Stage and outcomes of invasive cervical cancer patients in Botswana: A prospective cohort study from 2013 to 2020.
To present the stage distribution, patterns of care, and outcomes of patients from Botswana with invasive cervical cancer, living with or without HIV. Between 2013 and 2020, women with cervical cancer were prospectively enrolled in an observational cohort study. A total of 1,043 patients were enrolled; 69% were women living with HIV. The median age of the cohort was 47 years (interquartile range [IQR] 40-58 years), with women living with HIV presenting at a younger age compared to women without HIV (44 versus 61 years, p < 0.001). Among women living with HIV, the median CD4 count at the time of cancer diagnosis was 429.5 cells/μL (IQR 240-619.5 cells/μL), 13% had a detectable viral load, and 95% were on antiretroviral therapy. In regard to treatment, 6% (n = 58) underwent surgery, 33% (n = 341) received radiation therapy, 51% (n = 531) received chemoradiation, and 7% (n = 76) did not receive treatment. Stage distribution in the cohort was as follows: I 17% (n = 173), II 37% (n = 388), III 35% (n = 368), and IV 8% (n = 88). For all patients, 2-year OS was 67%. In multivariable Cox regression, worse OS was associated with stage: II (HR 1.91, p = 0.007), III (HR 3.99, p < 0.001), and IV (HR 5.06, p < 0.001) compared to stage I. Improved OS was associated with hemoglobin > 10 g/dL (HR 0.51, p < 0.001) compared to Hb ≤ 10 g/dL. Among women in Botswana with cervical cancer, most patients presented with stage II or III disease warranting radiation therapy or chemoradiation. While two-thirds of cervical cancer patients were women living with HIV, HIV did not impact OS.


Vital capacity induction with 8% sevoflurane and N2o causes cerebral hyperemia.
Little is known about the influence of high-dose sevoflurane on cerebral volume. We evaluated induction time and cerebral blood volume with 8% sevoflurane using the "vital capacity induction" technique. Thirty-four patients were randomly allocated into three groups. Group P received 2.0 mg x kg(-1) of propofol i.v. and inhalation of 67% N2o/O2, whereas group S5 and group S8 received inhalation of primed 5% and 8% sevoflurane in 67% N2O/O2, respectively. Induction time was measured as the time from the start of inhalation, or from the end of injection, until loss of eyelash reflex. Near-infrared spectroscopy and bispectral index (BIS) were monitored continuously until 3 min after tracheal intubation. Induction time was less in group S8 (17.3 +/- 6.4s, mean +/- SD) than in groups P (25.7 +/- 8.2s) and S5 (33.0 +/- 16.8s). There was a significant increase in cerebral blood volume after intubation in group S8, as suggested by higher cerebral oxyhemoglobin and total hemoglobin levels. There were no differences in BIS scores among the groups during the study period. Vital capacity inhalation of 8% sevoflurane produces a faster loss of eyelash reflex than does 5% sevoflurane or propofol, but increases cerebral blood volume.


Exploring the Efficacy of an Online Intervention in Processing Experiences of Heterosexism Among Autistic-LGBQ + Individuals.
This experimental study explored the use of online expressive writing interventions to cope with distress from heterosexist events among a sample of autistic-LBGQ + individuals. This study included an open writing condition and an emotion focused therapy guided writing condition. Over 89% of the participants indicated that the writing exercises were helpful in processing the event, with significant decreases for measures of depressive and trauma/stressor symptoms. A thematic analysis identified specific aspects of each condition that were helpful for participants in coping with heterosexist distress, such as the development of insight through the emotion-focused exercises. This low-demand exercise is promising as a solo exercise or as a therapy homework assignment, especially given the accessibility of this online intervention for autistic-LGBQ + people.


Factor VIIa induces tissue factor-dependent up-regulation of interleukin-8 in a human keratinocyte line.
Tissue factor (TF), a transmembrane receptor for the serine protease coagulation factor VII(a) (FVIIa), is the main initiator of the coagulation cascade. Through incompletely elucidated mechanisms, TF serves additional functions in tumor-associated angiogenesis and metastasis. We have studied interleukin-8 (IL-8) as a possible link between TF-FVIIa complex formation and subsequent processes. Recombinant human FVIIa induced the up-regulation of both IL-8 mRNA and protein in a FVIIa dose- and time-dependent fashion. A neutralizing antibody to TF reduced this induction by 93 +/- 5%. Active site-inhibited FVIIa had no stimulatory effect and completely blocked that of FVIIa. This confirms that the increased IL-8 production was dependent on the formation of TF-FVIIa complexes and the proteolytic activity of FVIIa. The IL-8 promoter contains DNA binding sites for nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). In response to FVIIa, the DNA binding activity of both NF-kappaB and AP-1 was enhanced in an electrophoretic mobility shift assay. In addition, the IL-8 promoter was transcriptionally activated both in a luciferase reporter system and a nuclear run-off assay. Moreover, IL-8 mRNA stability was significantly enhanced by FVIIa-induced activation of the mitogen-activated protein kinases ERK1/2 and p38. Taken together, TF-FVIIa signaling induced increased transcription as well as mRNA stabilization leading to the significant up-regulation of IL-8 protein synthesis.


