generation, size, and valve calcification. A total of 205 patients underwent TAVR with MDCT (n = 110) or balloon sizing (n = 95). Balloon-sized patients were older (83 years vs 81 years; P=.03), had more valve calcification (60.2% vs 30.9%; P<.001), and underwent more minimalist TAVR (61.1% vs 40%; P=.03). Although we found no difference between balloon and MDCT sizing in rates of acute renal failure (3.2% vs 0.9%; P=.34), annular rupture (1.1% vs 1.8%; P>.99), ≥ mild PVL by angiography (40% vs 35.5%; P=.57), or 30-day transthoracic echocardiography (40.7% vs 29.3%; P=.78), balloon-sized patients had a higher aortic regurgitation index (≥25) of 74.4% vs 54.1% (P=.01). Thirty-day rates of ≥ moderate PVL were 7.0% with balloon and 5.7% with MDCT sizing (P=.34). Balloon sizing recommended a different valve size in 34.0% of patients who underwent both methods (n = 50). A different recommendation occurred more often in patients with moderate/severe annular calcification (50.0% vs 33.3%; P=.01) and non-tubular left ventricular outflow tracts (LVOTs) (70.6% vs 30.3%; P=.01). Balloon sizing can be a complement to MDCT for annular sizing in TAVR, especially in patients with moderate/severe annular calcification, borderline annular size, and non-tubular LVOT.


The Effect of Piceatannol from Passion Fruit (Passiflora edulis) Seeds on Metabolic Health in Humans.
Animal studies have shown the beneficial effects of piceatannol on metabolic health; however, there is a lack of human studies designed to examine these effects. The objective of this study was to investigate the effects of piceatannol on metabolic health in humans. This randomized, placebo-controlled study was conducted on 39 subjects, including 10 overweight men and 9 overweight women (BMI ≥ 25), as well as 10 non-overweight men and 10 non-overweight women (BMI < 25). Subjects received piceatannol (20 mg/day) or placebo capsules for eight weeks in a random order. The primary outcome was the effect of piceatannol on glucose-metabolism, including insulin sensitivity. The secondary outcomes were the effects on other parameters, including blood pressure (BP), heart rate (HR), endothelial function, lipids, inflammation, oxidative stress, mood status, and Sirt1 and phospho-AMP-activated kinase (p-AMPK) expression in isolated peripheral blood mononuclear cells (PBMNCs). Supplementation with piceatannol in overweight men reduced serum insulin levels, HOMA-IR, BP and HR. Other groups, including non-overweight men, as well as overweight and non-overweight women, showed no beneficial effects on insulin sensitivity, BP and HR. Furthermore, piceatannol is not associated with other data, including body weight (BW), body composition, endothelial function, lipids, inflammation, oxidative stress, mood status, and Sirt1/p-AMPK expression in PBMNCs. In conclusion, supplementation with piceatannol can improve metabolic health, including insulin sensitivity, BP and HR, in overweight men.


Poor Health Behaviors Prior to Laparoscopic Sleeve Gastrectomy Surgery.
Identifying eating and lifestyle behaviors prior to bariatric surgery may assist in better selecting and preparing patients and might lead to improved success rate. The current study aimed to assess eating behaviors and lifestyle trends among laparoscopic sleeve gastrectomy (LSG) candidates and to compare those trends between genders. This descriptive study was conducted in the bariatric clinic at the Haifa Assuta Medical Center. Data was gathered from medical records of LSG candidates that were evaluated before surgery in our institution between 2008 and 2011. The data included demographics, comorbidities, anthropometrics, weight management history, and lifestyle parameters. Eating pattern and eating habits were determined by eating habits questionnaires. A total of 266 LSG surgery candidates (71.4 % female) with an average age of 40.7 ± 10.9 years and pre-surgery BMI of 42.4 ± 4.8 kg/m2 were studied. More than half of the patients have family history of obesity and their onset of obesity was before the age of 18 years (54.5 and 57.9 %, respectively). Most of the patients reported on poor eating habits and sedentary lifestyle: 65.1 % do not eat regular meals, 70.3 % skip over breakfast, 61.9 % presented loss of control eating, 45 % frequently consume sweets, and 80.1 % were classified as none active. There were no differences in eating patterns or lifestyle parameters between genders. High occurrence of unhealthy eating habits and a non-active lifestyle were detected in morbid obese candidates for LSG surgery. More efforts should be directed towards nutritional and lifestyle education prior to the surgery.


Synbiotic administration of canine-derived strain Lactobacillus fermentum CCM 7421 and inulin to healthy dogs.
The canine-derived strain Lactobacillus fermentum CCM 7421 has been demonstrated to exert certain health benefits as a probiotic in dogs. Synbiotic combinations are widely used but are rarely studied in dogs. In this study the prebiotic inulin in combination with L. fermentum CCM 7421 was tested for its effects on faecal microbial populations, faecal characteristics, and blood biochemistry in canine experiments. Healthy adult dogs (n = 36) were randomly assigned to 1 of 3 treatment groups (12 dogs/treatment): (i) the control group (C), (ii) the probiotic group (LF group: L. fermentum CCM 7421, 10(8) CFU/mL of Ringer buffer, 0.1 mL/kg of body mass), and (iii) the synbiotic group (LF+I group: L. fermentum CCM 7421 + inulin (I; Raftifeed IPS) added as 1% of diet). The experiment lasted for 7 weeks with a 2-week treatment period. We detected a significant increase of lactic acid bacteria (LF versus C, day 7; LF versus C and LF versus LF+I, days 28 and 49), a decrease of clostridia (LF versus C, day 14), a lower pH value (LF versus LF+I, day 28), and a higher ammonia concentration (LF versus LF+I, days 14 and 49) in faecal samples. The synbiotic LF+I combination did not intensify the probiotic L. fermentum CCM 7421 efficacy, but its slight laxative effect can be useful to prevent constipation, e.g., in senior dogs.


Nerve growth factor activates brain-derived neurotrophic factor promoter IV via extracellular signal-regulated protein kinase 1/2 in PC12 cells.
Brain-derived neurotrophic factor (BDNF) is a neuromodulator of nociceptive responses in the dorsal root ganglia (DRG) and spinal cord. BDNF synthesis increases in response to nerve growth factor (NGF) in trkA-expressing small and medium-sized DRG neurons after inflammation. Previously we demonstrated differential activation of multiple BDNF promoters in the DRG following peripheral nerve injury and inflammation. Using reporter constructs containing individual promoter regions, we investigated the effect of NGF on the multiple BDNF promoters, and the signaling pathway by which NGF activates these promoters in PC12 cells. Although all the promoters were activated 2.4-7.1-fold by NGF treatment, promoter IV gave the greatest induction. The p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, phosphatidylinositol 3-kinase (PI-3K) inhibitor, LY294003, protein kinase A (PKA) inhibitor, H89, and protein kinase C (PKC) inhibitor, chelerythrine, had no effect on activation of promoter IV by NGF. However, activation was completely abolished by the MAPK kinase (MEK) inhibitors, U0126 and PD98059. In addition, these inhibitors blocked NGF-induced phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2. Taken together, these results suggest that the ERK1/2 pathway activates BDNF promoter IV in response to NGF independently of NGF-activated signaling pathways involving PKA and PKC.


Increased lung resistance after diesel particulate and ozone co-exposure not associated with enhanced lung inflammation in allergic mice.
Exposure to diesel exhaust particulate matter (DEP) exacerbates asthma. Likewise, similar effects have been reported with exposure to the oxidizing air pollutant ozone (O(3)). Since levels of both pollutants in ambient air tend to be simultaneously elevated, we investigated the possible synergistic effect of these agents on the exacerbation of allergic airways disease in mice. Male BALB/c mice were sensitized ip with ovalbumin (Ova) or vehicle only, then exposed once per week for 4 wk via nose-only inhalation (4 h) to the PM(2.5) fraction of DEP (2 mg/m(3)), O(3) (0.5 ppm), DEP and O(3), or filtered air, and then challenged with aerosolized ovalbumin. Ova sensitization in air-exposed mice enhanced pulmonary inflammatory cell infiltration, several indicators of injury in the lung (lactate dehydrogenase, albumin and total protein), and lung resistance (R(L)) and elastance (E(L)) in response to methacholine (MCh) aerosol challenge. DEP exposure did not enhance the Ova-induced increase in pulmonary cell infiltration, indicators of injury, or R(L) and E(L). O(3) exposure enhanced the Ova-induced increase in inflammatory cell infiltration and N-acetylglucosaminidase (NAG) in the lung, but had no effect on R(L) or E(L). DEP co-exposure significantly attenuated the O(3)-induced increase in cell infiltration and indicators of injury; co-exposure had no effect on E(L) relative to air-exposed Ova-sensitized mice. However, only DEP-O(3) co-exposure significantly increased the Ova-induced increase in R(L). Thus, O(3) and DEP co-exposure exacerbated airways hyperresponsiveness, a response that was not associated with parallel increases in pulmonary inflammation and one that may be mediated by a unique mechanism.


