Statin use and survival from lung cancer: a population-based cohort study.
Preclinical evidence from lung cancer cell lines and animal models suggest that statins could have anticancer properties. We investigated whether statin users had reduced risk of cancer-specific mortality in a population-based cohort of lung cancer patients. Newly diagnosed lung cancer patients, from 1998 to 2009, were identified from English cancer registry data and linked to the UK Clinical Practice Research Datalink, providing prescription records, and to Office of National Statistics mortality data up to 2012. Cox regression models were used to calculate HRs for cancer-specific mortality and 95% confidence intervals (CI) by statin use before and after diagnosis, and to adjust these HRs for potential confounders. In 3,638 lung cancer patients, there was some evidence that statin use after diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR, 0.89; 95% CI, 0.78-1.02; P = 0.09). Associations were more marked after 12 prescriptions (adjusted HR, 0.81; 95% CI, 0.67-0.98; P = 0.03) and when lipophilic statins were investigated (adjusted HR, 0.81; 95% CI, 0.70-0.94; P = 0.01), but were attenuated in some sensitivity analyses. Furthermore, in 11,051 lung cancer patients, statin use before diagnosis was associated with reduced lung cancer-specific mortality (adjusted HR, 0.88; 95% CI, 0.83-0.93; P < 0.001). There was some evidence that lung cancer patients who used statins, and particularly simvastatin, had reduced rates of cancer-specific mortality. These findings should first be confirmed in observational studies, but provide some support for conducting randomized controlled trials of simvastatin as adjuvant cancer therapy in lung cancer patients.


Towards integrated pest and pollinator management in tropical crops.
Biotic pollination and pest control are two critical insect-mediated ecosystem services that support crop production. Although management of both services is usually treated separately, the new paradigm of Integrated Pest and Pollinator Management (IPPM) suggests synergetic benefits by considering them together. We reviewed the management practices in two major tropical perennial crops: cocoa and coffee, to assess IPPM applications under the tropics. We found potential synergies and antagonisms among crop pest and pollination management, however, very few studies considered these interactions. Interestingly, we also found management practices focusing mainly on a single service mediated by insects although species can show multiple ecological functions as pests, natural enemies, or pollinators. The tropics represent a promising area for the implementation of IPPM and future research should address this concept to move towards a more sustainable agriculture.


Non-enzymatic inhibitors of coagulation and platelet aggregation from Naja nigricollis venom are cardiotoxins.
Four non-enzymatic polypeptides from Naja nigricollis crawshawii venom were recently isolated and shown to inhibit plasma coagulation and platelet aggregation. We have now determined the amino acid compositions, amino terminal sequences and direct lytic activity of these anticoagulants. The results of these studies allow us to identify the anticoagulants as cardiotoxins. The anticoagulant activity of these cardiotoxins is far more potent than that of other cardiotoxins previously reported to have anticoagulant activity.


Nicotine regulates autophagy of human periodontal ligament cells through α7 nAchR that promotes secretion of inflammatory factors IL-1β and IL-8.
Nicotine is an important risk factor and the main toxic component associated with periodontitis. However, the mechanism of nicotine induced periodontitis is not clear. To investigated the mechanism through which nicotine regulates autophagy of human periodontal ligament cells (hPDLCs) through the alpha7 nicotinic acetylcholine receptor (α7 nAChR) and how autophagy further regulates the release of IL-1β and IL-8 secretion in hPDLCs. HPDLCs were obtained from root of extracted teeth and pre-incubated in alpha-bungarotoxin (α-BTX) or 3-Methyladenine (3-MA), followed by culturing in nicotine. We used a variety of experimental detection techniques including western blotting, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy (TEM) and RT-qPCR to assess the expression of the LC3 protein, autolysosome, and release of IL-1β and IL-8 from hPDLCs. Western blots, immunofluorescence and TEM results found that the nicotine significantly increased the autophagy expression in hPDLCs that was time and concentration dependent and reversed by α-BTX treatment (p < 0.05). RT-qPCR and ELISA results revealed a noticeable rise in the release of inflammatory factors IL-1β and IL-8 from hPDLCs in response to nicotine. RT-qPCR and ELISA results showed that nicotine can significantly up-regulate the release of inflammatory factors IL-1β and IL-8 in hPDLCs, and this effect can be inhibited by 3-MA (p < 0.05). Nicotine regulated autophagy of hPDLCs through α7 nAChR and in turn the regulation of the release of inflammatory factors 1L-1β and 1L-8 by hPDLCs.


Molecular imaging of arterial fibroblast activation protein: association with calcified plaque burden and cardiovascular risk factors.
We aimed to assess prevalence, distribution, and intensity of in-vivo arterial wall fibroblast activation protein (FAP) uptake, and its association with calcified plaque burden, cardiovascular risk factors (CVRFs), and FAP-avid tumor burden. We analyzed 69 oncologic patients who underwent [68 Ga]Ga-FAPI-04 PET/CT. Arterial wall FAP inhibitor (FAPI) uptake in major vessel segments was evaluated. We then investigated the associations of arterial wall uptake with calcified plaque burden (including number of plaques, plaque thickness, and calcification circumference), CVRFs, FAP-positive total tumor burden, and image noise (coefficient of variation, from normal liver parenchyma). High focal arterial FAPI uptake (FAPI +) was recorded in 64/69 (92.8%) scans in 800 sites, of which 377 (47.1%) exhibited concordant vessel wall calcification. The number of FAPI + sites per patient and (FAPI +)-derived target-to-background ratio (TBR) correlated significantly with the number of calcified plaques (FAPI + number: r = 0.45, P < 0.01; TBR: r = - 0.26, P = 0.04), calcified plaque thickness (FAPI + number: r = 0.33, P < 0.01; TBR: r = - 0.29, P = 0.02), and calcification circumference (FAPI + number: r = 0.34, P < 0.01; TBR: r = - 0.26, P = 0.04). In univariate analysis, only body mass index was significantly associated with the number of FAPI + sites (OR 1.06; 95% CI, 1.02 - 1.12, P < 0.01). The numbers of FAPI + sites and FAPI + TBR, however, were not associated with other investigated CVRFs in univariate and multivariate regression analyses. Image noise, however, showed significant correlations with FAPI + TBR (r = 0.30) and the number of FAPI + sites (r = 0.28; P = 0.02, respectively). In addition, there was no significant interaction between FAP-positive tumor burden and arterial wall FAPI uptake (P ≥ 0.13). [68 Ga]Ga-FAPI-04 PET identifies arterial wall lesions and is linked to marked calcification and overall calcified plaque burden, but is not consistently associated with cardiovascular risk. Apparent wall uptake may be partially explained by image noise.


Expanded cohorts of maternal CD8+ T-cells specific for paternal MHC class I accumulate during pregnancy.
A recombinant H-2Kb transgene, GK, containing the human HLA-G gene promoter is expressed throughout the trophoblast when inherited paternally. Male GK transgenic mice were mated with female T-cell receptor (TCR) transgenic mice to assess the effect of fetal H-2Kb expression on maternal H-2Kb-specific CD8+ T-cells during pregnancy. The number of maternal H-2Kb-specific CD8+ T-cells in spleen increased significantly (approximately 3-fold) 10 days post coitus when the GK transgene was inherited from the father. A smaller (approximately 2-fold) increase was observed in the spleen of pregnant females mated with C57BL/10 (H-2b) males. No increase was observed in mothers mated to syngeneic male mice. In both cases where expanded cohorts of maternal CD8+ T-cells were observed the amount of surface CD8 and to a lesser extent, TCR molecules was reduced. No change in the amount of surface CD44 or CD45RB was detected when levels were compared with naive T-cells from control virgin female mice. Expanded cohorts of CD8+ T-cells were also detected in para-aortic and inguinal lymph nodes draining the uterus but no changes were observed in mesenteric lymph nodes. This study concludes that maternal CD8+ T-cells are exposed to paternally inherited fetal MHC class I antigens during pregnancy. Moreover, the phenotype of the CD8+ T-cells in maternal spleen and lymph nodes that drain the uterus is not typical of activated, antigen-experienced T-cells suggesting that contact with fetal H-2Kb molecules induces a state of functional unresponsiveness.


Systematic review of high-dose amikacin regimens for the treatment of Gram-negative infections based on EUCAST dosing recommendations.
Updated European Committee on Antimicrobial Susceptibility Testing (EUCAST) amikacin breakpoints for Enterobacterales and Pseudomonas aeruginosa included revised dosing recommendations of 25-30 mg/kg to achieve key pharmacokinetic/pharmacodynamic parameters, higher than recommended in the British National Formulary. The objectives of this review were to identify clinical evidence for high-dose amikacin regimens and to determine drug exposures that are related to adverse events and toxicity. The literature search was conducted in October 2021 and updated in May 2022 using electronic databases for any study reporting adult participants treated with amikacin at doses ≥20 mg/kg/day. Reference lists of included papers were also screened for potential papers. Data were extracted for pharmacokinetic parameters and clinical outcomes, presented in a summary table and consolidated narratively. Meta-analysis was not possible. Each study was assessed for bias before, during and after the intervention using the ROBINS-I tool. Nine studies (total 501 participants in 10 reports) were identified and included, eight of which were observational studies. Assessment of bias showed substantial flaws. Dosing regimens ranged from 25 to 30 mg/kg/day. Six studies adjusted the dose in obesity when participants had a body mass index of ≥30 kg/m2. Target peak serum concentrations ranged from 60 mg/L to 80 mg/L and 59.6-81.8% of patients achieved these targets, but there was no information on clinical outcomes. Two studies reported the impact of high-dose amikacin on renal function. No studies reporting auditory or vestibular toxicity were identified. All included papers were limited by a significant risk of bias, while methodological and reporting heterogeneity made drawing conclusions challenging. Lack of information on the impact on renal function or ototoxicity means high-dose regimens should be used cautiously in older people. There is a need for a consensus guideline for high-dose amikacin to be written. PROSPERO (CRD42021250022).


Errata.
[This corrects the article on p. 11 in vol. 15.][This corrects the article on p. 41 in vol. 15.].


Integrating cultural competency into the undergraduate medical curriculum.
A significant movement is underway to develop standardised curricula that provide medical students with a fundamental knowledge of cultural sensitivity. This paper reviews the recent initiative to integrate cultural competency training into the curricula of American undergraduate medical institutions. Despite these initiatives, few medical institutions have achieved a comprehensive curriculum providing for continued cultural experiences and assessment of related skill sets. The article proposes a framework for the introduction of continued instruction in and assessment of cultural competency within the undergraduate medical education. The described components of cultural competency education in the undergraduate medical curricula provide a framework to facilitate early and continued exposure to experiences designed to promote cultural sensitivity.