Modified platelet deposition on matrix metalloproteinase 13 digested collagen I.
Atherothrombosis underlies acute coronary syndromes, including unstable angina and acute myocardial infarction. Within the unstable plaque, monocytes express collagenolytic matrix metalloproteinases (MMPs), including MMP-13, which degrades fibrous collagen. Following rupture, vessel wall components including degraded collagen are exposed to circulating platelets. Platelet receptors then mediate the recruitment and activation of platelets to form a thrombus, blocking blood flow and resulting in myocardial infarction and sudden death. Here we aim to provide information on the effects of collagen degradation on platelet adhesion and thrombus formation. Using increasing concentrations of MMP-13, we induced progressive degradation of fibrous and monomeric collagen I, visualized by electrophoresis, and then investigated the capacity of the resulting fragments to support static platelet adhesion and thrombus formation in whole flowing blood. Both integrin and glycoprotein VI-dependent interactions with fibrous collagen underpin high levels of platelet adhesion under both conditions, with little obvious effect of MMP-13 treatment. Static platelet adhesion to monomeric collagen was strongly α2β1-dependent regardless of degradation status. Under flow conditions, partially degraded monomeric collagen supported increased thrombus deposition at 10 μg mL(-1) MMP-13, falling close to background when collagen degradation was complete (100 μg mL(-1) MMP-13). New binding activities come into play after partial digestion of collagen monomers, and net platelet-reactivity through all axes is abolished as degradation becomes more complete.


Targeting oxidative stress as a preventive and therapeutic approach for cardiovascular disease.
Cardiovascular diseases (CVDs) continue to exert a significant impact on global mortality rates, encompassing conditions like pulmonary arterial hypertension (PAH), atherosclerosis (AS), and myocardial infarction (MI). Oxidative stress (OS) plays a crucial role in the pathogenesis and advancement of CVDs, highlighting its significance as a contributing factor. Maintaining an equilibrium between reactive oxygen species (ROS) and antioxidant systems not only aids in mitigating oxidative stress but also confers protective benefits on cardiac health. Herbal monomers can inhibit OS in CVDs by activating multiple signaling pathways, such as increasing the activity of endogenous antioxidant systems and decreasing the level of ROS expression. Given the actions of herbal monomers to significantly protect the normal function of the heart and reduce the damage caused by OS to the organism. Hence, it is imperative to recognize the significance of herbal monomers as prospective therapeutic interventions for mitigating oxidative damage in CVDs. This paper aims to comprehensively review the origins and mechanisms underlying OS, elucidate the intricate association between CVDs and OS, and explore the therapeutic potential of antioxidant treatment utilizing herbal monomers. Furthermore, particular emphasis will be placed on examining the cardioprotective effects of herbal monomers by evaluating their impact on cardiac signaling pathways subsequent to treatment.


Biomimetic superhydrophobic metal/nonmetal surface manufactured by etching methods: A mini review.
As an emerging fringe science, bionics integrates the understanding of nature, imitation of nature, and surpassing nature in one aspect, and it organically combines the synergistic complementarity of function and structure-function integrated materials which is of great scientific interest. By imitating the microstructure of a natural biological surface, the bionic superhydrophobic surface prepared by human beings has the properties of self-cleaning, anti-icing, water collection, anti-corrosion and oil-water separation, and the preparation research methods are increasing. The preparation methods of superhydrophobic surface include vapor deposition, etching modification, sol-gel, template, electrostatic spinning, and electrostatic spraying, which can be applied to fields such as medical care, military industry, ship industry, and textile. The etching modification method can directly modify the substrate, so there is no need to worry about the adhesion between the coating and the substrate. The most obvious advantage of this method is that the obtained superhydrophobic surface is integrated with the substrate and has good stability and corrosion resistance. In this article, the different preparation methods of bionic superhydrophobic materials were summarized, especially the etching modification methods, we discussed the detailed classification, advantages, and disadvantages of these methods, and the future development direction of the field was prospected.


The effect of transcranial direct current stimulation on social cognition in schizophrenia: A preliminary study.
In this preliminary study, we examined the effect of transcranial direct current stimulation (tDCS) on social cognition in 36 individuals with schizophrenia. Participants received a baseline assessment and one week later received either anodal, cathodal, or sham tDCS, with 12 participants randomized to each condition. A single 20-minute session tDCS was administered bilaterally over the dorsolateral prefrontal cortex (centered at positions Fp1 and Fp2) at 2 mA. Among the 4 social cognitive tasks, participants showed a significant improvement on one of them, emotion identification, following anodal stimulation. Findings demonstrate the safety of this procedure and suggest potential therapeutic effects on one aspect of social cognition in schizophrenia.


The histone chaperone FACT facilitates heterochromatin spreading by regulating histone turnover and H3K9 methylation states.
Heterochromatin formation requires three distinct steps: nucleation, self-propagation (spreading) along the chromosome, and faithful maintenance after each replication cycle. Impeding any of those steps induces heterochromatin defects and improper gene expression. The essential histone chaperone FACT (facilitates chromatin transcription) has been implicated in heterochromatin silencing, but the mechanisms by which FACT engages in this process remain opaque. Here, we pinpoint its function to the heterochromatin spreading process in fission yeast. FACT impairment reduces nucleation-distal H3K9me3 and HP1/Swi6 accumulation at subtelomeres and derepresses genes in the vicinity of heterochromatin boundaries. FACT promotes spreading by repressing heterochromatic histone turnover, which is crucial for the H3K9me2 to me3 transition that enables spreading. FACT mutant spreading defects are suppressed by removal of the H3K9 methylation antagonist Epe1. Together, our study identifies FACT as a histone chaperone that promotes heterochromatin spreading and lends support to the model that regulated histone turnover controls the propagation of repressive methylation marks.