Reward Comparison: The Achilles' heel and hope for addiction.
In the words of the late Charles Flaherty, reward comparison is commonplace. Rats and man, it appears, compare all rewards and this capacity likely contributes to our ability to select the most appropriate reward/behavior (food, water, salt, sex), at the most ideal level (e.g., a certain sweetness), at any given time. A second advantage of our predisposition for reward comparison is that the availability of rich alternative rewards can protect against our becoming addicted to any single reward/behavior. Thus, the potential protective effects of natural rewards/enrichment are addressed. Despite this, behavior can become inflexible when, through the development of addiction, stress, drug, or cues elicit craving, withdrawal, and ultimately, drug-seeking. Drug-seeking corresponds with a 'window of inopportunity', when even potent natural rewards have little or no impact on behavior. During this time, there is a unitary solution to the need state, and that solution is drug. The present animal model explores this 'window of inopportunity' when natural rewards are devalued and drug-seeking is engaged and considers a mode of possible intervention.


Monitoring the mycotoxins in food and their biomarkers in the Czech Republic.
Testing of the presence of toxigenic microfungi and mycotoxins in foodstuffs in the food chain is an important part of the food safety strategy in The Czech Republic. At the national level, control of their presence in the entire food chain is assured by Public Health Protection Agencies, by the Veterinary Administration and by the Czech Agriculture and Food Inspection Authority. This article summarizes surveillance activities of Public Health Protection Agencies and mycotoxins findings in dietary raw materials and foodstuffs from the 1990s to 2004 in the Czech Republic. At present, the health risk from the mycotoxins exposure from foodstuffs is assessed to be relatively low in the Czech Republic, especially as far as the foodstuffs of the Czech origin are concerned. It may result in late toxic effects (e. g., carcinogenic risk) following a single or repeated ingestion of low mycotoxins doses from foodstuffs. Nevertheless, the overall situation may change due to the globalization of the food market. In order to minimize the risk associated with mycotoxins and eliminate their impact on Czech public health, continuous monitoring of the presence of toxigenic moulds, mycotoxins, and their biomarkers is necessary, in conjunction with strict respect to European Union legislation.


Sample size considerations for studies of intervention efficacy in the occupational setting.
Due to a shared environment and similarities among workers within a worksite, the strongest analytical design to evaluate the efficacy of an intervention to reduce occupational health or safety hazards is to randomly assign worksites, not workers, to the intervention and comparison conditions. Statistical methods are well described for estimating the sample size when the unit of assignment is a group but these methods have not been applied in the evaluation of occupational health and safety interventions. We review and apply the statistical methods for group-randomized trials in planning a study to evaluate the effectiveness of technical/behavioral interventions to reduce wood dust levels among small woodworking businesses. We conducted a pilot study in five small woodworking businesses to estimate variance components between and within worksites and between and within workers. In each worksite, 8 h time-weighted dust concentrations were obtained for each production employee on between two and five occasions. With these data, we estimated the parameters necessary to calculate the percent change in dust concentrations that we could detect (alpha = 0.05, power = 80%) for a range of worksites per condition, workers per worksite and repeat measurements per worker. The mean wood dust concentration across woodworking businesses was 4.53 mg/m3. The measure of similarity among workers within a woodworking business was large (intraclass correlation = 0.5086). Repeated measurements within a worker were weakly correlated (r = 0.1927) while repeated measurements within a worksite were strongly correlated (r = 0.8925). The dominant factor in the sample size calculation was the number of worksites per condition, with the number of workers per worksite playing a lesser role. We also observed that increasing the number of repeat measurements per person had little benefit given the low within-worker correlation in our data. We found that 30 worksites per condition and 10 workers per worksite would give us 80% power to detect a reduction of approximately 30% in wood dust levels (alpha = 0.05). Our results demonstrate the application of the group-randomized trials methodology to evaluate interventions to reduce occupational hazards. The methodology is widely applicable and not limited to the context of wood dust reduction.


Maximizing synchronizability of networks with community structure based on node similarity.
In reality, numerous networks have a community structure characterized by dense intra-community connections and sparse inter-community connections. In this article, strategies are proposed to enhance synchronizability of such networks by rewiring a certain number of inter-community links, where the research scope is complete synchronization on undirected and diffusively coupled dynamic networks. First, we explore the effect of adding links between unconnected nodes with different similarity levels on network synchronizability and find that preferentially adding links between nodes with lower similarity can improve network synchronizability more than that with higher similarity, where node similarity is measured by our improved Asymmetric Katz (AKatz) and Asymmetric Leicht-Holme-Newman (ALHNII) methods from the perspective of link prediction. Additional simulations demonstrate that the node similarity-based link-addition strategy is more effective in enhancing network synchronizability than the node centrality-based methods. Furthermore, we apply the node similarity-based link-addition or deletion strategy as the valid criteria to the rewiring process of inter-community links and then propose a Node Similarity-Based Rewiring Optimization (NSBRO) algorithm, where the optimization process is realized by a modified simulated annealing technique. Simulations show that our proposed method performs better in optimizing synchronization of such networks compared with other centrality-based heuristic methods. Finally, simulations on the Rössler system indicate that the network structure optimized by the NSBRO algorithm also leads to better synchronizability of coupled oscillators.


Fitting an inhibitor into the active site of thermolysin: a molecular dynamics case study.
We used molecular dynamics computer simulation to "fly" a small flexible ligand, L-leucine hydroxamic acid, into the active site of thermolysin. The potential, which imposed no constraints between protein and ligand, produced conformations close to the crystallographically determined one. The calculations made use of the combined molecular mechanics/grid method of Luty et al. (J. Comp. Chem. 16:454-464, 1995), in which atoms of the active site are free to move whereas the rest of the protein, assumed to be rigid, is represented as points of a grid, and which also includes an implicit solvation model. The method is sufficiently fast that large sets of simulations could be carried out, enabling statistical sampling and exploration of the effect of initial position and conformation of the ligand on the probability of successful docking. In a charged catalytic Glu/uncharged ligand regime, when the initial position of the ligand was determined by random translations and rotations that kept the center of mass within 8.0 angstroms of the crystal one, none of the 20 runs placed the ligand correctly. In a second set with uncharged Glu and zwitterionic ligand, 3 of 24 similarly placed random structures flew the ligand in successfully. In a third set with the same protonation scheme as the second the starting positions had randomly determined conformations but kept the hydroxamate oxygens within 4.0 angstroms of the zinc; in this case 22 of 25 runs reoriented correctly. A diverse set of energetic, structural, and dynamic criteria was used for evaluation of the calculations. The results indicate the method to be a promising tool for the rational drug design process.


Hyaluronan-Chondroitin Sulfate Anomalous Crosslinking Due to Temperature Changes.
Glycosaminoglycans are a wide class of biopolymers showing great lubricating properties due to their structure and high affinity to water. Two of them, hyaluronic acid and chondroitin sulfate, play an important role in articular cartilage lubrication. In this work, we present results of the all-atom molecular dynamics simulations of both molecules placed in water-based solution. To mimic changes of the physiological conditions, especially temperature, of the synovial fluid in joints under successive load (e.g., walking, jogging, jumping), simulations have been performed at different physiological temperatures in the range of 300 to 320 Kelvin (normal intra-articular temperature is 305 K). The stability of the biopolymeric network at equilibrium (isothermal and isobaric) conditions has been studied. To understand the process of physical crosslinking, the dynamics of intra- and intermolecular hydrogen bonds forming and breaking have been studied. The results show that following addition of chondroitin sulfate, hyaluronan creates more intermolecular hydrogen bonds than when in homogeneous solution. The presence of chondroitin in a hyaluronan network is beneficial as it may increase its stability. Presented data show hyaluronic acid and chondroitin sulfate as viscosity modifiers related to their crosslinking properties in different physicochemical conditions.