Preconception care by family physicians and general practitioners in Japan.
Preconception care provided by family physicians/general practitioners (FP/GPs) can provide predictable benefits to mothers and infants. The objective of this study was to elucidate knowledge of, attitudes about, and practices of preconception care by FP/GPs in Japan. A survey was distributed to physician members of the Japanese Academy of Family Medicine. The questionnaire addressed experiences of preconception education in medical school and residency, frequency of preconception care in clinical practice, attitudes about providing preconception care, and perceived need for preconception education to medical students and residents. Two hundred and sixty-eight of 347 (77%) eligible physicians responded. The most common education they reported receiving was about smoking cessation (71%), and the least was about folic acid supplementation (12%). Many participants reported providing smoking cessation in their practice (60%), though only about one third of respondents advise restricting alcohol intake. Few reported advising calcium supplementation (10%) or folic acid supplementation (4%). About 70% reported their willingness to provide preconception care. Almost all participants believe medical students and residents should have education about preconception care. FP/GPs in Japan report little training in preconception care and few currently provide it. With training, most participants are willing to provide preconception care themselves and think medical students and residents should receive this education.


Characterization of light-harvesting mutants of Rhodopseudomonas sphaeroides. I. Measurement of the efficiency of energy transfer from light-harvesting complexes to the reaction center.
Light-harvesting mutants of Rhodopseudomonas sphaeroides lacking either the B800-850 complex or the B875 complex have been characterized by their absorption spectra in the visible and near-infrared region, and by their ability to transfer energy from the light-harvesting complexes to the reaction center. A new method of measuring the relative efficiency of energy transfer from the light-harvesting complexes to the reaction center is described. The B875- mutant had absorption maxima in the near-infrared at 800 and 849 nm with no evidence of an 875-nm shoulder. The efficiency of energy transfer from the light-harvesting complexes to the reaction center in the B875- mutant was 24% of the value measured for the wild-type strain and the B800-850- mutant. Yet, despite the fact that the efficiency of energy transfer for the B800-850- mutant and the wild-type strain were the same, there was a large difference in their photosynthetic unit size. These results are discussed in the context of a model in which light energy captured by the B800-850 complexes is transferred through the B875 complexes to the reaction center.


The safety and regulatory process for low calorie sweeteners in the United States.
Low calorie sweeteners are some of the most thoroughly tested and evaluated of all food additives. Products including aspartame and saccharin, have undergone several rounds of risk assessment by the United States Food and Drug Administration (FDA) and the European Food Safety Authority (EFSA), in relation to a number of potential safety concerns, including carcinogenicity and more recently, effects on body weight gain, glycemic control and effects on the gut microbiome. The majority of the modern day sweeteners; acesulfame K, advantame, aspartame, neotame and sucralose have been approved in the United States through the food additive process, whereas the most recent sweetener approvals for steviol glycosides and lo han guo have occurred through the Generally Recognized as Safe (GRAS) system, based on scientific procedures. While the regulatory process and review time of these two types of sweetener evaluations by the FDA differ, the same level of scientific evidence is required to support safety, so as to ensure a reasonable certainty of no harm.


A new technique for post-embedding immunogold localization of vasopressin in the rat median eminence.
A modified cryosubstitution method is described which simultaneously preserves the ultrastructure and antigenicity of the osmium-sensitive neuropeptide vasopressin in rat median eminences. The organs were aldehyde-fixed, osmicated, and embedded in Epon. Thin sections were no longer needed to be etched and the titer of primary antiserum was near to the light microscopic level. Furthermore ice crystallization could not be observed.


Development of CXCR3 antagonists. Part 2: Identification of 2-amino(4-piperidinyl)azoles as potent CXCR3 antagonists.
Development of a lead series of piperidinylurea CXCR3 antagonists has led to the identification of molecules with alternative linkages which retain good potency. A novel 5-(piperidin-4-yl)amino-1,2,4-thiadiazole derivative was found to have satisfactory in vitro metabolic stability and to be orally bioavailable in mice, giving high plasma concentrations and a half life of 5.4h.


Starch and fiber intake effects on energy metabolism, growth, and carapacial scute pyramiding of red-footed tortoise hatchlings (Chelonoidis carbonaria).
Tortoise husbandry includes reports of excessive growth and carapace pyramiding, although triggers still remain to be fully elucidated. Juvenile red-footed tortoises (Chelonoidis carbonaria) were fed with two different diets, one high in fiber (HF; 14.2% crude fiber; 39.2% neutral detergent fiber, NDF; dry matter basis, DMB) and one high in starch (HS; 27.7% DMB), to assess effects on energy metabolism, nutrient digestibility, and growth. A total of 20 hatchlings (10 per diet) were used to evaluate: apparent digestibility coefficients (Da) of nutrients and gross energy (GE), passage times at 5 and 11 months of age; resting and post-prandial metabolic rates at 6 and 12 months of age; growth rates; pyramiding; and estimated body composition. Animals fed HS showed higher mass-specific intake of digestible energy (113.9 ± 32.1 kJ kg-1 day-1 vs. 99.6 ± 35.3 kJ kg-1 day-1; P < 0.05), digestible DM (6.1 ± 1.8 g kg-1 day-1 vs. 5.0 ± 1.8 g kg-1 day-1; P < 0.01), shorter transit (3 ± 1 days vs. 4 ± 1 days; P < 0.01) and retention times (8 ± 2 days vs. 10 ± 2 days; P < 0.01), and higher Da of DM, starch, NDF, and GE. Crude protein Da was higher for HF. Rest and post-prandial metabolic rates, and pyramiding degree were not affected by diets. At 13 months, the animals from HS presented wider plastrons and carapaces, and higher carapace width growth rates. In addition, these animals had lower body mineral content (1.88 ± 0.15% vs. 2.15 ± 0.19%; P < 0.01) and bone density (0.13 ± 0.01 g mm-2 vs. 0.15 ± 0.02 g mm-2; P < 0.02). Results provide evidence that highly digestible foods can accelerate shell growth and lower mineralization in this species.


Immunotherapy in the treatment of acute myelogenous leukemia (AML): rationale, results and future prospects.
Patients with AML in complete remission (CR) are immunosuppressed; remission lymphocytes of at least a part of the patients are able to recognize autologous leukemic blasts; the CR represents a minimal residual disease. Thus, important conditions for a potentially successful active immunotherapy are given. Results of most earlier randomized trials on immunotherapy revealed some, but limited benefit with respect to survival. Encouraging effects, however, have been achieved by immunizing CR patients with high-dose neuraminidase-treated allogeneic blasts. Because these data have not been confirmed until now we recently initiated a randomized study utilizing identical treatment protocols. The preliminary results of the ongoing study still do not allow to draw any firm conclusions. Specific monoclonal antibodies or autologous cytotoxic T-cells may be useful tools for future immunotherapy of AML.


Toxic epidermal necrolysis caused by acetaminophen featuring almost 100% skin detachment: Acetaminophen is associated with a risk of severe cutaneous adverse reactions.
Toxic epidermal necrolysis (TEN) is an adverse reaction that can be induced by various drugs; the associated mortality rate is 20-25%. A previous report showed a weak association between TEN and acetaminophen. Recently, the US Food and Drug Administration declared that acetaminophen is associated with a risk of serious skin reactions, including TEN. Here, we describe the case of a 43-year-old Japanese woman with TEN caused by acetaminophen. She had poorly controlled ulcerative colitis and was treated with high doses of prednisolone, infliximab, acetaminophen and lansoprazole. Nine days after administrating acetaminophen, targetoid erythematous and bullous lesions appeared on the patient's trunk, palms and the soles of her feet. The skin lesions expanded rapidly; within 3 weeks, skin detachment was detected across nearly 100% of the patient's body. However, no mucosal involvement of the eyes, oral cavity or genitalia was found. We performed lymphocyte transformation tests using various drugs; however, a high stimulation index was obtained only with acetaminophen. The patient recovered following treatment with plasmapheresis, i.v. immunoglobulin therapy, topical medication and supportive therapy. Acetaminophen is included in many prescription and over-the-counter products; thus, clinicians should monitor their patients for severe drug reactions, including TEN.


Territorial responses to energy manipulations in the Anna hummingbird.
Territorial activity in the Anna hummingbird (Calypte anna) was measured while energy availability on the territory was varied. On days when energy availability was unlimited, residents defended highly exclusive territories primarily by energetically expensive defense behaviors. As energy availability decreased, exclusiveness declined gradually, relative use of energetically inexpensive defense increased, and owners spent less time on the territory.Territorial behavior also varied with short term depressions in energy availability: A lower percentage of intruders was chased and departures of an owner from its territory were more frequent shortly after feeding.When resource dispersion was increased without changing substantially total rewards per territory, chasing by owners increased.


Impact of duration of symptoms on CSF dynamics in idiopathic normal pressure hydrocephalus.
Cerebrospinal fluid (CSF) pressure-volume compensation may change over time as part of normal ageing, where the resistance to CSF outflow increases and the formation of CSF decreases with age. Is CSF compensation dependent on duration of symptoms in idiopathic normal pressure hydrocephalus (iNPH)? We investigated 92 patients presenting with iNPH. Mean age was 73 (range 47-86). There were 60 men and 32 women. They all presented with gait disturbance and ventricular dilatation. Memory deficit occurred in 72% and urinary incontinence in 52% of patients. All patients underwent computerized CSF infusion tests. Sixty-four shunted patients were available for follow-up, and their improvement was expressed using the NPH score. Mean intracranial pressure (ICP) was 10.1±5.1 mmHg, and mean resistance to CSF outflow was 17.3±5.2 mmHg/(ml/min). Mean duration of symptoms was 24±19 months (range from 2 weeks to 86 months). Baseline ICP, magnitude of ICP pulse waveform, brain compliance and improvement after shunting (72% of patients improved) did not exhibit any dependency on the duration of symptoms. The resistance to CSF outflow showed a strong tendency to decrease in time with the duration of symptoms beyond 2 years (R= -0.702; P<0.005). This is a preliminary observation, and it suggests that for patients with duration of symptoms longer than 2-3 years, the threshold for normal resistance to CSF outflow should be duration-adjusted.