Skeletal muscle glycogen synthase activity in subjects with non-insulin-dependent diabetes mellitus after glyburide therapy.
Sulfonylureas are used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) largely because of their ability to enhance insulin secretion and possibly to potentiate insulin action. In this study, we investigated the effects of chronic glyburide treatment on glycogen synthase activity determined in skeletal muscle biopsies taken during euglycemic hyperinsulinemic clamps in nine Pima Indians with NIDDM. Insulin was infused at the rate of 40 mU/m2/min (low dose) followed by 400 mU/m2/min (high dose). Compared with the fasting value, the mean glycogen synthase activity assayed at low glucose-6-phosphate (G6P) concentration (active glycogen synthase) showed no significant changes during insulin infusion before glyburide treatment. After glyburide treatment, the mean active glycogen synthase increased by 39% (P less than .05) above the fasting value during the high-dose insulin infusion. Total glycogen synthase activity assayed at high G6P concentration did not change after glyburide treatment. Changes of insulin-stimulated active glycogen synthase associated with glyburide treatment correlated with changes in total body glucose disposal rates (r = .70, P less than .05) during euglycemic clamps. We conclude that glyburide treatment of subjects with NIDDM is associated with an increase in insulin action in vivo and concomitantly with improved insulin action on skeletal muscle glycogen synthase.


Environmental prevention of infection in stem cell transplant recipients: a survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.
The developments of peripheral blood stem cells in autologous hematopoietic stem cell transplantation (auto-HCT), and of reduced-intensity conditioning (RIC) regimens in allogeneic HCT (allo-HCT), have considerably changed the transplant approach. Prolonged neutropenia combined with severe mucosal damage and organ dysfunction is no longer the rule in the early post-HCT pancytopenic phase. Although strict isolation during pancytopenia was followed by most HCT units in the past, this may not be the current practice. In 2008, a questionnaire was sent out to the 463 European Group for Blood and Marrow Transplantation centers, enquiring about their current environmental protection procedures; 89 (20%) returned the questionnaire. Most centers housed auto-HCT recipients in high-efficiency particulate air (HEPA)-filtered rooms without (52%) or with laminar air flow (LAF) (29%) after total body irradiation (TBI), whereas HEPA-filtered rooms were used in 53% of auto-HCT conditioned without TBI. During the initial pancytopenic phase after allo-HCT, patients were housed in HEPA/LAF rooms in 50% and 42% of the centers, if a high-dose myeloablative conditioning regimen or a RIC regimen was used, respectively. Surprisingly, 8-24% of the centers reported that no isolation procedures were used in patients colonized or infected with highly transmissible pathogens (i.e., Clostridium difficile, respiratory viruses, and varicella zoster virus). In conclusion, universal recommendations for infected or colonized patients may be poorly known or applied in many HCT units.


Marine-derived sea urchin compounds as potential anti-cancer drug candidate against colorectal cancer: In silico and in vitro studies.
Sea urchin-derived compounds are potential candidates for the development of effective drugs for the treatment of cancer diseases. In this study, 19 compounds derived from sea urchin (Diadema savignyi) were used to treat colorectal cancer using the HCT116 cell line. However, molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamic (MD) simulation, and molecular mechanics generalized Born surface area (MM-GBSA) were used to confirm the ligand-protein interaction. Interactions of Importin-11 receptor with sea urchin compounds reveal that four compounds have higher binding affinities (ranging from -8.6 to -7.1 kcal/mol). In vitro testing revealed that the CID 6432458 compound was effective (docking score of -8.6 kcal/mol) against the HCT116 cell line. The cytotoxicity of HCT116 has been documented, with an IC50 value of 6.885 ± 4. MTT assay, apoptosis analysis, and cell cycle assay were utilized to examine cell death in colorectal cancer. In the MTT experiment, 15 µM and 20 µM dosages were associated with 77% cell death; however, flow cytometry analysis using the IC50 value revealed that the selected chemical induced greater apoptosis in the HCT116 cell line (58.5%). The gene expression data revealed that the apoptotic gene BAX is expressed at a higher level than the BCL-2 gene. The IPO11 gene was downregulated during treatment. In the experiment involving the cell cycle, the S phase for the 30 µM dose showed 75.1% apoptosis, which was greater than the other concentrations used alone. These in silico and in vitro analysis will not only provide new information about Importin-11 receptor and insight into colorectal cancer but will also facilitate the development of natural compounds in a significant and worthwhile manner.


Value of CTA/MRA in the setting of intraparenchymal hemorrhage in the emergency department.
To assess the diagnostic yield of computed tomography angiography (CTA)/magnetic resonance angiography (MRA) brain and neck ordered in the emergency department (ED) for patients who have intraparenchymal hemorrhage (IPH) on their initial noncontrast CT (NCCT) of the head. In this retrospective study, we reviewed 156 patients presenting to the ED with nontraumatic IPH, documented on NCCT. We assessed if the subsequent CTA/MRA was positive, and collected data regarding the location of the bleed, patients' age group, and presence/absence of associated SAH/IVH. Two neuroradiologists were asked to predict, based on age and NCCT appearance, whether the CTA/MRA would be positive or negative for demonstrating a vascular etiology of the hemorrhage. The yield of CTA/MRA head for patients above 75 years old was 2% (1/49), as the etiology for IPH in such age group was more commonly related to hypertensive bleed or amyloid angiopathy. The concomitant presence of subarachnoid hemorrhage (SAH) and intraventricular hemorrhage (IVH), particularly in patients younger than 75 years, correlated with a higher likelihood of a positive CTA. Statistically, the neuroradiologists were able to exclude a vascular source of the IPH based on CT appearance, bleed location, and patient's age in over 92% of cases. CTA/MRA for IPH has a lower yield in patients at older age and with deep gray matter distribution without SAH. Neuroradiologists were accurate at excluding a vascular source of the IPH in most cases. This study suggests that CTA/MRA can be omitted in certain scenarios, thereby preventing overutilization, and leading to optimal use of health care resources.