Quantitative assessment of left ventricular size and function: side-by-side comparison of real-time three-dimensional echocardiography and computed tomography with magnetic resonance reference.
Cardiac CT (CCT) and real-time 3D echocardiography (RT3DE) are being used increasingly in clinical cardiology. CCT offers superb spatial and contrast resolution, resulting in excellent endocardial definition. RT3DE has the advantages of low cost, portability, and live 3D imaging without offline reconstruction. We sought to compare both CCT and RT3DE measurements of left ventricular size and function with the standard reference technique, cardiac MR (CMR). In 31 patients, RT3DE data sets (Philips 7500) and long-axis CMR (Siemens, 1.5 T) and CCT (Toshiba, 16-slice MDCT) images were obtained on the same day without beta-blockers. All images were analyzed to obtain end-systolic and end-diastolic volumes and ejection fractions using the same rotational analysis to eliminate possible analysis-related differences. Intertechnique agreement was tested through linear regression and Bland-Altman analyses. Repeated measurements were performed to determine intraobserver and interobserver variability. Both CCT and RT3DE measurements resulted in high correlation (r2 > 0.85) compared with CMR. However, CCT significantly overestimated end-diastolic and end-systolic volumes (26 and 19 mL; P < 0.05), resulting in a small but significant bias in ejection fraction (-2.8%). RT3DE underestimated end-diastolic and end-systolic volumes only slightly (5 and 6 mL), with no significant bias in EF (0.3%; P = 0.68). The limits of agreement with CMR were comparable for the 2 techniques. The variability in the CCT measurements was roughly half of that in either RT3DE or CMR values. CCT provides highly reproducible measurements of left ventricular volumes, which are significantly larger than CMR values. RT3DE measurements compared more favorably with the CMR reference, albeit with higher variability.


An unusual tropical endomyocardial fibrosis: a case report.
Tropical endomyocardial fibrosis (TEF) is a rare condition that occurs primarily in tropical countries, leading to a severe heart failure with heart restrictive filling patterns. Eosinophilia appears to be a trigger leading to the development of the disease; thus, numerous etiologic factors accompanied by eosinophilia have been postulated, although none have been confirmed. The massively calcified form of TEF is exceptional and easily diagnosed by multimodal imaging; but it is a very rare condition with high surgical challenge. the best prevention remains the testing and treatment of parasitic infections frequently encountered in these countries.


Clinical presentation in relation to diversity within the Helicobacter pylori cag pathogenicity island.
This study investigated the genetic diversity of the cag pathogenicity island (PAI) in Helicobacter pylori (H. pylori) in relation to clinical outcome and interleukin (IL)-8 production. Seven genes in the cag PAI (cagA, cagE, cagG, cagM, cagT, open reading frame 13 and 10) were examined by polymerase chain reaction and Southern blot hybridization using H. pylori from 120 patients with different presentations (duodenal ulcer, gastric cancer, gastritis alone). IL-8 production from AGS cells (gastric cancer cell line) cocultured with H. pylori was measured by ELISA. An intact cag PAI was present in 104 (87%) isolates, and five (4%) had deletions within the cag PAI; 11 (9%) lacked the entire cag PAI. Clinical isolates containing the complete cag PAI induced a greater secretion of IL-8 as compared with those without the cag PAI (3048 +/- 263 vs 480 +/- 28 pg/ml, p < 0.001). Deletion of only cagG reduced IL-8 secretion by two thirds. Deletions of more than one locus reduced IL-8 secretion to background. A similar proportion of H. pylori from patients with gastritis, duodenal ulcer, or gastric cancer had intact cag PAI (88%, 88%, and 85%, respectively). Although the presence of cagG was a better predictor of the presence of an intact cag PAI than cagA or cagE, the presence or absence of any of these genes had no association with clinical presentation. Although the cag PAI plays an important role in IL-8 production, clinical presentation cannot be predicted by the presence of an intact cag PAI or any of these seven cag PAI genes.


An exploration of the potential benefits of pet-facilitated therapy.
There is mounting evidence to suggest that those who keep pets are likely to benefit from various improvements in health. Despite founders of nursing such as Florence Nightingale advocating the importance of animals within the care environment, their integration into hospitals and other health care settings has been slow. The literature on animal-induced health benefits is reviewed and the conclusion is drawn that the potential benefits of pet therapy are considerable. It is suggested that nurses can assume an active role in advocating ward pet or pet-visiting schemes.


Asymmetries and three-dimensional features of vestibular cross-coupled stimuli illuminated through modeling.
Head movements during sustained rotation can cause angular cross-coupling which leads to tumbling illusions. Even though angular vectors predict equal magnitude illusions for head movements in opposite directions, the magnitudes of the illusions are often surprisingly asymmetric, such as during leftward versus rightward yaw while horizontal in a centrifuge. This paper presents a comprehensive investigation of the angular-linear stimulus combinations from eight different published papers in which asymmetries were found. Interactions between all angular and linear vectors, including gravity, are taken into account to model the three-dimensional consequences of the stimuli. Three main results followed. First, for every pair of head yaw movements, an asymmetry was found in the stimulus itself when considered in a fully three-dimensional manner, and the direction of the asymmetry matched the subjectively reported magnitude asymmetry. Second, for pitch and roll head movements for which motion sickness was measured, the stimulus was found symmetric in every case except one, and motion sickness generally aligned with other factors such as the existence of a head rest. Third, three-dimensional modeling predicted subjective inconsistency in the direction of perceived rotation when linear and angular components were oppositely-directed, and predicted surplus illusory rotation in the direction of head movement.


Factors Associated with the Prevalence of Cognitive Impairment in a Rural Elderly Cameroonian Population: A Community-Based Study in Sub-Saharan Africa.
With rising elderly populations, age-related health problems such as cognitive impairment and dementia are major public health concerns. We sought to assess the prevalence of cognitive impairment and associated factors in rural elderly Cameroonians. The Mini Mental State Examination was used to assess the cognitive function of participants randomly recruited during a house-to-house survey of the Batibo Health District. The prevalence of cognitive impairment in our study was 33.3%. Increasing age, female gender, being single, a lack of formal education, and higher systolic blood pressure values were significantly and independently associated with cognitive impairment. The identification of modifiable factors would inform evidence-based policy to decrease the health and social burdens of cognitive impairment and dementia in the elderly in rural Cameroon.


Cold Acclimation for Enhancing the Cold Tolerance of Zebrafish Cells.
Cold stress is an important threat in the life history of fish. However, current research on the tolerance mechanisms of fish to cold stress is incomplete. To explore the relevant molecular mechanisms enabling cold stress tolerance in fish, here we studied ZF4 cells subjected to short-term (4 days) low temperature stress and long-term (3 months) low temperature acclimation. The results showed that cell viability decreased and the cytoskeleton shrank under short-term (4 days) low temperature stress, while the cell viability and the cytoskeleton became normal after cold acclimation at 18°C for 3 months. Further, when the cells were transferred to the lower temperature (13°C), the survival rate was higher in the acclimated than non-acclimated group. By investigating the oxidative stress pathway, we found that the ROS (reactive oxygen species) content increased under short-term (4 days) cold stress, coupled with changes in glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) enzyme activity levels. In addition, overproduction of ROS disrupted physiological cellular homeostasis that generated apoptosis via the activation of the mitochondrial pathway. However, when compared with the non-domesticated group, both ROS levels and apoptosis were lowered in the long-term (3 months) domesticated cells. Taken together, these findings suggest that cold acclimation can improve the low temperature tolerance of the cells. This exploration of the mechanism by which zebrafish cells tolerate cold stress, thus contributes to laying the foundation for future study of the molecular mechanism of cold adaptation in fish.


Acute febrile neutrophilic vasculitis of the skin of young Shar-Pei dogs.
Three young Shar-Pei dogs were presented for signs of an acute widespread dermatopathy associated with fever and malaise. Cutaneous lesions initially consisted of multifocal areas of skin discolouration (haemorrhagic papules, macules or plaques) or oedema, preferentially affecting the head and limbs. In some locations, pus-filled bullae were evident also. Cutaneous lesions exuded seropurulent liquid and, in time, usually progressed to full thickness necrosis and ulceration. Lesions were so widespread and severe that one of the dogs was euthanased because its owners could not afford the reconstructive surgery required to close the skin deficits left at the completion of otherwise successful therapy. Histological examination of representative biopsies showed neutrophilic dermatitis and vasculitis, which ultimately resulted in ischaemic necrosis of skin. Therapy with immunosuppressive doses of corticosteroids, and in one case cyclophosphamide, resulted in prompt amelioration of the underlying inflammatory process, although regions of skin deprived of their blood supply eventually became necrotic and sloughed. Healing occurred through granulation, contraction and epithelialisation. The physical findings in these three dogs were so similar that it is likely all suffered from the same breed-related syndrome, an immune-mediated vasculitis precipitated by some event, such as vaccination or an undetected infection. Whatever the inciting cause, it was most likely a one-off event, as the two surviving dogs were readily weaned off immunosuppressive medication without relapse.