Association of HLA class II alleles with sensitization to cow dander Bos d 2, an important occupational allergen.
Allergic sensitization results from a complex interaction between genetic and environmental factors. Earlier studies have shown that highly polymorphic HLA genes are associated with a variety of allergies. Several important respiratory allergens belong to the family of lipocalin proteins. These include occupational sensitizers, such as cow Bos d 2 or rat Rat n 1, and prevalent indoor sensitizers, such as dog Can f 1 or cockroach Bla g 4. HLA associations with sensitization to lipocalin allergens are incompletely known. In the present study we have investigated an association between HLA alleles and sensitization to the major cow allergen Bos d 2. The HLA-DR/DQ genotypes of 40 Bos d 2-sensitized subjects having occupational asthma were determined by polymerase chain reaction (PCR) and the results were compared with the genotypes of 151 unrelated Finnish subjects. The frequencies of HLA class II alleles DRB1*0101, DRB1*0404, DQB1*0302, and DQB1*0501 were significantly higher among Bos d 2-sensitized than among control subjects. In addition, the allergic subjects expressed significantly lower frequencies of HLA-DRB1*0301 and DQB1*0201 alleles than did the control subjects. These data suggest that the HLA class II alleles DRB1*0101, DRB1*0404, DQB1*0302, and DQB1*0501, and the haplotypes that include them, are associated with sensitization to the major cow allergen Bos d 2, whereas HLA-DRB1*0301 and DQB1*0201 are dissociated with it. Amino acid analysis provides a biologically plausible explanation for the HLA associations.


The correlation between cutout and eccentric distance (ED) of the cephalic fixator tip in geriatric intertrochanteric fractures with internal fixation.
The location of cephalic fixator tip with different eccentric distance (ED) should have different risks of cutout. This study aims to evaluate the cephalic fixator tip position by measuring ED of the cephalic fixator tip in geriatric ITF patients with single-screw cephalomedullary nail (SCMN) fixation and analyze the correlation between the cutout and the ED. Firstly, we assumed all the femoral head was a regular sphere and standardized the radius of the femoral head (RFD) as "3" no matter how big the RFD was for complete match of the Cleveland zone system and convenient identification of artificial intelligence. Secondly, we measured the ED of the cephalic fixator tip by calculating the distances from the cephalic fixator tip to the geometric central axis of the femoral neck and head on both AP view and lateral view radiographs. Thirdly, we evaluated all the ED of the cephalic fixator tip in the eligible 123 geriatric ITF patients and analyzed the correlation between the cutout and the ED. The ED in cutout group (1.25 ± 0.43) is much bigger than that in non-cutout group (0.64 ± 0.34) with significant difference (OR = 50.01, 95% CI 8.42-297.19, p < 0.001). The probability of cutout increased with ED increasing, especially when "ED ≥ 1." The best cutoff value of ED for predicting cutout was "1.022" ("1.022" was just a little bit more than 1/3 times of RFD because "RFD = 3," sensitivity = 73.3%, specificity = 86.1%, and AUC = 0.867, p < 0.001). ED is suitable for evaluation of the cephalic fixator tip position for predicting cutout in geriatric ITF patients with SCMN fixation, and ED can potentially be used as artificial intelligence application during surgery. The smaller the ED, the lower the cutout rate. For avoiding cutout, the ED of the cephalic fixator tip should be less than one-third times of the radius of the femoral head.


Improving β-glucosidase and xylanase production in a combination of waste substrate from domestic wastewater treatment system and agriculture residues.
Cellulase and hemicellulase activities are considered to the major bottlenecks in the lignocellulosic biorefinery process, especially in an enzyme cocktail lacking β-glucosidase (BGL) and xylanase (XYL). In view of this issue, higher levels of BGL and XYL activities were obtained in the presence of wastewater and activated sludge as an induction medium mixed with 5% of rice straw by Hypocrea sp. W63. The analysis of the ionic content showed that a relatively low sludge dose could enhance the production of BGL and XYL. Most importantly, compared to a medium using freshwater, the proportion of 1:10 sludge to wastewater, which contained nutrient elements, led to 3.4-fold BGL and 3.7-fold XYL production improvements. This research describes the reuse of substrates that are largely and continuously generated from domestic wastewater treatment systems and agriculture residues, which consequently leads to the development of a simultaneous enzyme production process for sustainable biorefinery practices.


Ligand binding kinetics of substance P and neurokinin A receptors stably expressed in Chinese hamster ovary cells and evidence for differential stimulation of inositol 1,4,5-trisphosphate and cyclic AMP second messenger responses.
Stably transfected Chinese hamster ovary cells expressing either the substance P receptor or neurokinin A receptor were constructed, isolated, and characterized. Equilibrium ligand binding studies performed on whole cells demonstrated that cell lines expressing either of these receptors contained a single class of high-affinity binding sites with an apparent KD of 0.16 nM for the substance P receptor and an apparent KD of 2.1 nM for the neurokinin A receptor. The higher affinity of substance P for its receptor was accounted for by both a greater association rate constant and a lesser dissociation rate constant. The time course and extent of ligand-stimulated inositol 1,4,5-trisphosphate mass increases in both cell lines were similar and displayed rapid and transient kinetics. Ligand-stimulated cyclic AMP accumulation was also apparent in the cell lines, although the time course and magnitude of the responses were substantially different, with the neurokinin A receptor mediating a greater and more prolonged response. These studies establish the presence of functional substance P receptors and neurokinin A receptors in the stably transfected cell lines and provide evidence for agonist-dependent differential stimulation of second messenger responses.


Extracellular oxidases of the lignin-degrading fungus Panus tigrinus.
Two extracellular oxidases (laccases) were isolated from the extracellular fluid of the fungus Panus (Lentinus) tigrinus cultivated in low-nitrogen medium supplemented with birch sawdust. The enzymes were purified by successive chromatography on columns with TEAE-cellulose and DEAE-Toyopearl 650M. Both oxidases catalyze oxidation of pyrocatechol and ABTS. Moreover, oxidase 1 also catalyzes oxidation of guaiacol, o-phenylenediamine, and syringaldazine. The enzymes have identical pH (7.0) and temperature (60-65 degrees C) optimums. Absorption spectra of the oxidases differ from the spectra of typical "blue" laccases and are similar to the spectrum of yellow oxidase.


Relationship between SARS-CoV-2 vaccination and cases, program breakthrough cases, and deaths in Dois Vizinhos, Paraná, Brazil.
Several vaccines have been produced in 2 years of the COVID-19 pandemic to control the infection outbreak. This study demonstrated the success of vaccination in controlling COVID-19 cases and deaths in a small city (41 424 people) with a low population density in Brazil. This study was based on a 1-year dataset since the application of the first dose in January 2021. The results show a reduction in positive cases and deaths as the vaccination coverage increased in the city, mainly after 15 000 inhabitants were vaccinated (35.21% of the population) in July 2021. At the time, 49.06% of administered vaccines were ChAdOx1-S recombinant, 39.80% inactivated SARS-CoV-2 virus (CZ02 strain), 9.70% Tozinameran, and 1.44% Ad26.COV2-S recombinant. From August 2021, a marked reduction in daily positive cases and deaths was observed, and incidence (≤2.49 per 1000 inhabitants) and mortality (≤0.02 per 1000 inhabitants) rates remained stabilized until January 2022, when a new outbreak occurred upon the emergence of the Omicron variant. However, the mortality rate (0.07 per 1000 inhabitants) remained low regardless of the Omicron high incidence rate (68.41 per 1000 inhabitants). These data demonstrate the COVID-19 vaccination effectiveness with a threshold of 35.21% of the population vaccinated in this city model.


Fingolimod mitigates memory loss in a mouse model of Gulf War Illness amid decreasing the activation of microglia, protein kinase R, and NFκB.
Gulf War Illness (GWI) is an unrelenting multi-symptom illness with chronic central nervous system and peripheral pathology affecting veterans from the 1991 Gulf War and for which effective treatment is lacking. An increasing number of studies indicate that persistent neuroinflammation is likely the underlying cause of cognitive and mood dysfunction that affects veterans with GWI. We have previously reported that fingolimod, a drug approved for the treatment of relapsing-remitting multiple sclerosis, decreases neuroinflammation and improves cognition in a mouse model of Alzheimer's disease. In this study, we investigated the effect of fingolimod treatment on cognition and neuroinflammation in a mouse model of GWI. We exposed C57BL/6 J male mice to GWI-related chemicals pyridostigmine bromide, DEET, and permethrin, and to mild restraint stress for 28 days (GWI mice). Control mice were exposed to the chemicals' vehicle only. Starting 3 months post-exposure, half of the GWI mice and control mice were orally treated with fingolimod (1 mg/kg/day) for 1 month, and the other half were left untreated. Decreased memory on the Morris water maze test was detected in GWI mice compared to control mice and was reversed by fingolimod treatment. Immunohistochemical analysis of brain sections with antibodies to Iba1 and GFAP revealed that GWI mice had increased microglia activation in the hippocampal dentate gyrus, but no difference in reactive astrocytes was detected. The increased activation of microglia in GWI mice was decreased to the level in control mice by treatment with fingolimod. No effect of fingolimod treatment on gliosis in control mice was detected. To explore the signaling pathways by which decreased memory and increased neuroinflammation in GWI may be protected by fingolimod, we investigated the involvement of the inflammatory signaling pathways of protein kinase R (PKR) in the cerebral cortex of these mice. We found increased phosphorylation of PKR in the brain of GWI mice compared to controls, as well as increased phosphorylation of its most recognized downstream effectors: the α subunit of eukaryotic initiation factor 2 (eIF2α), IκB kinase (IKK), and the p65 subunit of nuclear factor-κB (NFκB-p65). Furthermore, we found that the increased phosphorylation level of these three proteins were suppressed in GWI mice treated with fingolimod. These results suggest that activation of PKR and NFκB signaling may be important for the regulation of cognition and neuroinflammation in the GWI condition and that fingolimod, a drug already approved for human use, may be a potential candidate for the treatment of GWI.