Gold nanostar-enhanced surface plasmon resonance biosensor based on carboxyl-functionalized graphene oxide.
A new high-sensitivity surface plasmon resonance (SPR) biosensor based on biofunctional gold nanostars (AuNSs) and carboxyl-functionalized graphene oxide (cGO) sheets was described. Compared with spherical gold nanoparticles (AuNPs), the anisotropic structure of AuNSs, which concentrates the electric charge density on its sharp tips, could enhance the local electromagnetic field and the electronic coupling effect significantly. cGO was obtained by a diazonium reaction of graphene oxide (GO) with 4-aminobenzoic acid. Compared with GO, cGO could immobilize more antibodies due to the abundant carboxylic groups on its surface. Testing results show that there are fairly large improvements in the analytical performance of the SPR biosensor using cGO/AuNSs-antigen conjugate, and the detection limit of the proposed biosensor is 0.0375 μg mL(-1), which is 32 times lower than that of graphene oxide-based biosensor.


Endoscopic cytology of cancer of the esophagus and cardia: a long-term evaluation.
Between January 1979 and December 1986, 858 endoscopic cytological examinations of the esophagus were performed, including 309 patients with confirmed malignancies. A positive cytological diagnosis of cancer was made in 289 (93.5%). Adequate biopsies were obtained in 269 instances (87.0%), being positive in 238 cases (overall positivity of biopsy, 77.02%). The combined use of biopsy and cytology provided a correct diagnosis in 98.0% of cases. The cytological examinations were positive in 30 of 40 patients (75.0%) with obstructing lesions in whom no satisfactory biopsies could be obtained. No false positive diagnosis was made among the 550 patients with benign conditions. In this series, cytology increased the yield of biopsy by 20.8%.


Basic reproduction number for the Brazilian Spotted Fever.
Brazilian Spotted Fever (BSF) is an emerging and lethal disease in South America which basic reproduction number (R0) is unknown. Calculating R0 for this disease is crucial to design control interventions and prevent human deaths. BSF endemic areas are related to the presence of capybaras Hydrochoerus hydrochaeris, amplifier hosts of Rickettsia rickettsii and primary hosts of the tick Amblyomma sculptum, main vector of the agent in this area. Because of the complexity of its dynamics, we calculated R0 for the BSF system by constructing a next-generation matrix considering different categories of vectors and hosts. Each matrix element was considered as the expected number of infected individuals of one category produced by a single infected individual of a second category. We used field and experimental data to parameterize the next-generation matrix and obtain the final calculation (R0 ≈ 1.7). We demonstrated the low impact of the matrix elements corresponding to the transovarial transmission and the transmission from infected larvae in the maintenance of R. rickettsii. Sensitivity and elasticity analyzes were performed to quantify the perturbations of each matrix element in R0. We noted that the elements equivalent to the number of infected attached nymphs produced by an infected capybara, and the number of infected capybaras produced by an infected attached nymph or adult are the major contributors to changes in R0. Our results provide insights into the strategic design of preventive interventions in BSF endemic areas.


Hodgkin's disease involving the large bowel.
A case is described in which Hodgkin's disease occurred in the descending colon and adjacent mesenteric nodes as the only site of relapse. This rare presentation is discussed, with a review of the available literature.


Breast cancer incidence and mortality before and after implementation of the German mammography screening program.
Effective population-based mammography screening should impact breast cancer (BC) incidence, age and stage-specific incidence and BC mortality. We aim to investigate such effects in a time period of 10 years after implementation of the German mammography screening program. Data on 323,719 breast cancer patients from 2003 to 2014 for defined regions covering a population of 30 million inhabitants and official mortality data from 1998 to 2016 for almost the whole of Germany were used. We compared incidence and mortality rates for the prescreening time period (2003/2004) and the latest available data (2013/2014 and 2015/2016, respectively) and performed trend analyses using joinpoint regression models. In the screening exposed age groups (50-59 and 60-69 years), BC incidence showed a typical prevalence peak with the introduction of the mammography screening, mainly driven by an increase of early-stage BC. For Stage III and IV BC incidence in 2013/2014 was 24.2 and 23.0% (age group 50-59 years) and 28.3 and 24.2% (age group 60-69 years) lower than in the prescreening period. From 2003/2004 to 2015/2016 BC mortality decreased by 25.8 and 21.2%, respectively. As corresponding trends in nonexposed age groups were distinctly unfavorable, the reduction of late-stage BC incidence and BC mortality in the screening exposed age groups in Germany is most likely to be attributed to the introduction of the national mammography screening program. These positive effects are bought at the cost of a moderate occurrence of overdiagnosis, especially by a sharp increase of in situ cancers.


15-Deoxy-delta12,14-prostaglandin J2, a neuroprotectant or a neurotoxicant?
15-Deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) is a potent ligand for peroxisome proliferators-activated receptor gamma (PPARgamma). However, its various effects independent of PPARgamma have recently been observed. The effect of 15d-PGJ2 on neuronal cells is still controversial. We investigated its effect on neuronal cells (N18D3 cells). When N18D3 cells were treated with 15d-PGJ2, the viability was not changed up to 8 microM, but decreased at higher than 8 microM. The expressions of survival signals, such as p85a phosphatidylinositol 3-kinase, phospho-Akt, and phospho-glycogen synthase kinase-3 beta (Ser-9), slightly increased up to 8 microM, however, decreased at higher than 8 microM. The levels of free radicals and membrane lipid peroxidation and the expression of c-Jun N-terminal Kinase increased in a dose-dependent manner, especially at higher than 8 microM. However, the expressions of death signals, such as cytosolic cytochrome c, activated caspase-3, and cleaved poly(ADP-ribose) polymerase, decreased up to 8 microM, however, increased at higher than 8 microM. In the study to evaluate whether low dose of 15d-PGJ2, up to 8 microM, had protective effect on oxidative stress-injured N18D3 cells, compared to the cells treated with only 100 microM H2O2, the pretreatment with 8 microM 15d-PGJ2 increased the viability and the expressions of the survival signals, but decreased them of the death signals. These results indicate that 15d-PGJ2 could be a neuroprotectant or a neurotoxicant, depending on its concentration. Therefore, some specific optimum dose of 15d-PGJ2 may be a new potential therapeutic candidate for oxidative stress-injury model of neurodegenerative diseases.