Increases in hypertension and blood pressure during pregnancy with increased bone lead levels.
Prior studies have revealed associations of current lead exposure (blood lead) and past lead exposure (bone lead) with risks of hypertension and elevated blood pressure. The authors examined the effects of blood and bone lead on hypertension and elevated blood pressure in the third trimester and postpartum among 1,006 women enrolled in Los Angeles prenatal care clinics between 1995 and 2001. The authors measured bone lead concentration by K-shell x-ray fluorescence in the tibia (mean = 8.0 micro g/g (standard deviation (SD) 11.4)) and calcaneus (heel) (mean = 10.7 micro g/g (SD 11.9)). Geometric mean prenatal and postnatal blood lead levels were 1.9 micro g/dl (geometric SD +3.6/-1.0) and 2.3 micro g/dl (geometric SD +4.3/-1.2), respectively. For each 10- micro g/g increase in calcaneus bone lead level, the odds ratio for third-trimester hypertension (systolic blood pressure > or =140 mmHg or diastolic blood pressure > or =90 mmHg) was 1.86 (95% confidence interval (CI): 1.04, 3.32). In normotensive subjects, each 10- micro g/g increase in calcaneus bone lead level was associated with a 0.70-mmHg (95% CI: 0.04, 1.36) increase in third-trimester systolic blood pressure and a 0.54-mmHg (95% CI: 0.01, 1.08) increase in diastolic blood pressure. Tibia bone lead concentration was not related to hypertension or elevated blood pressure either in the third trimester or postpartum, nor was calcaneus bone lead related to postpartum hypertension or elevated blood pressure. Past lead exposure influences hypertension and elevated blood pressure during pregnancy. Controlling blood pressure may require reduction of lead exposure long before pregnancy.


Biochemical, Serological and Immunological Tests for Diagnosis of Coronavirus Disease 2019 (COVID-19) Patients: A Comprehensive Systematic Review and Meta-analysis.
Recent studies have suggested the role of primary laboratory tests in addition to clinical symptoms for patients suspected to have coronavirus disease 2019 (COVID-19), which play a significant role in the diagnosis of COVID-19. However, the results of these studies are contradictory. The present study was conducted to evaluate biochemical, serological, and immunological tests for the diagnosis of COVID-19 patients. This study was presented in accordance with the PRISMA protocol. This protocol is registered with the code CRD42019145410 in PROSPERO. We conducted a comprehensive literature search in databases, including Web of Science, PubMed/Medline, CINAHL Scopus, Cochrane Library, EMBASE, Science Direct, and EBSCO to find citations from the beginning of January 2019 until the beginning of April 2020 without any restrictions. Finally, 51 studies, including 5,490 COVID-19 patients, were included in the present metaanalysis. The prevalence of different factors observed in laboratory findings was as follows: the prevalence of lymphopenia in patients with COVID-19 accounted for 51.6% (95% CI: 44.0-59.1), elevated C-reactive protein (CRP) was 63.6% (95% CI: 57.0-69.8), elevated erythrocyte sedimentation rate (ESR) was 62.5% (95% CI: 50.1-73.5), elevated tumor necrosis factor alpha (TNFα) was 28.7% (95% CI: 9.0-62.1), elevated serum amyloid-A level was 74.7% (95% CI: 50.0-89.7), elevated procalcitonin level was 72.6% (95% CI: 58.1-83.5), elevated interleukin-6 level was 59.9% (95% CI: 48.2-70.5), reduced CD3 level was 68.3% (95% CI: 50.1-82.2), reduced CD4 level was 62.0% (95% CI: 51.1- 71.6), elevated lactate dehydrogenase (LDH) level accounted for 53.1% (95% CI: 43.6-62.4), elevated brain natriuretic peptide (BNP) accounted for 48.9% (95% CI: 30.4-67.7), reduced albumin and reduced pre-albumin levels in patients with COVID-19 were estimated to be 54.7% (95% CI: 38.1-70.2) and 49.0% (95% CI: 26.6-71.8), and D-dimer level was 44.9% (95% CI: 31.0-59.6). The results show lymphopenia, elevated ESR level, elevated CRP level, elevated serum amyloid-A, elevated TNFα, elevated procalcitonin level, elevated interleukin-6 level, reduced CD3, reduced CD4, elevated BNP, elevated LDH, reduced albumin, reduced pre-albumin, and elevated Ddimer levels as the most common findings at the time of admission.


Comparison of the T helper cell response induced by respiratory syncytial virus and its fusion protein in BALB/c mice.
Specific proliferative T-cell responses were induced in the lymph node cells (LNC) of mice immunised with a sucrose density gradient purified preparation of respiratory syncytial (RS) virus or an immunoaffinity purified preparation of the F glycoprotein. Inhibition studies and flow cytometric analysis showed that the responding cell population were CD4+ T cells. The cytokines produced by virus-specific and F-specific cells were assessed using the CTLL cell line. Peak quantities of cytokine were consistently detected in the supernatants of stimulated cultures 24 h prior to maximum proliferation. The proportion of IL-2 released was determined by blocking IL-2 activity with an anti-IL-2 monoclonal antibody. In cultures of RS virus primed LNC challenged with whole virus there was a switch of cytokine production from 70% IL-2 at day 3 to 80% IL-4 by 6 days of culture. In contrast, LNC cultures from mice immunised with F protein secreted 75-100% IL-2 throughout the culture period. These data suggest that after 6 days of challenge with viral antigen, the RS virus-primed LNC response consists of T helper cells which are predominantly of the Th2 subset, secreting IL-4, whilst F protein-primed LNC secrete large quantities of IL-2 and can therefore be classified as predominantly of the Th1 subset.


A comparison of the energy use of in situ product recovery techniques for the Acetone Butanol Ethanol fermentation.
The productivity of the Acetone Butanol Ethanol (ABE) fermentation can be significantly increased by application of various in situ product recovery (ISPR) techniques. There are numerous technically viable processes, but it is not clear which is the most economically viable in practice. There is little available information about the energy requirements and economics of ISPR for the ABE fermentation. This work compares various ISPR techniques based on UniSim process simulations of the ABE fermentation. The simulations provide information on the process energy and separation efficiency, which is fed into an economic assessment. Perstraction was the only technique to reduce the energy demand below that of a batch process, by approximately 5%. Perstraction also had the highest profit increase over a batch process, by 175%. However, perstraction is an immature technology, so would need significant development before being integrated to an industrial process.


EVALUATION OF IRRADIATION DOSES DELIVERED TO PATIENTS IN COMPUTED TOMOGRAPHY EXAMINATIONS IN 10 RADIOLOGY DEPARTMENTS IN DOUALA-CAMEROON.
Computed tomography (CT) scan is currently the most irradiating radio diagnostic procedure for the patients. The effective dose delivered by a CT-scan exploration corresponds to 1-20 years of natural irradiation of an individual. Hence, there is need to evaluate this medical exposure, in order to provide indicators and propose guidelines for its daily practice. The purpose of this work was to assess patient exposure levels due to CT-scan exams and propose a local diagnostic reference levels for the most common CT examinations performed in the radiology units of Douala/Cameroon. Data from 1775 CT scans, amongst which 10 different types of common CT examinations on adults and children, were collected, of which 1378 were adult CT scans and 397 were pediatric CT scans. The dose-length product (DLP) values in the adult population for head, abdomen-pelvic and lumber spine CT scans were high as compared to the Institute for Radiological Protection and Nuclear Safety recommendations and previous local DRL with an increase of 36, 15 and 23%, respectively. A general decrease of the DLP for CT-scans examinations in the pediatric population was observed.


[Intravenous 3-day Helicobacter pylori eradication therapy is highly effective in patients with bleeding peptic ulcer].
To evaluate the efficacy of 3-day intravenous Helicobacter pylori eradication therapy in patients with bleeding peptic ulcer associated with H. pylori infection. We studied 53 patients admitted to hospital with bleeding of the upper gastrointestinal tract due to peptic ulcer and positive urease test over a 12-month period. After endoscopic diagnosis, intravenous pantoprazole (40 mg/12 hours), metronidazole (500 mg/8 hours) and amoxicillin-clavulanic acid (1,000 mg/200 mg/8 hours) was administered for 72 hours. The efficacy of eradication therapy was evaluated by 13C-urea breath test at least 2 months after the end of treatment. Fifty-one patients were included. Of these, 40 had duodenal ulcer and 11 had gastric ulcer. H. pylori eradication was achieved in 87.5% of those with duodenal ulcers and in 63.6% of those with gastric ulcers (p = 0.066). No adverse reactions or episodes of bleeding recurrence were found and none of the patients withdrew from treatment. The ultra-short course eradication therapy used in this study is highly effective. Its efficacy is similar to that of oral treatment and it avoids certain problems such as adverse effects and adherence to treatment.