The burden and trend of gastric cancer and possible risk factors in five Asian countries from 1990 to 2019.
The burdens and trends of gastric cancer are poorly understood, especially in high-prevalence countries. Based on the Global Burden of Disease Study 2019, we analyzed the incidence, death, and possible risk factors of gastric cancer in five Asian countries, in relation to year, age, sex, and sociodemographic index. The annual percentage change was calculated to estimate the trends in age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR). The highest ASIR per 100,000 person-years in 2019 was in Mongolia [44 (95% uncertainty interval (UI), 34 to 55)], while the lowest was in the Democratic People's Republic of Korea (DPRK) [23 (95% UI, 19 to 29)]. The highest ASDR per 100,000 person-years was in Mongolia [46 (95% UI, 37 to 57)], while the lowest was in Japan [14 (95% UI, 12 to 15)]. Despite the increase in the absolute number of cases and deaths from 1990 to 2019, the ASIRs and ASDRs in all five countries decreased with time and improved sociodemographic index but increased with age. Smoking and a high-sodium diet were two possible risk factors for gastric cancer. In 2019, the proportion of age-standardized disability-adjusted life-years attributable to smoking was highest in Japan [23% (95% UI, 19 to 28%)], and the proportions attributable to a high-sodium diet were highest in China [8.8% (95% UI, 0.21 to 33%)], DPRK, and the Republic of Korea. There are substantial variations in the incidence and death of gastric cancer in the five studied Asian countries. This study may be crucial in helping policymakers to make better decisions and allocate appropriate resources.


Physical exercise increases the expression of TNFalpha and GLUT 1 in muscle tissue of diabetes prone Psammomys obesus.
Tumor necrosis factor-alpha (TNFalpha) is a major mediator of insulin resistance. On the other hand, it has been suggested that TNFalpha may facilitate glucose uptake through GLUT 1 expression. We recently found that physical exercise prevented the progression to type 2 diabetes mellitus in diabetes prone Psammomys obesus (sand rat). The aim of the present study was to characterize the influence of physical exercise on the expression of TNFalpha, its receptor R1 and GLUT 1 in muscle tissue of this animal model. Animals were assigned for 4 weeks to four groups: high-energy diet (HC), high-energy diet and exercise (HE), low-energy diet (LC), low-energy diet and exercise (LE). TNFalpha, R1 and GLUT 1 expression were analyzed using Western blot technique. None of the animals in the HE group became diabetic while all the animals in the HC group became diabetic. TNFalpha, its receptor (R1) and GLUT 1 expressions were significantly higher in the two exercising groups (LE and HE) and significantly lower in the HC group compared to the control LC group. Physical exercise augments the expression of TNFalpha, its receptor R1 and the glucose transporter GLUT 1 in muscle tissue. We suggest that this mechanism may improve glucose uptake through pathways parallel and unrelated to insulin signaling that may include MAPK and/or NO. These biochemical processes contribute to the beneficial effects of physical exercise on the prevention of type 2 diabetes mellitus.


Nursing education on palliative care across Europe: Results and recommendations from the EAPC Taskforce on preparation for practice in palliative care nursing across the EU based on an online-survey and country reports.
Nurses are the largest regulated group of healthcare professionals involved in palliative care. In 2004, a taskforce of the European Association for Palliative Care (EAPC) launched the 'Guide for development of palliative nurse education in Europe' (hereinafter, the EAPC 2004 Guide). No systematic evaluation of its impact in the development of palliative care education was undertaken. To describe current undergraduate and postgraduate nursing education across Europe; to identify the roles that nurses with different palliative care educational levels have in palliative care; and to assess the uptake of the EAPC 2004 Guide in the development of palliative care nursing in Europe. Descriptive research involving an online survey among nursing experts, and the consultation of national representatives. A total of 135 nurses (52% response rate) from 25 countries completed the online survey; representatives from 16 countries were consulted. In 14 (56%) countries, palliative care was not identified as a mandatory subject within undergraduate nursing education. The EAPC 2004 Guide is widely known and was/is being used in many countries to promote palliative care nursing education. Large variations were found across and within country responses. Palliative care nursing education varies largely in Europe. The wide awareness and use of the EAPC 2004 Guide show how policy measures can influence the development of palliative care education. Recommendations are built and focus on both fostering the use of this guide and implementing policy measures to ensure that palliative care nursing is recognised and certified as a specialty in all European countries.


Trace metal stabilisation in a shooting range soil: mobility and phytotoxicity.
Due to impact and abrasion of projectiles firing berms of shooting ranges frequently exhibit increased levels of bullet-borne contaminants. Stabilisation of backstop soils may be a promising pre- and post-use treatment to minimise leaching and bioavailability. This study focused on mobility and phytotoxicity of antimony, copper, and lead in stabilised berm material compared to an untreated control. Ferric (goethite, deferrisation sludge) and phosphatic amendments (diammonium phosphate, calcium dihydrogen phosphate) were used. Batch and column experiments demonstrated effective stabilisation of the contaminants by ferric amendments. Sequential extractions showed an increase of contaminant fractions associated with iron (hydr)oxides. Stabilisation was accompanied by a detoxification of seepage water compared to the control soil as shown by Duckweed growth inhibition. Contrasting the ferric additives, phosphatic amendments effectively stabilised lead but mobilised copper and antimony possibly due to a competitive displacement process. Thereby, benefits of lead stabilisation were completely overridden; this was underlined by increased phytotoxicity relative to the untreated soil. Overall, understanding stabilised soil as a multicomponent system is a prerequisite for the choice of appropriate amendments. This requires the synopsis of results from complementary test methods and a screening for a wide range of substances.


Standardized ethanol extract, essential oil and zerumbone of Zingiber zerumbet rhizome suppress phagocytic activity of human neutrophils.
Zingiber zerumbet rhizome and its bioactive metabolites have previously been reported to exhibit innumerable pharmacological properties particularly anti-inflammatory activities. In the present study, the 80% ethanol extract, essential oil and zerumbone of Z. zerumbet rhizomes were explored for their in vitro immunosuppressive properties on chemotaxis, CD11b/CD18 expression, phagocytosis and chemiluminescence of isolated human polymorphonuclear neutrophils (PMNs). The extract was analyzed quantitatively by performing a validated reversed phase high performance liquid chromatography (RP-HPLC). Zerumbone was isolated by chromatographic technique while the essential oil was acquired through hydro-distillation of the rhizomes and further analyzed by gas chromatography (GC) and GC-MS. Chemotaxis assay was assessed by using a 24-well cell migration assay kit, while CD18 integrin expression and phagocytic engulfment were measured using flow cytometry. The reactive oxygen species (ROS) production was evaluated by applying lucigenin- and luminol-enhanced chemiluminescence assays. Zerumbone was found to be the most abundant compound in the extract (242.73 mg/g) and the oil (58.44%). Among the samples tested, the oil revealed the highest inhibition on cell migration with an IC50 value of 3.24 μg/mL. The extract, oil and zerumbone showed moderate inhibition of CD18 integrin expression in a dose-dependent trend. Z. zerumbet extract showed the highest inhibitory effect on phagocytic engulfment with percentage of phagocytizing cells of 55.43% for PMN. Zerumbone exhibited strong inhibitory activity on oxidative burst of zymosan- and PMA-stimulated neutrophils. Zerumbone remarkably inhibited extracellular ROS production in PMNs with an IC50 value of 17.36 μM which was comparable to that of aspirin. The strong inhibition on the phagocytosis of neutrophils by Z. zerumbet extract and its essential oil might be due the presence of its chemical components particularly zerumbone which was capable of impeding phagocytosis at different stages.


A method for measuring the accuracy of multi-modal image fusion system for catheter-based cardiac interventions using a novel motion enabled targeting phantom.
Targeted stem cell therapy offers great potential for the repair of infarcted cardiac tissue following heart attack. Safe delivery of stem-cells via catheter based interventions remains a challenge. A multi-modal image fusion approach has been considered for safe targeting of myocardial infarct border zones. In this paper we present an apparatus and method for measuring the accuracy of catheter-based injections using a multi-modal image fusion system. We also present results of the accuracy of our image fusion system under varying levels of cardio-respiratory motion.


Effect of magnetization on the adsorptive removal of an emerging contaminant ciprofloxacin by magnetic acid activated carbon.
Magnetic acid activated carbons (MAAC) were prepared from the shells of Sterculia villosa Roxb by activating the biomass and magnetizing it using the co-precipitation technique. Characterization of MAAC prior and post adsorption was performed using various microscopic and spectroscopic analytical techniques, and they verified the formation of magnetic aggregates over porous activated carbon surface. Vibrating Sample Magnetometer (VSM) analysis confirmed the superparamagnetic behaviour of the adsorbent with saturation magnetization (Ms) value of 18.2 emu/g, causing an easy and rapid recovery from the adsorption setup in the presence of an external magnetic field. Langmuir isotherm and pseudo-second-order kinetic model best fit the experimental data with theoretical Langmuir maximum adsorption capacity as 81.97 mg/g and verifying chemisorption type of adsorption process, respectively. Thermodynamic analysis verified the interaction among adsorbate and adsorbent as endothermic, spontaneous, and thermodynamically favourable. Co-existing metal cations showed a significant reduction in ciprofloxacin removal efficiency; co-existing anions, though, showed a negligible influence on the adsorption efficiency of MAAC. Recyclability studies verified that the adsorption efficiency fell from 98% in the first cycle to 43% in the fifth cycle. The Ms value fell to 7.6 emu/g (after five adsorption cycles), affecting the adsorbent's recovery. The Phyto-toxicological assessment was performed to evaluate the environmental risk to human and aquatic life using Vigna mungo seeds. MAAC proved to be an effective and magnetically separable adsorbent for removing antibiotics.


Acquired involution of the maxillary antrum.
Maxillary sinus shrinkage can occur secondary to acquired benign osteomeatal disease. This may be associated with an external deformity and sinus wall sclerosis.


Bidirectional ventricular tachycardia with alternating right and left bundle branch block morphology in a patient with metastatic cardiac tumors.
A case is reported of bidirectional ventricular tachycardia and syncope in a 16-year-old male with a previous history of a paratesticular rhabdomyosarcoma that achieved complete remission with treatment. At the electrophysiological study, frequent ectopy of both right and left bundle branch block pattern were present, with runs of monomorphic and bidirectional VT alternating the two morphologies. The study suggested a single focus at the interventricular septum with two exit sites, depolarizing the right and left ventricle in an alternate fashion. Reassessment of the malignancy status showed multiple cardiac metastases with a 4 mm nodule at the interventricular septum.