Effect of acute Yersinia enterocolitica infection on in vivo and in vitro small intestinal solute and fluid absorption in the rabbit.
The impact of acute Yersinia enterocolitica infection on jejunal and ileal solute and water transport was examined. New Zealand White rabbits (500-600 g) were infected with Y. enterocolitica and compared with unmanipulated controls and pair-fed controls. Transport studies were performed 6 days after infection on jejunum and ileum by an in vivo single-pass perfusion technique and in vitro under short-circuited conditions in Ussing chambers. When studied in vivo, Y. enterocolitica infection resulted in decreased water and electrolyte absorption in the jejunum under basal conditions and in both jejunum and ileum in the presence of glucose. Glucose absorption was also decreased in jejunum and ileum. When studied in vitro, net basal Na+ and Cl- transport was not altered in jejunal or ileal epithelium from infected animals. Glucose-stimulated Na+ absorption was decreased in ileal epithelium, and absorption of 3-O-methyl-D-glucose was decreased in both jejunum and ileum. Secretory capacity of Cl-, as assessed by isobutylmethyl xanthine stimulation, was unimpaired in both jejunum and ileum. Decreased food intake alone, in the pair-fed animals, had little effect on intestinal transport. The results indicate that malabsorption, rather than active intestinal secretion, is the major small intestinal transport defect in acute Y. enterocolitica infection. Furthermore, the abnormalities can be directly attributed to injury induced by the organism itself, rather than malnutrition.


Monitoring of fusarium toxins in cereals and feed-stuffs from thuringia (1998 - 2001).
From 1998 to 2001 a total of about 1172 conventionally and organically produced samples of wheat, rye, barley and triticale were examined for the presence of deoxynivalenol (DON) and zearalenone (ZON). Furthermore, feedstuffs for pigs were included in the monitoring of Fusarium toxins. DON and ZON analyses were performed using ELISA or HPLC. The incidences and levels of toxins varied from year to year. Overall contamination levels were highest in wheat and triticale, followed by rye and barley. The highest DON contaminations were found in 1998. The probes of the years 1999-2001 showed lower incidences of Fusarium toxins. The second examined mycotoxin ZON was detected at lower levels in cereals. Similar results were observed in the monitoring of feedstuffs.


Coverage of a carpal tunnel wound dehiscence with the abductor digiti minimi muscle flap.
A 41-year-old man who was taking 60 mg of prednisone a day for dermatomyositis developed a wound dehiscence following a carpal tunnel release and flexor tenosynovectomy. Coverage of the exposed carpal contents was provided by using the abductor digiti minimi as a local transposition flap.


Dutch nursing home policies and guidelines on physician-assisted death and decisions to forego treatment.
The purpose of this study was to describe: (a) the prevalence and content of policies on euthanasia or assisted suicide (EAS) in three different types of nursing homes; (b) specific content items of written guidelines for EAS; and (c) the prevalence of guidelines on withholding or withdrawing treatment from severely demented patients and patients in a persistent vegetative state in the nursing homes. Descriptive, cross-sectional. We have used a postal survey among directors of patient care of all (n = 304) Dutch somatic nursing homes (meant for physically handicapped patients), psychogeriatric nursing homes (meant for patients suffering from dementia) and combined nursing homes. Data were collected from October 1994 through January 1995. Results indicate that psychogeriatric nursing homes less often had a written EAS policy than somatic and combined nursing homes (62, 68 and 80% respectively). The most frequently reported aspects in the EAS guidelines, by the nursing homes with guidelines based on a policy that EAS was accepted under certain conditions; were consultation of another physician (97%), referral to another physician if the attending physician had in-principle objections (82%), and the involvement of the nurse in the decision-making procedure (82%). Of the nursing homes, 9% reported having specific written procedures concerning withholding or withdrawing treatment from severely demented patients. Guidelines in the nursing homes on euthanasia and assisted suicide might be improved. Especially with regard to withholding or withdrawing treatment from incompetent patients, more guidelines should be developed.


Frequency of Breakfast, Lunch, and Dinner and Incidence of Proteinuria: A Retrospective Cohort Study.
Although multiple studies have revealed a close association of skipping breakfast with cardiometabolic diseases, few studies have reported its association with chronic kidney disease (CKD). Furthermore, there is scant reporting on the clinical impacts that skipping lunch and dinner has on cardiometabolic diseases and CKD. This retrospective cohort study, including 5439 female and 4674 male workers of a national university in Japan who underwent annual health checkups between January 2005 and March 2013, aimed to assess an association of frequencies of breakfast, lunch, and dinner with incidence of proteinuria (dipstick urinary protein ≥1+). The incidence of proteinuria was observed in 763 (14.0%) females and 617 (13.2%) males during the median 4.3 and 5.9 years of the observational period, respectively. In females, skipping breakfast as well as skipping dinner, but not lunch, were associated with the incidence of proteinuria (adjusted hazard ratios of breakfast frequency of "every day", "sometimes", and "rarely": 1.00 (reference), 1.35 (1.09-1.66), and 1.54 (1.22-1.94), respectively; those of dinner frequency of "every day" and "≤sometimes": 1.00 (reference) and 1.31 (1.00-1.72), respectively). However, no association was observed in male workers. Skipping breakfast and skipping dinner were identified as risk factors of proteinuria in females, but not in males.