Two cases of intrahepatic cholangiocarcinoma detected after interferon therapy for chronic hepatitis C.
Recently, it has been suggested that hepatitis C virus infection plays a role in the pathogenesis of some intrahepatic cholangiocarcinomas (ICC). We describe two patients with small ICC detected after interferon therapy for chronic hepatitis C. Case 1 was diagnosed with ICC by preoperative biopsy and underwent anterior segmentectomy of the liver, while Case 2 was diagnosed with hepatocellular carcinoma preoperatively and the tumor was diagnosed as ICC after biopsy and microwave coagulonecrotic therapy. Both patients are in good health six months and five months, respectively, after operation. It is important to monitor carefully for ICC as well as hepatocellular carcinoma in patients with chronic hepatitis C, even when interferon therapy has been carried out, since the outcome of treatment for small ICC is favorable.


Light Induced Polarity of Redox Reactions in Leaves of Elodea canadensis Michx.
This paper reports that extracellular reductase activity in leaves of Elodea canadensis, hitherto never associated with polar processes thought to be involved in bicarbonate utilization, also shows a very marked polarity in light. The effect of ferricyanide, applied to the lower side of illuminated leaves, was a depolarization of the membrane electrical potential of up to 110 millivolts, while no depolarization was induced when ferricyanide was applied to the upper side. In the dark ferricyanide induced a depolarization when applied to either the upper or to the lower side of the leaf. Staining with tetrazolium salts, specific indicators for reductase activity, resulted in the formation of a precipitate on the lower side of the leaf when illuminated and on both sides in the dark. The precipitate was only located along the plasmalemma.


[Erectile dysfunction, an urologic and multidisciplinary approach].
Erectile dysfunction (ED) is a common complaint, both in the general medicine and the urology out-patient clinic. The quite recent availability of effective treatments has profoundly changed the perception of sexual health in society, which has become more demanding. We should see erectile or sexual function as a health marker. Its causes are often diverse but we can classify them as somatic (vascular, neurological, endocrine, tissue-related, iatrogenic) or psychogenic. Management should be etiological if possible. It often goes first by reducing cardiovascular risk factors and then by prescribing a vasodilating agent functioning through the inhibition of phosphodiesterase 5. When modifiable cardiovascular risk factors are identified, we refer the patient to a specialized consultation. ED is to be seen as a warning sign of a preventable disease or cardiovascular event.


Next-generation sequencing-based multi-gene mutation profiling of solid tumors using fine needle aspiration samples: promises and challenges for routine clinical diagnostics.
Increasing use of fine needle aspiration for oncological diagnosis, while minimally invasive, poses a challenge for molecular testing by traditional sequencing platforms due to high sample requirements. The advent of affordable benchtop next-generation sequencing platforms such as the semiconductor-based Ion Personal Genome Machine (PGM) Sequencer has facilitated multi-gene mutational profiling using only nanograms of DNA. We describe successful next-generation sequencing-based testing of fine needle aspiration cytological specimens in a clinical laboratory setting. We selected 61 tumor specimens, obtained by fine needle aspiration, with known mutational status for clinically relevant genes; of these, 31 specimens yielded sufficient DNA for next-generation sequencing testing. Ten nanograms of DNA from each sample was tested for mutations in the hotspot regions of 46 cancer-related genes using a 318-chip on Ion PGM Sequencer. All tested samples underwent successful targeted sequencing of 46 genes. We showed 100% concordance of results between next-generation sequencing and conventional test platforms for all previously known point mutations that included BRAF, EGFR, KRAS, MET, NRAS, PIK3CA, RET and TP53, deletions of EGFR and wild-type calls. Furthermore, next-generation sequencing detected variants in 19 of the 31 (61%) patient samples that were not detected by traditional platforms, thus increasing the utility of mutation analysis; these variants involved the APC, ATM, CDKN2A, CTNNB1, FGFR2, FLT3, KDR, KIT, KRAS, MLH1, NRAS, PIK3CA, SMAD4, STK11 and TP53 genes. The results of this study show that next-generation sequencing-based mutational profiling can be performed on fine needle aspiration cytological smears and cell blocks. Next-generation sequencing can be performed with only nanograms of DNA and has better sensitivity than traditional sequencing platforms. Use of next-generation sequencing also enhances the power of fine needle aspiration by providing gene mutation results that can direct personalized cancer therapy.


Lone Actor Terrorist Attack Planning and Preparation: A Data-Driven Analysis.
This article provides an in-depth assessment of lone actor terrorists' attack planning and preparation. A codebook of 198 variables related to different aspects of pre-attack behavior is applied to a sample of 55 lone actor terrorists. Data were drawn from open-source materials and complemented where possible with primary sources. Most lone actors are not highly lethal or surreptitious attackers. They are generally poor at maintaining operational security, leak their motivations and capabilities in numerous ways, and generally do so months and even years before an attack. Moreover, the "loneness" thought to define this type of terrorism is generally absent; most lone actors uphold social ties that are crucial to their adoption and maintenance of the motivation and capability to commit terrorist violence. The results offer concrete input for those working to detect and prevent this form of terrorism and argue for a re-evaluation of the "lone actor" concept.


Relation between Object Position and Autocorrelation Spots in the Vander Lugt Filtering Process. 2: Influence of the Volume Nature of the Photographic Emulsion.
It is well known that the optical Fourier spectrum of an object does not depend on its position in the object space. One generally concludes that the correlation with a Vander-Lugt filter is likewise invariant with respect to object position. The present investigation shows that the correlation signal is not object position independent, at least, when the filter is recorded on a recording material of nonvanishing thickness. For a conventional photographic emulsion, we show that the correlation signal depends very strongly on object position.


Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).
In this review, we focus on the adult stem/progenitor cells that were initially isolated from bone marrow and first referred to as colony forming units-fibroblastic, then as marrow stromal cells and subsequently as either mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). The current interest in MSCs and similar cells from other tissues is reflected in over 10,000 citations in PubMed at the time of this writing with 5 to 10 new publications per day. It is also reflected in over 100 registered clinical trials with MSCs or related cells (http//www.clinicaltrials.gov). As a guide to the vast literature, this review will attempt to summarize many of the publications in terms of three paradigms that have directed much of the work: an initial paradigm that the primary role of the cells was to form niches for haematopoietic stem cells (paradigm I); a second paradigm that the cells repaired tissues by engraftment and differentiation to replace injured cells (paradigm II); and the more recent paradigm that MSCs engage in cross-talk with injured tissues and thereby generate microenvironments or 'quasi-niches' that enhance the repair tissues (paradigm III).


Detection of cadmium exposure in rats by induction of lymphocyte metallothionein gene expression.
The induction of metallothionein (MT) gene expression in lymphocytes of rats was determined in order to detect exposure in vivo to cadmium. Both acute and chronic CdCl2 exposures resulted in the induction of the MT-1 gene in lymphocytes as measured by standard RNA Northern blot analysis. Twenty-four hours following an ip injection of 3.4 mg/kg CdCl2, a ninefold increase in MT gene expression was observed in lymphocytes, as well as five- and sevenfold increases in liver and kidney, respectively. Oral exposure of rats to 1-100 ppm CdCl2 via drinking water resulted in an approximate twofold enhanced MT signal in lymphocytes after 6 wk, and a threefold increase after 13 wk of exposure to 100 ppm Cd. No increases in lymphocyte MT gene expression were observed after 3 wk of Cd exposure. Liver MT gene expression was substantially induced following chronic Cd exposure, while kidney was not, although this organ had a higher basal expression of the MT-1 gene. Analysis of tissue Cd burdens demonstrated a dose-response Cd accumulation in liver and kidney, but only kidney burdens increased substantially with prolonged Cd exposure. These results demonstrate the utility of lymphocyte gene expression assays to detect in vivo toxicant exposure, and thus their applicability as molecular biomarker assays for human exposure assessment.