Serological testing for syphilis in the differential diagnosis of cognitive decline and polyneuropathy in geriatric patients.
In the 19th century, neurosyphilis was the most frequent cause of dementia in Western Europe. Now dementia caused by syphilis has become rare in Germany. We studied whether routine testing of patients with cognitive abnormalities or neuropathy for antibodies against Treponema pallidum has therapeutic consequences in geriatric patients. A Treponema pallidum electrochemiluminescence immunoassay (TP-ECLIA) is routinely performed in all in-patients treated at our institution with cognitve decline or neuropathy and no or insufficient previous diagnostic workup. Patients with a positive TP-ECLIA treated from October 2015 to January 2022 (76 months) were retrospectively evaluated. In cases of positive TP-ECLIA, further specific laboratory investigations were performed to assess whether antibiotic therapy was indicated. In 42 of 4116 patients (1.0%), TP-ECLIA detected antibodies directed against Treponema in serum. Specifity of these antibodies was ensured by immunoblot in 22 patients (11 × positiv, 11 × borderline values). Treponema-specific IgM was detectable in the serum of one patient, in 3 patients the Rapid Plasma Reagin (RPR) test, a modified Venereal Disease Research Laboratory test (VDRL), in serum was positiv. CSF analysis was performed in 10 patients. One patient had CSF pleocytosis. In 2 other patients, the Treponema-specific IgG antibody index was elevated. 5 patients received antibiotic therapy (4 × ceftriaxone 2 g/d i.v., 1 × doxycycline 300 mg/d p.o.). In approx. 1‰ of patients with previously undiagnosed or not sufficiently diagnosed cognitive decline or neuropathy, the diagnostic workup for active syphilis resulted in a course of antibiotic treatment.


Contextual cuing and memory performance in brain-damaged amnesics and old people.
In Experiment 1, groups of Korsakoff amnesics and alcoholic controls learned a list of paired-associate words in a standard testing room or in a room with distinctive contextual features. Recall was tested 48 hr later in the same or other context. This procedure was repeated in Experiment 2 with old people living in institutions or in the community, but matched for age, health, education, and socioeconomic background. The amnesic patients and institutionalized old people, relative to their comparison groups, were more impaired in recalling the lists under standard conditions and were more responsive to contextual cuing, especially when the distinctive cues were provided during original learning. The results highlight the susceptibility to interference of Korsakoff amnesics and institutionalized old people and offer further evidence that both groups are more responsive to salient contextual cues than either young people or old people living in the community.


Further studies on 4-hydroxy-3-methoxyphenylglycol oxidation in humans: effect of pool expansion and stereochemistry.
The in vivo oxidation of the norepinephrine metabolite 4-hydroxy-3-methoxyphenylglycol (HMPG) to 4-hydroxy-3-methoxymandelic acid was studied in man with two different doses of deuterium-labeled HMPG and a tracer dose of [14C]HMPG. HMPG oxidation appeared to be dose-dependent with an oxidation of 62-70% for doses below or equal to 2.2 mumol. With the use of a capillary column coated with an optically active phase (Chirasil-Val) and gas chromatography mass-spectrometry the human urinary excretions of the two stereoisomers of deuterium-labelled HMPG (free + conjugates) were found to be equal.


In nonhospitalized, unvaccinated adults with COVID-19, molnupiravir reduced hospitalization or death at 29 d.
Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 2022;386:509-20. 34914868.


Improving sustainability in the remediation of contaminated soils by the use of compost and energy valorization by Paulownia fortunei.
The plantation of fast growing trees in contaminated sites, in combination with the use of organic wastes, could partially solve a dual environmental problem: the disposal of these wastes and the improvement of soil quality in these degraded soils. This study evaluated the effects of two compost on the quantity and quality of Paulownia fortunei biomass and on syngas production by biomass gasification, produced by plants growing on trace elements contaminated soils. Compost increased biomass production to values similar to those produced in non-contaminated soils, due to the improvement in plant nutritional status. Moreover, biomass quality for gasification was increased by compost addition. Trace element accumulation in the biomass was relatively low and not related to biomass production or the gas quality obtained through gasification. Thus, P. fortunei plantations could pose an opportunity to improve the economic balance of the revegetation of contaminated soils, given that other commercial uses such as food or fodder crop production is not recommended in these soils.


Inhibition of human red cell sodium and potassium transport by divalent cations.
The influx and efflux of Na and K across the human red cell membrane by the bumetanide-sensitive (Na-K co-transport) and residual (ouabain- and bumetanide-insensitive) routes were inhibited by increasing concentrations of external Mg. Ca, Sr, Ba, Mn and Co also inhibited bumetanide-sensitive and residual K transport. External Mg inhibited choline uptake and the Na-dependent fractions of L-alanine and L-serine uptakes. External Mg reduced the maximal rate (app. Vmax) but not the affinity (app. Km) of the bumetanide-sensitive K and Na influxes when they were measured as functions of external K and Na respectively. The inhibitory effect of Mg was not due to a small reduction in zeta potential since much larger reductions in zeta potential produced by neuraminidase did not affect transport. Internal Mg stimulated the ouabain-sensitive K influx but inhibited the co-transport and residual components of K influx. Bumetanide was a poor co-transport inhibitor in red cells pre-treated with A23187 and EDTA. It was concluded that the inhibitory effects of external Mg were probably not due to changes in the ionic composition of the diffuse double layer adjacent to the cell membrane. Mg and other divalent cations should not be used as 'inert' ionic substitutes in human red cell Na and K transport studies.


Psychosocial factors of risk and protection associated with juvenile cyberbullying victimization: results from an international multi-city study (International Self-Report Delinquency Study 3, ISRD3).
The growing use of technologies makes it easy for children and young people to access or produce offensive content, giving rise to a new form of bullying: cyberbullying. Several individual and environmental protection and risk factors are involved with cyberbullying victimization. The present study aims to provide some empirical data that can help in understanding cyberbullying and in the formulation of programmes for its prevention. For this purpose, the data of the ISRD3 (International Self-Report Delinquency Study 3) survey were used. Data show that, for strategies of prevention and intervention to be effective, they should consider multiple systems, such as the family, peers, school and community.


Accuracy of pedicle screw placement in patients with Marfan syndrome.
There is no study concerning safety and accuracy of pedicle screw placement in Marfan syndrome. The objective of this study is to investigate accuracy and safety of pedicle screw placement in scoliosis associated with Marfan syndrome. CT scanning was performed to analyze accuracy of pedicle screw placement. Pedicle perforations were classified as medial, lateral or anterior and categorized to four grades: ≤ 2 mm as Grade 1, 2.1-4.0 mm as Grade 2, 4.1-6.0 mm as Grade 3, ≥6.1 mm as Grade 4. Fully contained screws or with medial wall perforation ≤ 2 mm or with lateral wall perforation ≤ 6 mm and without injury of visceral organs were considered acceptable, otherwise were unacceptable. 976 pedicle screws were placed, 713 screws (73.1%) were fully contained within the cortical boundaries of the pedicle. 924 (94.7%) screws were considered as acceptable, and 52 (5.3%) as unacceptable. The perforation rate was higher using free-hand technique than O-arm navigation technique (30.8% VS. 11.4%, P < 0.05), higher in lumbar region than in thoracic region (34.1% VS. 22.3%, P < 0.05) and higher in concave side than in convex side (33.5% VS. 21.9%, P < 0.05). No injury of visceral organs especially aorta erosion was noted in the series. 7 cases of dural tear caused by misplaced screws occurred, and 4 cases developed cerebro-spinal fluid leak. Drainage and pressure dressings were applied for these patients, and no infection was observed. Leg pain was observed in 7 cases, and 2 cases simultaneously complained of leg weakness. Revision surgery was conducted to remove the misplaced screws for these 2 patients. Conservative treatment was applied for the 5 patients without leg weakness. Symptoms of leg weakness and pain resolved in all patients. Placement of pedicle screw in Marfan syndrome is accuracy and safe. O-arm navigation was an effective modality to ensure the safety and accuracy of screw placement. Special attention should be paid when screws were placed at the lumber spine and the concave side of spine deformity to avoid the higher rate of complications.


Relationships between the duration of illness and the current status of diabetes in elderly patients with type 2 diabetes mellitus.
The aim of the present study was to clarify the relationships between the duration of diabetes and the current statuses of diabetes in elderly (aged ≥65 years) patients with type 2 diabetes. Clinical characteristics were cross-sectionally examined in 1436 patients (684 elderly and 752 non-elderly) with type 2 diabetes. As the duration of diabetes increased, the patients' age, frequency of receiving insulin therapy and glycated hemoglobin value increased in both the elderly and non-elderly groups, whereas the urinary C-peptide immunoreactivity and glomerular filtration rate decreased. The duration of diabetes (years) was significantly associated with the prevalence of diabetic retinopathy (OR 1.05, 95% CI 1.03-1.07, P < 0.01), nephropathy (OR 1.03, 95% CI 1.01-1.05, P < 0.01) and neuropathy (OR 1.08, 95% CI 1.05-1.12, P < 0.01), but not with cerebrovascular disease (OR 1.01, 95% CI 0.99-1.03, P = 0.38), coronary heart disease (OR 1.02, 95% CI 1.00-1.04, P = 0.09) or peripheral artery disease (OR 1.02, 95%CI 0.99-1.05, P = 0.12) in the elderly patients after adjusting for the traditional risk factors of diabetic angiopathies. In contrast, the duration of diabetes showed a significant association with the prevalence of both diabetic micro- and macroangiopathies in the non-elderly patients. It should be noted that atherosclerotic diseases are present in the clinical setting for the management of elderly diabetic patients independent of the duration of diabetes. Geriatr Gerontol Int 2017; 17: 24-30.


Effort and cognition in schizophrenia patients.
The aim of this study was to determine whether low cognitive test scores in schizophrenia patients are due to insufficient effort and, if so, to what extent. Mental effort was measured with the Word Memory Test (WMT), an effort test that has been extensively validated. Schizophrenic patients (n=64), non-psychotic psychiatric patients (n=63), neurological controls (n=20), and normal controls (n=44) were tested with a neuropsychological test battery measuring memory, attention and executive functioning. The majority of the schizophrenia patients and a quarter of the psychiatric patients scored below the cut-offs for normal effort on the WMT. Scores on the effort test explained a significant amount of variance in the neuropsychological test performance of schizophrenic patients. This lends support to the notion that cognitive functioning in schizophrenia is compromised by insufficient effort. Furthermore, poor mental effort was related to negative symptoms. Poor mental effort might be considered a core symptom of schizophrenia, representing an executive, monitoring or motivational problem. Mental effort should be taken into consideration in the neuropsychological assessment of schizophrenic patients and of psychiatric patients in general. Controlling for this variable may have a considerable impact on research, assessment and treatment of cognitive disorders in schizophrenic patients.