Cost-effectiveness of future lockdown policies against the COVID-19 pandemic.
While the European Union (EU) has approved several COVID-19 vaccines, new variants of concern may be able to escape immunity. The purpose of this study is to project the cost-effectiveness of future lockdown policies in conjunction with a variant-adapted vaccine booster. The exemplary scenario foresees a 25% decline in the vaccine protection against severe disease. A decision model was constructed using, for example, information on age-specific fatality rates, intensive care unit (ICU) costs and outcomes, and herd protection threshold. The costs and benefits of a future lockdown strategy were determined from a societal viewpoint under three future scenarios-a booster shot's efficacy of 0%, 50%, and 95%. The cost-effectiveness ratio of a lockdown policy in conjunction with a booster dose with 95% efficacy is €44,214 per life year gained. A lockdown is cost-effective when the probability of approving a booster dose with 95% efficacy is at least 48% (76% when considering uncertainty in input factors). In this exemplary scenario, a future lockdown policy appears to be cost-effective if the probability of approving a variant-adapted vaccine booster with an efficacy of 95% is at least 48%.


A novel hybrid evaluation framework for public organizations based on employees' performance factors.
Performance evaluation is a comprehensive process for comparing activities compared with predetermined organizational criteria. Based on the results of performance evaluation, organizations can embark on purposeful actions to improve their situation. Obviously, the success of organizations and the economic development of the country depend on the performance of human resources (HR). This paper proposes a novel hybrid evaluation framework for analyzing the performance of public sector organizations. The suggested setting allows for performance evaluation based on a comprehensive approach involving expert knowledge. For this purpose, the research integrates the Balanced Scorecard (BSC) approach and fuzzy multi-criteria decision-making (MCDM) methods. Initially, the employees' performance factors (criteria) are identified from the literature based on the BSC dimensions. Then, the most relevant of them are finalized through the fuzzy Delphi method (FDM) questionnaires and experts' opinions. In the second stage, the weights of criteria are determined by adopting the fuzzy best-worst method (FBWM). Moreover, two fuzzy MCDM techniques, namely VIKOR and Grey Relational Analysis (GRA), are used to examine the performance of the eight important public sector organizations of Iran. Finally, a Monte Carlo simulation-based (MCSB) approach and a scenario-based (SCB) approach are applied to compare the effectiveness of fuzzy VIKOR and fuzzy GRA. The results suggest that the critical employees' performance factors include sharing knowledge with colleagues (0.136), optimal use of facilities (0.123) and participation in solving organizational issues (0.118). Additionally, based on the implemented sensitivity analysis approaches, fuzzy VIKOR generates more reliable results and also has higher robustness than fuzzy GRA.


Specific lysis of antigenically irrelevant cells by cytotoxic T lymphocytes upon insertion of appropriate antigens into the target cell plasma membranes.
The importance of the membrane milieu to functional presentation of target cell (TC) antigens to cytotoxic T lymphocytes (CTL) was investigated by examining the interaction of CTL with TC plasma membrane (PM) fractions, in isolated form or integrated into antigenically irrelevant TC. Isolated ascitic vesicles, microsomes, and purified PM, containing serologically defined alloantigens that have been implicated as the relevant TC antigens, effectively, yet nonspecifically, inhibited the binding and lysis of TC by CTL. The same PM fractions, when inserted into antigenically irrelevant TC via vesicles containing Sendai virus components, rendered the TC susceptible to CTL-mediated lysis directed against the inserted antigens. These findings suggest that CTL interact specifically with TC determinants only when they are embedded in the proper membrane environment.


Effects of T-2 toxin and its congeners on membrane functions of cultured human fibroblasts.
Cytotoxicity of T-2 toxin, HT-2 toxin, acetyl T-2, neosolaniol, and T-2 tetraol was compared between normal human fibroblasts and mutant I-cell human fibroblasts, which only produce 10 to 15% of lysosomal hydrolases present in normal fibroblasts. Both cleavage of 3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and cell count by hemocytometer were used for evaluations. For all toxins, dose-related effects on both types of cultures were evident. Cytotoxicity of the above mycotoxins on both cell lines were similar, indicating that lysosomal enzymes were not involved in the toxicity of T-2 toxin and its congeners. An inhibitor of lysosomal cysteine proteases (E-64) did not alter the cytotoxicity of T-2 toxin. The decreasing order of toxicity was T-2 toxin, HT-2 toxin, neosolaniol, acetyl T-2 toxin, and T-2 tetraol in both cell lines. When normal human fibroblasts were loaded with the fluorescent dye Lucifer yellow CH (LY), a subsequent treatment of T-2 toxin did not disrupt lysosomal membranes. The uptake of LY was not affected by T-2 toxin, which indicated that T-2 toxin did not interfere with the endocytic pathway. Results indicate that T-2 toxin and its congeners do not exert their primary toxic effect through lysosomal enzymes, membranes, or via the endocytic pathway.


Radiofrequency ablation versus laparoscopic hepatectomy for hepatocellular carcinoma: A real world single center study.
Both radiofrequency ablation (RFA) and laparoscopic hepatectomy (LH) are minimally invasive approach for hepatocellular carcinoma (HCC) at early stage. This study aimed to compare the efficacy of RFA and LH for treating HCC with a large cohort. From March 2014 to July 2016, 477 patients who underwent RFA (n = 314) or LH (n = 163) for HCC tumors meeting the criteria were included. Overall survival (OS) and recurrence-free survival (RFS) were compared. Propensity score matching (PSM) was performed to balance for the factors that may affect the choice of treatment. Collectively, the 1-, 2- and 3-year OS rates were significantly greater after LH than RFA, as well the corresponding RFS rates, before and after PSM by 2:1. However, the RFA group had fewer major complications (P=0.004), shorter postoperative stays (P=0.023) and lower hospital charges (P<0.001) than the LH group. In the subgroup analysis, RFA demonstrated comparable RFS in treating less than 3 cm tumor (P=0.22) located in noncentral bisection (SII, SIII, SVI, SVII) and tumor between 3 cm and 5 cm (P=0.07) located in central bisections (SIV, SV, SVIII). The female, HBV infection, and RFA are factors of worse OS, and the latter two factors also indicated higher RFS. Though, LH possessed superior intrahepatic control rate than RFA in most condition of tumor smaller than 5 cm, the RFA could be an optimal approach achieved comparable outcomes in patients with centrally located HCC, with fewer major complications, shorter postoperative stays and lower hospital charges.