Effectiveness and Economic Viability of Johne's Disease (Paratuberculosis) Control Practices in Dairy Herds.
Johne's disease (JD or paratuberculosis) control programs have been established in many dairy-producing regions. However, the effectiveness (reduction of within-herd prevalence) and the relative economic impact as measured by, for example, the ratio of benefits to costs (BCR) across a comprehensive selection of regions and potential control practices require further investigation. Within a Markovian framework using region-specific economic variables, it was estimated that vaccination was the most promising type of JD control practice modeled, with dual-effect vaccines (reducing shedding and providing protective immunity) having BCRs between 1.48 and 2.13 in Canada, with a break-even period of between 6.17 and 7.61 years. Dual-effect vaccines were also estimated to yield BCRs greater than one in almost all major dairy-producing regions, with greater ratios in regions characterized by above-average farm-gate prices and annual production per cow. Testing and culling was comparably effective to a dual-effect vaccine at test sensitivities >70% but would remain economically unviable in almost all regions modeled.


The impact of marrow transplant preparative regimens on subsequent growth and development. The Seattle Marrow Transplant Team.
These data demonstrate that endocrine function abnormalities influencing subsequent growth and development in children after marrow transplantation rarely occur after preparation with CY alone. However, after administration of regimens containing TBI, multiple endocrine function abnormalities can occur. Although longer follow-up is needed, it appears that the addition of BU to CY does not result in thyroid function or growth abnormalities. Pubertal development and gonadal function, however, may be adversely influenced by BU and patients may require supplementation with appropriate gonadal hormones.


MELD score and AST-to-platelet ratio index (APRI) predict long-term survival in patients with a small hepatocellular carcinoma following non-transplant therapies: a pilot study.
Liver transplantation (LT) is the most effective treatment for long-term survival from hepatocellular carcinoma (HCC); however, insufficient donors limit therapy. We sought to identify characteristics that predicted long-term survival after non-transplant therapies in patients with small HCC. In a database of 1,050 HCC patients, we identified those with single HCC ≤ 3.0 cm, who underwent hepatic resection (HR, n = 16), radiofrequency ablation (RFA, n = 55), or LT (n = 23) with 5-years follow-up. Survival and odds-ratios for survival (OS) after HR/RFA were calculated for MELD score, platelet count, creatinine, albumin, AST/Platelet Ratio Index (APRI), INR, and bilirubin. LT patients had 3 and 5-year OS of 82.6% and 73.9% compared to HR/RFA patients with 3 and 5-year OS of 40.8% and 33.8%. The strongest predictors of survival after HR/RFA were MELD < 10 (OR 4.43, 95% CI 1.85-10.58) and APRI ≤ 0.5 (OR 4.25, 95% CI 1.63-11.08). HR/RFA patients with both MELD < 10 and APRI ≤ 0.5 had 3- and 5-year OS of 77.3% and 72.7%. Patients with MELD < 10 and APRI ≤ 0.5 who undergo HR/RFA have survival approaching LT. Perhaps patients who meet these criteria can safely undergo non-transplant therapy and donor livers can be allocated to patients with a greater need.


[A case of gas gangrene following operation of cervical esophageal carcinoma].
A 74-year-old woman underwent surgery for cervical esophageal carcinoma. After operation, she had abdominal distension, high fever, and suddenly fell into shock and died. Autopsy revealed necrosis and multiple gas blebs in the entire digestive tract and liver. Direct smear specimens Gram-stained disclosed clostridium septicum and the cause of death was found to be gas gangrene. This is the first of clostridium infection localized in the digestive tract and liver after operation. Abdominal radiogram showed massive gas in the intestine, intramural bowel gas and gas in the portal vein, and these are very suggestive of gas gangrene of the intestinal tract.


Kaposi's sarcoma-associated herpesvirus ORF57 protein: exploiting all stages of viral mRNA processing.
Nuclear mRNA export is a highly complex and regulated process in cells. Cellular transcripts must undergo successful maturation processes, including splicing, 5'-, and 3'-end processing, which are essential for assembly of an export competent ribonucleoprotein particle. Many viruses replicate in the nucleus of the host cell and require cellular mRNA export factors to efficiently export viral transcripts. However, some viral mRNAs undergo aberrant mRNA processing, thus prompting the viruses to express their own specific mRNA export proteins to facilitate efficient export of viral transcripts and allowing translation in the cytoplasm. This review will focus on the Kaposi's sarcoma-associated herpesvirus ORF57 protein, a multifunctional protein involved in all stages of viral mRNA processing and that is essential for virus replication. Using the example of ORF57, we will describe cellular bulk mRNA export pathways and highlight their distinct features, before exploring how the virus has evolved to exploit these mechanisms.


Citizens' obligation to obey the law: an empirical study of Guangzhou, China.
For thousands of years, China primarily used morality for its social control. Since its economic reform starting in 1978, China has moved toward legal control. Two fundamental questions, however, remain understudied in China: (a) the degree to which citizens feel obligated to obey the law and (b) the sources of citizens' perceived obligation to obey the law. This study was intended to answer these questions based on random surveys of 1,196 residents from Guangzhou, China. The study revealed that the vast majority of citizens in Guangzhou felt obligated to obey the law irrespective of their personal feelings. Normative and instrumental perspectives were important sources of Guangzhou citizens' perceived obligation to obey the law. In addition, Guangzhou citizens' perception of obligation to obey the law was related to not only individual-level variables but also neighborhood contextual factors.


Principal feature analysis: a multivariate feature selection method for fMRI data.
Brain decoding with functional magnetic resonance imaging (fMRI) requires analysis of complex, multivariate data. Multivoxel pattern analysis (MVPA) has been widely used in recent years. MVPA treats the activation of multiple voxels from fMRI data as a pattern and decodes brain states using pattern classification methods. Feature selection is a critical procedure of MVPA because it decides which features will be included in the classification analysis of fMRI data, thereby improving the performance of the classifier. Features can be selected by limiting the analysis to specific anatomical regions or by computing univariate (voxel-wise) or multivariate statistics. However, these methods either discard some informative features or select features with redundant information. This paper introduces the principal feature analysis as a novel multivariate feature selection method for fMRI data processing. This multivariate approach aims to remove features with redundant information, thereby selecting fewer features, while retaining the most information.


Association between the presence of Treponema denticola and reduced levels of antiatherogenic high density lipoprotein in periodontitis.
Dyslipidemia, a disorder in the levels of cholesterol or lipoproteins in the plasma, is a feature of atherosclerosis, leading to cardiovascular disease. The objective of this study was to evaluate whether Tanerella forsythia and Treponema denticola are related to reduced levels of antiatherogenic high density lipoprotein (HDL). In this cross-sectional study, 108 patients were invited to participate. The diagnosis of chronic periodontitis and the diagnosis of adipose tissue disorders were made based on criteria previously defined. The presence of T forsythia and T denticola was detected by polymerase chain reaction. A total of 61 women and 19 men with chronic periodontitis, and 18 women and 10 men without periodontitis were studied. The serum levels of total cholesterol and low density lipoprotein were similar in both groups. Inversely, the levels of triglycerides (TG) were higher in periodontitis patients compared to subjects without periodontitis (178 mg/dL vs 165 mg/dL; P < .05), and the levels of HDL were lower (44 mg/dL vs 50 mg/dL; P < .05), respectively. The presence of T denticola was associated with low levels of HDL in periodontitis patients after adjustment for possible confounders (OR, 3.03; 95% CI, 1.2-7.2). Higher levels of TG and lower levels of HDL were associated with the presence of T denticola in chronic periodontitis. These results may suggest that the presence of T denticola could reduce the antiatherogenic potency of HDL and may increase the risk for cardiovascular disease in patients with chronic periodontitis.


Smartphone dongle for simultaneous measurement of hemoglobin concentration and detection of HIV antibodies.
It is traditionally difficult to incorporate two classes of diagnostic tests into a single platform. In this work, we demonstrate a microfluidic-based smartphone dongle that simultaneously measures concentration of hemoglobin and detects HIV antibodies. Specifically, we demonstrate how a previously published immunoassay device, which measured optical density of silver precipitation on gold colloids, can be expanded to quantitatively measure hemoglobin concentration via a colorimetric assay. By lysing whole blood components with CHAPS detergent, we achieved highly reproducible measurement of hemoglobin concentration with the device. We tested this dual test on 38 patient samples from Columbia University Medical Center. Compared with the Hemocue Hb 201+ analyzer, hemoglobin concentrations from our device were accurate within 1.2 g dL(-1), while the HIV immunoassay (in the presence of CHAPS detergent) showed 95% sensitivity and 95% specificity, comparable to our previous studies. This work demonstrates the feasibility of integrating two classes of diagnostic tests (a colorimetric-based quantitative measurement and an immunoassay based on silver precipitation on gold colloids) into a low-cost, fast, and low-power dongle that works with smartphones, and creates a novel dual panel with clinical utility for antenatal-care settings.