Evaluation of the modified FINDRISC to identify individuals at high risk for diabetes among middle-aged white and black ARIC study participants.
To evaluate a modified Finnish Diabetes Risk Score (FINDRISC) for predicting the risk of incident diabetes among white and black middle-aged participants from the Atherosclerosis Risk in Communities (ARIC) study. We assessed 9754 ARIC cohort participants who were free of diabetes at baseline. Logistic regression and receiver operator characteristic (ROC) curves were used to evaluate a modified FINDRISC for predicting incident diabetes after 9 years of follow-up, overall and by race/gender group. The modified FINDRISC used comprised age, body mass index, waist circumference, blood pressure medication and family history. The mean FINDRISC (range, 2 [lowest risk] to 17 [highest risk]) for black women was higher (9.9 ± 3.6) than that for black men (7.6 ± 3.9), white women (8.0 ± 3.6) and white men (7.6 ± 3.5). The incidence of diabetes increased generally across deciles of FINDRISC for all 4 race/gender groups. ROC curve statistics for the FINDRISC showed the highest area under the curve for white women (0.77) and the lowest for black men (0.70). We used a modified FINDRISC to predict the 9-year risk of incident diabetes in a biracial US population. The modified risk score can be useful for early screening of incident diabetes in biracial populations, which may be helpful for early interventions to delay or prevent diabetes.


Effects of X-rays on cell membranes. II. Changes of permeability measured by fluorescein efflux.
The effect of irradiation on the permeability of cell membranes of L-929 cells was investigated. Efflux of fluorescein, accumulated by hydrolysis of fluoresceindiacetate in the cells, was measured using flow cytometry. The changes of rate constants for the permeation of florescein through the cell membrane at different temperatures and after various X-ray doses were studied. Decreasing temperatures yielded substantially slower efflux of fluorescein. After irradiation of cells, the rate constant of fluorescein efflux increased linearly with dose; 180 Gy are required to cause an increase by a factor of 2. The results are discussed with respect to radiation damage of active and passive transport mechanisms.


A dynamic approach to supply chain reconfiguration and ripple effect analysis in an epidemic.
The COVID-19 pandemic has illustrated the unprecedented challenges of ensuring the continuity of operations in a supply chain as suppliers' and their suppliers stop producing due the spread of infection, leading to a degradation of downstream customer service levels in a ripple effect. In this paper, we contextualize a dynamic approach and propose an optimal control model for supply chain reconfiguration and ripple effect analysis integrated with an epidemic dynamics model. We provide supply chain managers with the optimal choice over a planning horizon among subsets of interchangeable suppliers and corresponding orders; this will maximize demand satisfaction given their prices, lead times, exposure to infection, and upstream suppliers' risk exposure. Numerical illustrations show that our prescriptive forward-looking model can help reconfigure a supply chain and mitigate the ripple effect due to reduced production because of suppliers' infected workers. A risk aversion factor incorporates a measure of supplier risk exposure at the upstream echelons. We examine three scenarios: (a) infection limits the capacity of suppliers, (b) the pandemic recedes but not at the same pace for all suppliers, and (c) infection waves affect the capacity of some suppliers, while others are in a recovery phase. We illustrate through a case study how our model can be immediately deployed in manufacturing or retail supply chains since the data are readily accessible from suppliers and health authorities. This work opens new avenues for prescriptive models in operations management and the study of viable supply chains by combining optimal control and epidemiological models.


Ultrastructural identification and localization of climbing fiber terminals in the fastigial nucleus of the cat.
Following injections of 3H-leucine and 35S-methionine in the caudal half of the medial accessory olive, labeled climbing fibers were found contralateral to the injection site in the sagittal A-zone of the cerebellar vermis and in the fastigial nucleus. Labeling in the fastigial nucleus was analyzed with ultrastructural autoradiography. Labeled boutons of climbing fibers were found in the neuropil but never on somata. They contain spherical vesicles and occasionally some dense core vesicles in an electron-lucent matrix. The terminals of climbing fiber collaterals in the fastigial nucleus resemble climbing fiber terminals in the molecular layer with respect to their internal ultrastructural characteristics.


Surveillance of tobacco use among young adolescents: trends and predictors across three years in Sousse, Tunisia.
In developed countries, there was an overall decrease in tobacco use over the last decades. In Tunisia, a national strategy to reduce tobacco use was set up since 2008. However, this strategy was rarely evaluated. The objective of the current study was to examine the trends in tobacco use among the middle schoolchildren of the governorate of Sousse (Tunisia) between 2014 and 2016 and to determine predictors of its experimentation. Three cross-sectional studies were conducted in 2014, 2015 and 2016 school years among middle schoolchildren randomly selected from the governorate of Sousse-Tunisia. The required sample size for each study was 760 participants. Each year, the same procedure was used to recruit pupils from the same middle schools. The same pre-established and pre-tested questionnaire was self-administered anonymously to participants in their classrooms. Lifetime tobacco use rose from 11% in 2014 to 17.3% in 2016 (p = 0.001). Across the 3 years of survey, predictors of lifetime tobacco use were: The male sex (OR, 95% CI: 4.4 [3.2-6.1]), age above 13 (OR, 95% CI: 2.3 [1.7-3.1]), lifetime illicit substances use (OR, 95% CI: 3.9 [1.1- 13.8), lifetime inhalant products use (OR, 95% CI: 2.2 [1.2-4.3]), tobacco use among the father (OR, 95% CI: 2.2 [1.2-4.3]), tobacco use among siblings (OR, 95% CI: 1.7 [1.2-2.4]) and current anxiety symptoms (OR, 95% CI: 1.8 [1.4-2.4]). Lifetime tobacco use is in expansion among the young adolescents of Sousse. The current national tobacco prevention program should be strengthened and expanded to cover other substances use issues with emphasis on secondhand smoking and mental health problems.


Risk factors and associations with clinical outcomes of cytomegalovirus reactivation after haploidentical versus matched-sibling unmanipulated PBSCT in patients with hematologic malignancies.
In allogeneic hematopoietic stem cell transplantation recipients, cytomegalovirus (CMV) infection can cause overt CMV-associated disease, which is a main cause of transplantation-associated mortality. CMV infection correlates closely with donor's type. We therefore examined whether risk factors of CMV reactivation and clinical endpoints in patients with hematologic malignancies after allogeneic peripheral blood stem cell transplantation (PBSCT) differed between using matched-sibling donors (MSD-SCT) and haploidentical donors (HID-SCT). In this retrospective cohort study, we enrolled in 200 consecutive patients received an unmanipulated G-CSF-mobilized allogeneic PBSCT. Ninety (45%) patients received MSD-SCT and 110 (55%) received HID-SCT. Quantitative PCR was used for monitoring of CMV reactivation after transplantation. One-year cumulative incidence of CMV DNAemia was 55.0%, ranging from 23.5% in MSD-SCT group to 81.0% in HID-SCT group (p < 0.001). Although univariate analyses showed that non-myeloid malignancies, disease in complete remission status at transplantation, pretreatment with antithymocyte globulin, HLA-haploidentical donors, male donors, previous Epstein-Barr virus DNAemia, and absolute lymphocyte count on day 30 < 0.6 × 109/L were respectively associated with CMV reactivation after transplantation in total cohort of recipients (all p < 0.05), haploidentical donors were found to be the only independent predictor in multivariate analyses (Hazard ratio = 6.4, p < 0.001). Furthermore, univariate analyses revealed that non-myeloid malignancies and previous Epstein-Barr virus DNAemia were respectively associated with CMV reactivation in MSD-SCT recipients, and female was associated with CMV reactivation in HID-SCT recipients (all p < 0.05). In HID-SCT recipients, but not MSD-SCT recipients, previous CMV DNAemia was associated with a lower cumulative incidence of acute graft-versus-host disease (49.2% vs. 72.6%, p < 0.001). CMV DNAemia did not play a role in the relapse rate, but it was strongly associated with an increased risk of non-relapse mortality either in total cohort of recipients (30.5% vs. 13.7%; p = 0.003) or in the HID-SCT subgroup (36.0% vs. 16.7%; p = 0.030). Relapse-free survival and overall survival in total cohort of recipients with CMV DNAemia were both inferior to those without CMV DNAemia (45.3% vs. 57.6% and 54.8% vs. 65.8%, respectively; both p < 0.05). However, in subgroup analysis according to donor's type, neither relapse-free survival nor overall survival was impacted by CMV status (both p > 0.05). This study addressed differences in incidence, risk factors, and associations with clinical outcomes of CMV reactivation after haploidentical versus matched-sibling PBSCT.


Asbestos exposure indices.
The ability of inhaled asbestos to produce asbestosis, lung cancer, and mesothelioma in both humans and animals is well established, and asbestos exposures in the occupational and general community environment are recognized as significant hazards. However, it has not been possible to establish realistic and credible dose-response relationships, primarily because of our inability to define which constituents of the aerosols produce or initiate the pathological responses. It is generally acknowledged that the responses are associated with the fibers rather than the nonfibrous silicate mineral of the same chemical composition. Available data from experimental studies in animals exposed by injection and inhalation to fibers of defined size distributions are reviewed, alone with data from studies of fiber distributions in lungs of exposed humans in relation to the effects associated with the retained fibers. It is concluded that asbestosis is most closely related to the surface area of retained fibers, that mesothelioma is most closely associated with numbers of fibers longer than approximately 5 microns and thinner than approximately 0.1 micron, and that lung cancer is most closely associated with fibers longer than approximately 10 microns and thicker than approximately 0.15 micron. The implications of these conclusions on methods for fiber sampling and analyses are discussed.


Incidence of Unreliable Automated Computed Tomography Perfusion Maps.
Despite the increasing national adoption of automated computed tomography perfusion (CTP) to select thrombectomy patients 6 hours after last known well, reliability issues have been anecdotally reported. Unreliable diagnostic tests add time and confusion to a process that requires efficiency. Our study aims to critically assess an automated CTP program in a contemporary cohort of patients presenting with large vessel occlusion (LVO) in the extended time window by evaluating the rate of unreliable automated CTP maps and whether this influences clinical outcomes. A retrospective review of consecutive thrombectomy candidates undergoing CTP imaging in the extended time window was performed. All automated CTP maps using RAPID software (iSchemaView, Menlo Park, CA) were assessed for reliability. Clinical outcomes were compared between patients with and without reliable RAPID reports. Ninety-nine consecutive thrombectomy candidates underwent automated CTP imaging from February 2017 to December 2018. Of these, 78 (79%) had LVO determined by CT angiographyand were included in the study population. Automated CTP maps were unreliable in 13% of cases as a result of motion artifact (n = 3) and contrast bolus flow issues (n = 7). Heart failure was more frequent in patients with unreliable studies. Clinical outcomes did not significantly differ between patients with and without unreliable studies. Thirteen percent of CTP maps generated by automated software were unreliable, with an increased frequency among patients with heart failure. Given the rate of unreliable automated CTP maps, further studies are warranted to not only establish the true necessity of currently available CTP software, but also more reliable methods to select patients for thrombectomy presenting in the extended time window.