Use of NSAIDs and infection with Helicobacter pylori--what does the rheumatologist need to know?
NSAID-induced gastroduodenal lesions are a frequent and potentially serious health problem in patients with rheumatic diseases. Helicobacter pylori (H. pylori) has also been recognized as a major risk factor for the development of ulcer disease. However, the role of H. pylori in the pathogenesis of NSAID-induced gastroduodenal lesions has remained controversial, and there is currently no clear consensus on the management of NSAID users who are infected with H. pylori. To clarify this situation we have performed a systematic literature search to find randomized controlled trials comparing the efficacy of eradication in patients receiving NSAIDs to prevent ulcer development. Seven randomized controlled trials and one meta-analysis were identified. There were three papers on NSAID-naive patients. According to this data, NSAID-naive users benefit from testing for H. pylori infection and subsequent H. pylori eradication therapy prior to the initiation of NSAID. In contrast, H. pylori eradication alone does not protect chronic NSAID users with recent ulcer complications from further gastrointestinal (GI) events. To prevent recurrent ulcer bleeding long-term acid suppressive therapy is needed. In conclusion, ulcer risk reduction after H. pylori eradication therapy is clearly more marked in patients beginning NSAID therapy than in patients who were already receiving and tolerating NSAID therapy. Thus, the management of H. pylori infection and the prevention of GI complications in NSAID users need to be individualized on the basis of recently published data.


High-performance liquid chromatographic assay for mitoxantrone in plasma using electrochemical detection.
A sensitive and specific high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of mitoxantrone in plasma using electrochemical detection. Bisantrene was chosen as the internal standard. A reversed-phase, 10-microns muBondapak C18 analytical column (30 cm X 3.9 mm) with an isocratic mobile phase of 28% acetonitrile in 80 mM sodium formate buffer (pH 3.0) was used. The eluent was monitored by both electrochemical detection at an applied potential of +0.75 V vs. Ag/AgCl and visible absorbance at 660 nm. Only electrochemical detection was able to quantitate the internal standard and provided ten times higher sensitivity than visible absorbance for mitoxantrone with a detection limit as low as 0.1 ng/ml. Calibration curves in the range 0.1-1000 ng/ml showed good linearity (r = 0.998) and precision (coefficient of variation less than 10%). This HPLC method utilized a reproducible and inexpensive liquid-liquid extraction procedure. Using methylene chloride, the extraction efficacy of mitoxantrone from plasma was 85.3% with a coefficient of variation less than 2.1%. This new assay was then applied to measure mitoxantrone concentrations in plasma obtained from two leukemic patients receiving 12 mg/m2 mitoxantrone as a 1-h infusion.


Determination of neomycin and related substances in pharmaceutical preparations by reversed-phase high performance liquid chromatography with mass spectrometry and charged aerosol detection.
A new, simple and repeatable liquid chromatographic method with charged aerosol detection (LC-CAD) for determination of neomycin and related substances has been developed. Analysis of neomycin or other aminoglycosides is problematic due to a lack of chromophores. Universal response of CAD enables direct quantification of neomycin and related substances, for which no reference standard are available. Separation was performed on C18 Hypersil(®) Gold aQ column using water, methanol and heptaflurobutyric acid as mobile phase. Under developed chromatographic conditions all impurities were well separated from neomycin B. Peaks identification was evaluated by electrospray ionization mass spectrometry. The proposed method was validated according to ICH guidelines and applied to the content determination of neomycin and related substances in pharmaceutical preparations.


A synthetic peptide encompassing the G5 antigenic region of the rabies virus induces high avidity but poorly neutralizing antibody in immunized animals.
The immunization of goats with a synthetic peptide encompassing the G5 antigenic site of the rabies virus surface glycoprotein induces a strong humoral immune response in the absence of a carrier protein. The immunized animals mounted high antibody titers and showed a strong avidity maturation of the B cell immune response to both the G5-peptide and purified surface glycoprotein G. This antibody weakly neutralized rabies virus carrying the G5 epitope but failed to neutralize escape mutants carrying a single point mutation in this epitope. A putative T helper cell epitope, functional in the context of different caprine MHC haplotypes, was identified by structure analysis of the G5-peptide. This striking dichotomy between high titers and antibody of high avidity to the glycoprotein G and poor neutralizing activity strongly suggests that antibody binding assays such as ELISA cannot always reliably predict the neutralizing activity of sera as measured in functional assays.


Quality assessment of Clinical Practice Guidelines (CPG) for the diagnosis and treatment of inflammatory bowel disease using the AGREE II instrument: a systematic review.
The incidence and diagnosis of inflammatory bowel disease (IBD) has increased considerably in recent years. Many clinical practice guidelines (CPG) have been developed for the management of this disease across different clinical contexts, however, little evidence exists on their methodological quality. Therefore, we aimed to systematically evaluate the quality of CPGs for the diagnosis and treatment of IBD using the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument. We identified CPGs by searching databases (MEDLINE - PubMed, EMBASE, CINAHL, LILACS) and other sources of gray literature on January 2022. We included guidelines with specific recommendations for the diagnosis and treatment of IBD and evaluated them with the AGREE II instrument to assess their methodological quality. Six independent reviewers assessed the quality of the guidelines and resolved conflicts by consensus. We assessed the degree of agreement using the intraclass correlation coefficient (ICC) and change in quality over time was appraised in two periods: from 2012 to 2017 and from 2018 to 2022. We analyzed and evaluated 26 CPGs that met the inclusion criteria. The overall agreement among reviewers was moderate (ICC: 0.74; 95% CI 0.36 - 0.89). The mean scores of the AGREE II domains were: "Scope and purpose" 84.51%, "Stakeholder involvement" 60.90%, "Rigor of development" 69.95%, "Clarity of presentation" 85.58%, "Applicability" 26.60%, and "Editorial independence" 62.02%. No changes in quality were found over time. The quality of the CPGs evaluated was generally good, with a large majority of the assessed guidelines being "recommended" and "recommended with modifications"; despite this, there is still room for improvement, especially in terms of stakeholder involvement and applicability. Efforts to develop high quality CPGs for IBD need to be further optimized.