Regulation of the central nervous system-pituitary-adrenal axis in rats after neonatal treatment with monosodium glutamate.
We have studied the regulation of adrenal function in male rats treated neonatally with monosodium glutamate (MSG) and in littermate controls. When 6-7 months old, MSG-treated rats presented reduced body, adrenal and pituitary weight, obesity, atrophy of the optic nerve and damage of the arcuate nuclei (ARN) of the hypothalamus. MSG-treated rats showed increased serum corticosterone (CORT) levels under resting conditions; after ether stress the increase in serum CORT was greater in MSG animals when compared to littermate controls. Plasma ACTH followed the same trend although it reached significance after ether stress only. Both circulating CORT and ACTH were normally suppressed by dexamethasone (DEX) administration. Levels of corticosteroid binding globulin were also increased, whereas daily circadian rhythm of serum CORT was blunted. We also determined cytosolic receptors in areas suggested to participate in the negative feedback of glucocorticoids at the central level. Binding of (3H)-DEX in MSG rats was similar to controls in hippocampus, whole hypothalamus and anterior pituitary, but a significant reduction (approximately equal to 50%) was obtained after microdissection in the area normally occupied by the ARN, without changes in the ventromedial nuclei of the hypothalamus. These results suggest that the ARN may be involved in the regulation of the pituitary-adrenal axis, although the abnormalities observed in the MSG syndrome partially differ from those in rats with hippocampal damage, previously studied in our laboratory.


Defining error in anatomic pathology.
Although much has been said and written about medical error and about error in pathology since the publication of the Institute of Medicine's report on medical error in 1999, precise definitions of what constitutes error in anatomic pathology do not exist for the specialty. Without better definitions, it is impossible to accurately judge errors in pathology. The lack of standardized definitions has implications for patient care and for the legal judgment of malpractice. To review the goals of anatomic pathology, to discuss the problems inherent in applying these goals to the judgment of error in pathology, to offer definitions of major and minor errors in pathology, and to discuss error in anatomic pathology in relation to the classic laboratory test cycle. Existing literature. Definitions for major and minor error in anatomic pathology are proffered, and anatomic pathology error is characterized in the classic test cycle.


Androgen receptor binding to nuclear matrix in vitro and its inhibition by 8S androgen receptor promoting factor.
The partially purified 4.5S [3H]dihydrotestosterone receptor binds to nuclear matrix isolated from rat Dunning prostate tumor with properties similar to those reported for androgen receptor binding in intact nuclei [Colvard, D.S., & Wilson, E.M. (1984) Biochemistry (preceding paper in this issue)] in that it requires Zn2+ and mercaptoethanol, is saturable, and is temperature dependent and of high affinity (Ka approximately 10(13) M-1). On a milligrams of DNA equivalent basis, the extent of matrix binding of androgen receptor (700 fmol of receptor bound/mg of matrix protein) is similar to that of intact nuclei, corresponding to approximately 1400 sites/nucleus. Association rate constants (ka) for 4.5S androgen receptor binding to matrix at 0, 15, and 25 degrees C are 2.7 X 10(5), 1.2 X 10(6), and 2.4 X 10(6) M-1 min-1, respectively, indicating an energy of activation of 15 kcal/mol. Up to 50% of matrix-bound receptor is extractable in buffer containing 3 mM ethylenediaminetetraacetic acid plus either 0.4 M KCl or 5 mM pyridoxal 5'-phosphate. A protein fraction designated 8S androgen receptor promoting factor that promotes conversion of the 4.5S androgen receptor to 8 S [Colvard, D. S., & Wilson, E. M. (1981) Endocrinology (Baltimore) 109, 496-504] has been further purified and found to inhibit the binding of the 4.5S androgen receptor to isolated nuclei and nuclear matrix in a concentration-dependent manner. The results support the hypothesis that the 8S steroid receptor is a complex of the activated 4.5S androgen receptor with a non-steroid binding protein that renders the receptor incapable of binding in nuclei.


Loss of DLK expression in WI-38 human diploid fibroblasts induces a senescent-like proliferation arrest.
DLK, a serine/threonine kinase that functions as an upstream activator of the mitogen-activated protein kinase (MAPK) pathways, has been shown to play a role in development, cell differentiation, apoptosis and neuronal response to injury. Interestingly, recent studies have shown that DLK may also be required for cell proliferation, although little is known about its specific functions. To start addressing this issue, we studied how DLK expression is modulated during cell cycle progression and what effect DLK depletion has on cell proliferation in WI-38 fibroblasts. Our results indicate that DLK protein levels are low in serum-starved cells, but that serum addition markedly stimulated it. Moreover, RNA interference experiments demonstrate that DLK is required for ERK activity, expression of the cell cycle regulator cyclin D1 and proliferation of WI-38 cells. DLK-depleted cells also show a senescent phenotype as revealed by senescence-associated galactosidase activity and up-regulation of the senescence pathway proteins p53 and p21. Consistent with a role for p53 in this response, inhibition of p53 expression by RNA interference significantly alleviated senescence induced by DLK knockdown. Together, these findings indicate that DLK participates in cell proliferation and/or survival, at least in part, by modulating the expression of cell cycle regulatory proteins.


Reducing and verifying haloacetic acids in treated drinking water using a biological filter system.
This study focused on reducing the haloacetic acid (HAA) concentrations in treated drinking water. HAA has been thought to be one possible nutrient supporting heterotrophic bacteria regrowth in drinking water. In this study, experiments were conducted using a pilot-scale system to evaluate the efficiency of biological filters (BF) for reducing excess HAA concentrations in water. The BF system reduced the total HAA concentration and the concentrations of five HAA species in the water. Dichloroacetic acid (DCAA), monobromoacetic acid (MBAA) and dibromoacetic acid (DBAA) were the three main HAA5 species that were present in the treated drinking water in this investigation. Combined, these three species represent approximately 77% of the HAA5 in the finished water after BF. The verification of the empirical HAA equation for the outlet in the BF system indicated linear relationships with high correlation coefficients. The empirical equation for the HAA5 concentrations in the finished water was established by examining other nutrients (e.g., dissolved organic carbon (DOC), ultraviolet absorbance at 254 nm wavelength (UV254), and ammonia nitrogen) that can reduce pathogenic contamination. These findings may be useful for designing advanced processes for conventional water treatment plants or for managing water treatment and distribution systems for providing high-quality drinking water.


Amplification of cDNA ends based on template-switching effect and step-out PCR.
A new method for amplifying cDNA ends is described which requires only first-strand cDNA synthesis and a single PCR to generate a correct product with very low or no background. The method can be successfully applied to total RNA as well as poly A+ RNA. The same first-strand cDNA can be used to amplify flanking sequences of any cDNA species present in the sample.


T Cell Metabolism Is Dependent on Anatomical Location within the Lung.
The metabolic shift from oxidative phosphorylation to glycolysis is universally accepted as a necessary step for immune cells to mount effector functions. However, it is unknown if this paradigm holds true for T cells regardless of anatomical location. In this study, we compared metabolic responses among distinct mouse pulmonary CD4+ effector T cell (Teff) pools following intranasal vaccination with either Francisella tularensis or Bordetella pertussis Surprisingly, in contrast to circulating CD4+ Teff, upon ex vivo stimulation, resident CD4+ Teff did not shift to glycolysis. This impairment in the resident pool was modestly overcome following in vivo infection. However, consistent with an ex vivo triggered shift toward glycolysis, circulating CD4+ Teff remained superior compared with resident CD4+ Teff after in vivo infection. These data indicate differences in lung T cell metabolism is associated with anatomic location, a feature which may be exploited to enhance or dampen pulmonary T cell responses.


Direct interaction of Ikaros and Foxp1 modulates expression of the G protein-coupled receptor G2A in B-lymphocytes and acute lymphoblastic leukemia.
Ikaros and Foxp1 are transcription factors that play key roles in normal lymphopoiesis and lymphoid malignancies. We describe a novel physical and functional interaction between the proteins, which requires the central zinc finger domain of Ikaros. The Ikaros-Foxp1 interaction is abolished by deletion of this region, which corresponds to the IK6 isoform that is commonly associated with high-risk acute lymphoblastic leukemia (ALL). We also identify the Gpr132 gene, which encodes the orphan G protein-coupled receptor G2A, as a novel target for Foxp1. Increased expression of Foxp1 enhanced Gpr132 transcription and caused cell cycle changes, including G2 arrest. Co-expression of wild-type Ikaros, but not IK6, displaced Foxp1 binding from the Gpr132 gene, reversed the increase in Gpr132 expression and inhibited G2 arrest. Analysis of primary ALL samples revealed a significant increase in GPR132 expression in IKZF1-deleted BCR-ABL negative patients, suggesting that levels of wild-type Ikaros may influence the regulation of G2A in B-ALL. Our results reveal a novel effect of Ikaros haploinsufficiency on Foxp1 functioning, and identify G2A as a potential modulator of the cell cycle in Ikaros-deleted B-ALL.