Basiparallel cut by pneumoencephalotomography and cerebellar atrophy.
The basiparallel cut is a nearly horizontal slice of the posterior fossa used in air study and the structures are observed on a plane parallel to the clivus. Total shrinkage of the cerebellum, with or without fourth ventricle dilatation, was found in cases of olivopontocerebellar atrophy, some intoxications, and a few senile subjects. Some atrophy of paleocerebellar portions was seen in Holmes-type degeneration. Another pattern was symmetric shrinkage of neocerebellar lobules and relatively specific for the cases of 'multiple system atrophy' such as progressive supranuclear palsy, striatonigral degeneration, Marie's ataxia, etc. Loss of the superior cerebellar peduncle was clearly demonstrated in this view.


Lack of correlation of immunosuppressive activity secreted by human in vitro fertilized (IVF) ova with successful pregnancy.
The high rate of implantation failure in humans following in vitro fertilization (IVF) has been attributed to a lack of production of immunosuppressive factors by cleaved embryos, rendering them vulnerable to maternal immune attack just before or around implantation. Systemic as well as blastocyst-secreted suppressor factors have been described and claimed to be responsible for successful pregnancy. Experimentally, we have screened in a double-blind fashion the suppressive activity of human embryo culture media (B2 Menezo system, France) in which zygotes after decoronization were individually cultured during 24 hr on lymphocyte proliferation as well as natural killer (NK) activity. Suppressive activity in media from cleaved and uncleaved ova did not differ significantly, and activity in media from transferred embryos was not correlated significantly with successful pregnancy. The implications of these data are discussed.


Micropercutaneous nephrolithotomy (microperc) in a two-year-old with the 'all-seeing needle'.
This paper presents the use of the single-step micropercutaneous nephrolithotomy (microperc) procedure for the treatment of a 13-mm renal stone using a 4.85-Fr 'all-seeing needle' in a 2-year-old toddler. In the current literature to date, this is the youngest case. Moreover, the advantages and reliability of this technique in toddler renal stone treatment are also evaluated.


Pan-Cancer Identification of Prognostic-Associated Metabolic Pathways.
Metabolic dysregulation has been reported involving in the clinical outcomes of multiple cancers. However, systematical identification of the impact of metabolic pathways on cancer prognosis is still lacking. Here, we performed a pan-cancer analysis of popular metabolic checkpoint genes and pathways with cancer prognosis by integrating information of clinical survival with gene expression and pathway activity in multiple cancer patients. By discarding the effects of age and sex, we revealed extensive and significant associations between the survival of cancer patients and the expression of metabolic checkpoint genes, as well as the activities of three primary metabolic pathways: amino acid metabolism, carbohydrate metabolism, lipid metabolism, and eight nonprimary metabolic pathways. Among multiple cancers, we found the survival of kidney renal clear cell carcinoma and low-grade glioma exhibit high metabolic dependence. Our work systematically assesses the impact of metabolic checkpoint genes and pathways on cancer prognosis, providing clues for further study of cancer diagnosis and therapy.


Effect of decreasing column inner diameter and use of off-line two-dimensional chromatography on metabolite detection in complex mixtures.
Capillary liquid chromatography coupled with electrospray ionization to a quadrupole ion trap mass spectrometer was explored as a method for the analysis of polar anionic compounds in complex metabolome mixtures. A ternary mobile phase gradient, consisting of aqueous acidic, aqueous neutral and organic phases in combination with an aqueous compatible reversed-phase stationary phase allowed metabolites with a wide range of polarities to be resolved and detected. Detection limits in the full scan mode for glycolysis and tricarboxylic acid cycle intermediates were from 0.9 to 36fmol. Using this system, 111+/-9 (n=3) metabolites were detected in Escherichia coli lysate samples. Reducing column I.D. from 50 to 25microm increased the number of metabolites detected to 156+/-17 (n=3). The improvement in number of metabolites detected was attributed to an increase in separation efficiency, an increase in sensitivity, and a decrease in adduct formation. Implementation of a second separation mode, strong anion exchange, to fractionate the sample prior to capillary RPLC increased the number of metabolites detected to 244+/-21 (n=3). This improvement was attributed to the increased peak capacity which decreased co-elution of molecules enabling more sensitive detection by mass spectrometry. This system was also applied to islets of Langerhans where more significant improvements in metabolite detection were observed. In islets, 391+/-33 small molecules were detected using the two-dimensional separation. The results demonstrate that column miniaturization and use of two-dimensional separations can yield a significant improvement in the coverage of the metabolome.


Anaerobic purinolytic enzymes enable dietary purine clearance by engineered gut bacteria.
Uric acid, the end product of purine degradation, causes hyperuricemia and gout, afflicting hundreds of millions of people. The debilitating effects of gout are exacerbated by dietary purine intake, and thus a potential therapeutic strategy is to enhance purine degradation in the gut microbiome. Aerobic purine degradation involves oxidative dearomatization of uric acid catalyzed by the O2-dependent uricase. The enzymes involved in purine degradation in strictly anaerobic bacteria remain unknown. Here we report the identification and characterization of these enzymes, which include four hydrolases belonging to different enzyme families, and a prenyl-flavin mononucleotide-dependent decarboxylase. Introduction of the first two hydrolases to Escherichia coli Nissle 1917 enabled its anaerobic growth on xanthine as the sole nitrogen source. Oral supplementation of these engineered probiotics ameliorated hyperuricemia in a Drosophila melanogaster model, including the formation of renal uric acid stones and a shortened lifespan, providing a route toward the development of purinolytic probiotics.


A study on the antibacterial property and biocompatibility of ramie fiber.
Ramie fiber (RF) has excellent tensile strength and breathability, making it a promising material for biomedical applications. However, few studies on the antibacterial properties and biocompatibility of RF have been reported. This study aimed to investigate the antibacterial property and biocompatibility of RF with bacteria and fibroblasts. The results showed that the antibacterial activity of RF was better than that of natural cotton fiber (NCF) and close to that of medical cotton fiber (MCF) for bothStaphylococcus aureus(S. aureus) andEscherichia coli(E.coli), and RF was more antibacterial againstS. aureusthanE.coli. The RF, MCF and NCF promoted the proliferation and spread of mouse fibroblast (L929) cells. The results indicated that RF has excellent antibacterial properties and biocompatibility, making it a potential biomaterial for biomedical applications.


Hemorrhage into fibrous dysplasia following minor head injury--effective decompression for the ophthalmic artery and optic nerve.
We performed an effective optic canal decompression in a patient with ethmoid and sphenoid fibrous dysplasia and visual impairment following minor head trauma. On admission, the patient's left visual acuity consisted only of light perception, and the left ophthalmic artery was not visible by angiography. A hematoma and fibrous dysplasia tissue in the sphenoid sinus were excised and the left optic canal was decompressed. The vision was markedly improved to an ability to count fingers in the following 2 weeks. The left ophthalmic artery was fully opacified in the postoperative angiogram.


Mice congenitally infected with low-to-moderate virulence Neospora caninum isolates exhibited clinical reactivation during the mating period without transmission to the next generation.
Endogenous transplacental transmission (EnTT) is the major transmission route of Neospora caninum in cattle. Thus, the development of a standardised experimental model of EnTT is needed for more appropriate testing of parasite biology and control strategies. A recent study reported up to 40-50% EnTT rates in chronically infected dams with either high or low-to-moderate virulence isolates, although low fertility rates were observed in dams inoculated with the high virulence isolate. Therefore, low-to-moderate virulence N. caninum isolates (Nc-Spain 3H; G1 and Nc-Spain 8; G2) that previously showed high TT rates versus low mortality and morbidity rates in a congenital mouse model were inoculated into BALB/c dams (first generation). The new approach followed in the present study aimed to start with a high number of congenitally infected mice (second generation), which allowed a more efficient EnTT from congenitally infected dams to their progeny (third generation). Interestingly, a reactivation of infection occurred in several congenitally infected non-pregnant females (second generation) from both infected groups. This fact was evidenced by neosporosis-associated clinical signs after mating accompanied by an increase of specific antibody levels (IgG1, IgG2a and specific antibodies against rNcGRA7) (P<0.0001; one-way ANOVA). Moreover, a higher number of PCR-positive mice compared to pregnant females were observed (P<0.05; Fisher's exact test). These results support the hypothesis that only mice without clinical signs and with a low parasite burden in the brain became pregnant, which may explain the posterior failure in inducing EnTT from the second to the third generation. These findings confirm that this mouse model is not a suitable experimental EnTT model for testing the efficacy of drugs and vaccine candidates against EnTT. The employment of other putative suitable species with a similar placenta structure, such as small ruminants, should be taken into consideration.


Antagonism of Paf-induced oedema formation in rabbit skin: a comparison of different antagonists.
1. Eight platelet activating factor (Paf) antagonists were evaluated as inhibitors of oedema formation in rabbit skin induced by intradermal injection of Paf plus prostaglandin E2 (PGE2). Antagonists were tested by both intradermal (i.d.) and intravenous (i.v.) routes. 2. Intradermal injection of two antagonists structurally-related to Paf (SRI 63-675 and CV-3988) resulted in a partial inhibition of Paf-induced oedema formation but at high doses of antagonist, marked agonist activities were detected. CV-3988 administered i.v. inhibited Paf-induced plasma leakage by 73-80%; however, oedema responses to a range of other inflammatory mediators were also reduced, albeit to a lesser extent (40-60%). SRI 63-675 administered i.v. did not significantly inhibit Paf-induced oedema. 3. The antagonist 48740 RP administered either i.d. or i.v. showed partial, but selective, inhibition of Paf-induced oedema formation, although the doses required were high when compared with other antagonists. 4. BN 52021 was a weak Paf antagonist when injected i.d., but following i.v. administration the responses to Paf were inhibited by 63-71%. Responses to all other mediators tested were unaffected. 5. Kadsurenone and its synthetic derivatives, L-652,731 and L-659,989 all blocked responses to Paf in the skin. L-659,989 was the most potent, achieving almost total inhibition when injected i.d. and i.v.; moreover, it was selective for Paf. L-652,731 was more potent than kadsurenone. 6. WEB 2086 given i.d. and i.v. showed similar activity to L-659,989 and it was also selective for Paf-induced oedema formation. 7. These results illustrate that in rabbit skin not all Paf antagonists are selective for Paf, some showing agonist-like activity which can mask antagonist properties. It is suggested that before ascribing a role for endogenous Paf in an inflammatory reaction based on results with antagonists, the activity of the antagonists in the model under investigation should be rigorously established.