[Bio-psycho-social history--is it still up to date in the time of media communication?].
Specialization in medicine changes the kind of communication between doctor and patient. The direct personal communication is quite often complemented by the indirect communication via interactive media. A clinical investigation still demands a broad bio-psycho-social anamnesis which should encompass the history of the illness, the patient, and his/her ailment. The bio-psycho-social anamnesis is subdivided into nine steps: Joining, "map", actual disease, former illnesses, family history, personal development, social anamnesis, overview of the functioning of the systems, finalization of the anamnesis. The different steps are explained, and adequate techniques of exploration are described. How to conduct a professional doctor-patient conversation and exploration can similarly be learnt as the techniques of a physical investigation. These communication skills should be continuously taught during the education of medical students as well as during the further training of physicians.


Impact of increasing one-carbon metabolites on traumatic brain injury outcome using pre-clinical models.
Traumatic brain injury is a major cause of death and disability worldwide, affecting over 69 million individuals yearly. One-carbon metabolism has been shown to have beneficial effects after brain damage, such as ischemic stroke. However, whether increasing one-carbon metabolite vitamins impacts traumatic brain injury outcomes in patients requires more investigation. The aim of this review is to evaluate how one-carbon metabolites impact outcomes after the onset of traumatic brain injury. PubMed, Web of Science, and Google Scholar databases were searched for studies that examined the impact of B-vitamin supplementation on traumatic brain injury outcomes. The search terms included combinations of the following words: traumatic brain injury, dietary supplementation, one-carbon metabolism, and B-vitamins. The focus of each literature search was basic science data. The year of publication in the literature searches was not limited. Our analysis of the literature has shown that dietary supplementation of B-vitamins has significantly improved the functional and behavioral recovery of animals with traumatic brain injury compared to controls. However, this improvement is dosage-dependent and is contingent upon the onset of supplementation and whether there is a sustained or continuous delivery of vitamin supplementation post-traumatic brain injury. The details of supplementation post-traumatic brain injury need to be further investigated. Overall, we conclude that B-vitamin supplementation improves behavioral outcomes and reduces cognitive impairment post-traumatic brain injury in animal model systems. Further investigation in a clinical setting should be strongly considered in conjunction with current medical treatments for traumatic brain injury-affected individuals.


The Effects of Childhood and Adolescent Adversity on Substance Use Disorders and Poor Health in Early Adulthood.
Childhood and adolescent adversity have been shown to predict later mental and physical health outcomes. Understanding which aspects and developmental timings of adversity are important, and the mechanisms by which they have their impact may help guide intervention approaches. A large subset of adolescents (N = 457; Female 68.9 %) from the 10-year longitudinal Youth Emotion Project was examined to better understand the associations among childhood/adolescent adversity, substance use disorder, and later health quality. Adolescent (but not childhood) adversities were associated with poorer health in late adolescence/early adulthood, adolescent adversities were associated with subsequent onset of substance use disorder, and adolescent adversities continued to be associated with poorer health in late adolescence/early adulthood after accounting for the variance explained by substance use disorder onset. These associations were observed after statistically accounting for emotional disorders and socioeconomic status. Specific domains of adversity uniquely predicted substance use disorder and poorer health outcomes. In contrast with current recent research, our findings suggest the association between childhood/adolescent adversity and poorer health outcomes in late adolescence and emerging adulthood are not entirely accounted for by substance use disorder, suggesting efforts to curtail family-based adolescent adversity may have downstream health benefits.


Treatment of metastatic adrenal cortical carcinoma with etoposide (VP-16) and cisplatin after failure with o,p'DDD. Clinical case reports.
A 42-year-old woman with liver metastasis from adrenal cortical carcinoma was treated with mitotane (o,p'DDD) for 11 months with a minimal response. Mitotane was stopped because of severe adverse effects. Thereafter a combination of cisplatin and etoposide was given every 3 weeks. A partial response was achieved after five chemotherapy courses. Following this chemotherapy, the patient had a surgical excision of the liver metastasis and entered into a complete remission for 17 months. Etoposide plus cisplatin may be an active combination for the treatment of adrenal cortical carcinoma.


Inhibition of apoptosis and prolongation of neutrophil functional longevity by inflammatory mediators.
Neutrophil apoptosis leads to macrophage ingestion of intact senescent neutrophils. This may represent a neutrophil removal mechanism that is important both in the control of inflammatory tissue injury and for the normal resolution processes of inflammation. Because apoptosis is likely to be a key control process in cell and tissue homeostasis, a number of inflammatory mediators were tested for their ability to modulate the rate of apoptosis in populations of neutrophils aging in culture. Endotoxic lipopolysaccharide, human recombinant complement factor 5a, and human recombinant granulocyte-macrophage colony-stimulating factor all markedly inhibited the rate of neutrophil apoptosis in a concentration-dependent fashion, without inducing necrosis (as assessed by trypan blue exclusion). This inhibitory effect on the rate of neutrophil apoptosis was shown by morphological criteria and confirmed by gel electrophoresis of extracted DNA. Inhibition of apoptosis of aging neutrophil populations was associated with prolongation of the functional life span of the population as assessed by the ability of neutrophils to spread on glass surfaces, to polarize in response to deliberate stimulation with N-formyl-Met-Leu-Phe (fMLP), and to release the granule enzyme marker myeloperoxidase on fMLP stimulation. These observations show that inflammatory mediators prolong the functional life span of neutrophils through modulation of apoptosis. Further elucidation of these mechanisms will lead to a better understanding of the processes controlling neutrophil residence and function in inflamed tissues and may provide further insights into the molecular mechanisms of apoptosis, which is of widespread importance in tissue biology.


Intermolecular interaction of myoglobin with water molecules along the pH denaturation curve.
A method of diffusion coefficient (D) measurement for proteins based on the pulsed laser-induced transient grating method using a photosensitive cross-linker was applied to the characterization of the pH denaturation process of holo- and apo-myoglobin (Mb) from the viewpoint of protein-water interaction. It was found that the pH denaturation curve monitored by D agrees quite well with that determined by the circular dichroism intensity for holo-Mb. This fact indicates that the changes in intermolecular interaction and the alpha-helix content occur simultaneously during the unfolding process. However, the pH dependence of D for apo-Mb was different from that of alpha-helix content. This different behavior can be explained in terms of the different denaturation steps for the secondary structure and the hydrogen bonding network of the intermediate species around pH 4; i.e., this intermediate is partially unfolded, but the hydrogen bonding network is dominantly an intramolecular one. Taking previously reported properties of this species into account, we conclude that water molecules are trapped in the hydrophobic core of the apo-Mb pH 4 intermediate. This fact suggests that the kinetic intermediate state of the protein folding process is a swollen state without water molecular exchange with the bulk phase.


Advanced seminoma and nonseminoma: SIU/ICUD Consensus Meeting on Germ Cell Tumors (GCT), Shanghai 2009.
The use of cisplatin-based combination chemotherapy has led to a dramatic improvement in the cure rate of patients with metastatic germ cell tumors (GCTs). With high complete response (CR) rates achieved in approximately 80% of patients with advanced testicular cancer after standard first-line cisplatin-based chemotherapy. Thereafter, the goals of various trials were to reduce the chemotherapy toxicity by limiting the number of chemotherapy cycles, the duration of therapy, and reducing the doses of, or even omitting, individual cytotoxic drugs, while maintaining efficacy, or to investigate the potential role of carboplatin as single agent or combined with etoposide and bleomycin for advanced seminoma. From prospective randomized trials and available data from additional sources, a European standard has been defined in several consensus conferences,(1-3) with the most recent consensus conference published by the European Society for Medical Oncology Consensus Group.(4,5) These international guidelines were developed from the previous published guidelines and data from available current trials. The principles of evidence-based medicine were scored (score 1-4) using a modified version of the Oxford levels of evidence and are listed in the present report in brackets. Draft guidelines were presented at an International Consensus in Urological Disease (ICUD) meeting (Shanghai, November 2009). The writing committee compiled the results of the discussion. All participants agreed to this final update.