PKC pathway associated with the expression of an A-type K+ channel induced by TGF-beta1 in rat vascular myofibroblasts.
Our previous study indicated that TGF-beta1 induced the expression of a transient outward K+ channel (A-type) during the phenotypic transformation of vascular fibroblasts to myofibroblasts. Here, we studied the relevant signal transduction pathway using whole cell recording and a quantitative RT-PCR technique. Results indicate that the protein kinase C (PKC) agonist phorbol-12-myristate-13-acetate (PMA, 1 microM) could mimic the effect of TGF-beta1 (20 ng/ml) on the expression of an A-type K+ channel and induced a similar A-type K+ current. Moreover, a PKC inhibitor, bisindolylmaleimide I (1 microM), could abrogate the effect of TGF-beta1 on K(V)4.2 expression. This result suggests that a PKC pathway may be involved in the expression of an A-type K+ channel induced by TGF-beta1 in rat vascular myofibroblasts.


Endoscopic Partial Proximal Hamstring Repair.
The contemporary treatment of hamstring avulsions has been evolving, as more patients are being identified as having persistently symptomatic partial hamstring tears recalcitrant to nonoperative treatment. The endoscopic hamstring repair allows surgeons improved visualization of the footprint, as well as safe dissection of the sciatic nerve. The present technique article provides a step-by-step technical note to allow for safe and effective surgical treatment of partial hamstring tears.


Implementation of oxide vertical channel TFTs with sub-150 nm channel length using atomic-layer deposited IGZO active and HfO2gate insulator.
We fabricated vertical channel thin film transistors (VTFTs) with a channel length of 130 nm using an ALD In-Ga-Zn-O (IGZO) active channel and high-k HfO2gate insulator layers. Solution-processed SiO2thin film, which exhibited an etch selectivity as high as 4.2 to drain electrode of indium-tin oxide, was introduced as a spacer material. For the formation of near-vertical sidewalls of the spacer patterns, the drain and spacer were successively patterned by means of two-step plasma etching technique using Ar/Cl2and Ar/CF4etch gas species, respectively. The SiO2spacer showed smooth surface morphology (Rq = 0.45 nm) and low leakage current component of 10-6A cm-2at 1 MV cm-1, which were suggested to be appropriate for working as spacer and back-channel. The fabricated VTFT showed sound transfer characteristics and negligible shifts in threshold voltage against the bias stresses of +5 and -5 V for 104s, even though there was abnormal increase in off-currents under the positive-bias stress due to the interactions between hydrogen-related defects and carriers. Despite the technical limitations of patterning process, our fabricated prototype IGZO VTFTs showed good operation stability even with an ultra-short channel length of 130 nm, demonstrating the potential of ALD IGZO thin film as an alternative channel for highly-scaled electronic devices.


Land use and food intake of future inhabitants: outlining a representative individual of the most exposed group for dose assessment.
The radiation doses to humans resulting from a potential release of radionuclides from a geological repository for long-lived waste are assessed over tens or even hundreds of thousands of years. Ingestion is expected to be the major exposure pathway, and the group with the highest exposures will be those that consume the most contaminated food. In this paper, we characterize the group of individuals with the highest exposures by considering the physical and biological characteristics of the contaminated area and human requirements for energy and nutrients. We then calculate intake rates based on land-use scenarios drawn from self-sustained communities spanning prehistoric times to an industrial-age agrarian culture. The approach is illustrated by simulating groundwater release of four radionuclides to an expected discharge area. We argue that the derived intake rates may serve as credible bounding cases when projected doses are evaluated for compliance with regulatory criteria.


First evidence of microplastic ingestion in the ocean giant sunfish (Mola mola).
Mola mola is the largest teleost inhabiting our ocean and the presence of microplastics (MP) in this flagship species was, before this study, never described. Thus, this investigation focused on analysing MP ingestion in 53 ocean giant sunfish in the Northeast Atlantic Ocean. A total of 116 MP were found in 79% of the specimens, with a median of 1 MP.ind-1, ranging from 0 to 11 MP.ind-1. Seasonal differences were observed, with more fibers registered in specimens caught in autumn. Among the different size classes observed, the smallest category (<300 μm) was the most frequent (43%). Blue (43%) was the most prevalent color, followed by green (29%) and black (10%). The majority of fragments were styrene acrylic copolymer (53%), while most fibers were rayon (78%). These findings emphasize that the ocean sunfish population crossing the southern waters of Portugal is exposed to microplastic pollution and highlight the need for effective management policies to address plastic pollution in marine ecosystems.


High TNF-alpha and IL-8 levels predict low blood dendritic cell counts in primary cytomegalovirus infection.
In vitro studies suggest that human cytomegalovirus (CMV) modulates the functions of dendritic cells (DCs). However, there are limited data on DC homeostasis in CMV-infected patients. The aim of this study was to characterize circulating DCs and plasma cytokine levels in immunocompetent patients with primary, symptomatic CMV infections. The study population consisted of 14 patients suffering of CMV mononucleosis and 14 healthy volunteers (11 CMV-seropositive and 3 CMV-seronegative subjects) included as controls. Peripheral blood mononuclear cells were isolated and used to characterize DCs and to quantify CMV in the blood. Plasma levels of pro-inflammatory and anti-inflammatory cytokines were also measured. We observed that patients who were developing CMV mononucleosis presented lower myeloid and plasmacytoid DC counts in peripheral blood compared with healthy controls. We also noted elevated levels of inflammatory mediators, of which tumor necrosis factor-α (TNF-α)-which activates DCs and endothelial cells-was the highest. Notably, the decrease in blood DCs correlated with high TNF-α and IL-8 levels by a hyperbolic function. Our results suggest that increased levels of inflammatory factors facilitate alterations in DC homeostasis during primary CMV infection, which may contribute to viral-induced modulation of host immunity.


Some aspects of size-dependent differential drug response in primary and metastatic tumors.
The response of cancer to various anticancer drugs is tumor-size dependent in many aspects. In general, problems stem partly from the fact that the entire tumor cell populations do not respond equally to a certain treatment. As a result of recent progress in cancer biology, it has become evident that cellular heterogeneity of the tumor underlies the difficulties of treating primary and metastatic tumors with chemotherapy. Moreover, as tumors grow, marked diversity develops on the tissue level as well. An uneven distribution with an increase of areas of lower growth fraction and of poorer drug delivery is more distinct in larger tumors. Heterogeneous distribution and low levels of tumor blood flow are considered to be causally related to the heterogeneous nature of tumor tissue. Considering the lack of evidence of a lymphatic system within the tumor, increased interstitial fluid pressure may be a natural result that further impedes blood flow in the tumor. The fact that the temporary and selective increase in tumor tissue blood flow by angiotensin-induced hypertension produces a remarkable chemotherapeutic effect should vividly indicate that delivery of the drug to the tumor is really the 'bottleneck' of cancer chemotherapy. Tumor-size-related change in the transvascular and extravascular transport of molecules and its relevance to chemotherapy are also discussed in this article.


Storing and interpreting genomic information in widely deployed electronic health record systems.
Electronic health record systems are in widespread use but currently have very limited genomic capabilities. Electronic health record systems are a logical place for patient genomic information to be stored and used for decision support and improvement of patient care. Genomic data and their automated interpretation are very challenging for electronic health record software development because they are substantially different than other kinds of electronic health record data and decision support. Those differences, the resulting challenges, and possible solutions are reviewed in this article.


Behaviour of energy metabolites and effect of allopurinol in the "stunned" isovolumic rat heart.
The pathogenesis of post-ischaemic depression of contractility in myocardium was examined in isovolumic rat heart. 31P-NMR was used to monitor changes in ATP, creatine phosphate (CrP), inorganic phosphate (Pi), and [H+] during brief periods of ischaemia and reperfusion with and without allopurinol treatment. During 5, 10, or 15 min of total global ischaemia, the decline in function (rate-pressure product) correlated inversely with [Pi] (r = 0.92, P less than 0.01). Cardiac function exhibited a slow progressive recovery during 20 min of reperfusion, ultimately reaching only 85%, 78%, and 69% of its pre-ischaemic value following 5, 10, and 15 min of global ischaemia respectively. Following each ischaemic period [ATP], [CrP], [Pi], and [H+] all recovered to control levels within 5-10 min of initiating reperfusion. Allopurinol (2 mM) treatment of hearts made ischaemic for 15 min significantly improved contractile recovery to 89 +/- 7%. Allopurinol also exhibited significant anti-arrhythmic activity during the reperfusion period, decreasing the incidence of premature contractions and the duration of tachy-arrhythmias. Allopurinol had no effect on the final repletion of [ATP] and [CrP], or the recovery of [Pi] and [H+], although the rate of ATP repletion was elevated in the initial 5 min of reperfusion. These results show that neither depletion of the cytosolic high-energy phosphate pool, nor sustained elevations in [Pi] or [H+] are important in the production of post-ischaemic contractile impairment. The beneficial action of allopurinol suggests that xanthine oxidase derived oxygen free-radicals may be involved in the sustained contractile dysfunction following brief ischaemic episodes.


Evaluation of Inhibition Efficiency for the Detection of Captan, 2,3,7,8-Tetrachlorodibenzodioxin, Pentachlorophenol and Carbosulfan in Water: An Electrochemical Approach.
A novel bio-analytical method has been devised based on the change in catalytic activity of acetylcholinesterase (AChE) enzyme induced by captan, carbosulfan, 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and pentachlorophenol (PCP) for the investigation of inhibition efficiency and sensitivity using Pt/ZnO/AChE/Chitosan bioelectrode. The inhibition curves of captan, carbosulfan, TCDD and PCP were similar to Michaelis-Menten curve. TCDD held the minimum inhibitor Michaelis-Menten constant ([Formula: see text]) value (10.2 nM) in comparison with PCP (10.9 nM), carbosulfan (14.5 nM) and captan (7.9 × 10(3) nM). The maximum inhibition of AChE enzyme by captan was about 100 %, which was much higher than that of TCDD (72.7 %), PCP (68.1 %) and carbosulfan (47.7 %). The calculated theoretical sensitivity was in the order of TCDD > PCP > carbosulfan > captan. Comparing with TCDD (35.3 %), PCP (47.8 %) and carbosulfan (20.9 %), only the inhibition efficiency of captan (55.0 %) was the maximum. The developed bioelectrode exhibited high recovery and low relative standard deviation in local tap water samples.