Cardiovascular nuclear medicine: an overview.
Some of the available cardiovascular nuclear medicine methods are incompletely validated, and others are incompletely developed. They are, however, of very great potential in diagnostic cardiology, and in patient management. A new era of clinical research and acute care monitoring has been opened by serial, noninvasive, hemodynamic measurements of right ventricular as well as left ventricular function. Stress testing has become more specific, and should, with future developments, become more specific, and should, with future developments, become more sensitive, using radionuclide procedures. Serious quality control and validation questions concerning thallium stress testing must be addressed. Intracoronary injection of radiogases has great potential, although minimal present application. Emission computerized tomography will be an important research tool. Compartmental analysis modeling of first pass tracer injections has much to offer, but is not yet validated. Present growth rate of these procedures is very rapid. Fully developed, cardiovascular nuclear medicine may become the largest component of clinical nuclear medicine practice.


Cardiac-specific disruption of Bin1 in mice enables a model of stress- and age-associated dilated cardiomyopathy.
Non-compensated dilated cardiomyopathy (DCM) leading to death from heart failure is rising rapidly in developed countries due to aging demographics, and there is a need for informative preclinical models to guide the development of effective therapeutic strategies to prevent or delay disease onset. In this study, we describe a novel model of heart failure based on cardiac-specific deletion of the prototypical mammalian BAR adapter-encoding gene Bin1, a modifier of age-associated disease. Bin1 deletion during embryonic development causes hypertrophic cardiomyopathy and neonatal lethality, but there is little information on how Bin1 affects cardiac function in adult animals. Here we report that cardiomyocyte-specific loss of Bin1 causes age-associated dilated cardiomyopathy (DCM) beginning by 8-10 months of age. Echocardiographic analysis showed that Bin1 loss caused a 45% reduction in ejection fraction during aging. Younger animals rapidly developed DCM if cardiac pressure overload was created by transverse aortic constriction. Heterozygotes exhibited an intermediate phenotype indicating Bin1 is haplo-insufficient to sustain normal heart function. Bin1 loss increased left ventricle (LV) volume and diameter during aging, but it did not alter LV volume or diameter in hearts from heterozygous mice nor did it affect LV mass. Bin1 loss increased interstitial fibrosis and mislocalization of the voltage-dependent calcium channel Cav 1.2, and the lipid raft scaffold protein caveolin-3, which normally complexes with Bin1 and Cav 1.2 in cardiomyocyte membranes. Our findings show how cardiac deficiency in Bin1 function causes age- and stress-associated heart failure, and they establish a new preclinical model of this terminal cardiac disease.


Advagraf(®) , a once-daily prolonged release tacrolimus formulation, in kidney transplantation: literature review and guidelines from a panel of experts.
The efficacy and safety of tacrolimus twice-a-day (BID) and once-a-day (QD) formulations are similar. However, the available information regarding the initiation and management of tacrolimus QD is sparse and practical information is lacking. A panel of French experts extensively reviewed the available literature on tacrolimus pharmacokinetics, clinical efficacy, and safety in kidney transplantation and, based on their own day-to-day experience, provided the practitioners with practical guidelines for the daily use and management of tacrolimus QD in de novo initiation or early conversion.


Pharmacometrics: The Already-Present Future of Precision Pharmacology.
The use of mathematical modeling to represent, analyze, make predictions or providing information on data obtained in drug research and development has made pharmacometrics an area of great prominence and importance. The main purpose of pharmacometrics is to provide information relevant to the search for efficacy and safety improvements in pharmacotherapy. Regulatory agencies have adopted pharmacometrics analysis to justify their regulatory decisions, making those decisions more efficient. Demand for specialists trained in the field is therefore growing. In this review, we describe the meaning, history, and development of pharmacometrics, analyzing the challenges faced in the training of professionals. Examples of applications in current use, perspectives for the future, and the importance of pharmacometrics for the development and growth of precision pharmacology are also presented.


Effects of concentric and repeated eccentric exercise on muscle damage and calpain-calpastatin gene expression in human skeletal muscle.
The purpose of this study was to compare the responsiveness of changes in Ca(2+)-content and calpain-calpastatin gene expression to concentric and eccentric single-bout and repeated exercise. An exercise group (n = 14) performed two bouts of bench-stepping exercise with 8 weeks between exercise bouts, and was compared to a control-group (n = 6). Muscle strength and soreness and plasma creatine kinase and myoglobin were measured before and during 7 days following exercise bouts. Muscle biopsies were collected from m. vastus lateralis of both legs prior to and at 3, 24 h and 7 days after exercise and quantified for muscle Ca(2+)-content and mRNA levels for calpain isoforms and calpastatin. Exercise reduced muscle strength and increased muscle soreness predominantly in the eccentric leg (P < 0.05). These responses as well as plasma levels of creatine kinase and myoglobin were all attenuated after the repeated eccentric exercise bout (P < 0.05). Total muscle Ca(2+)-content did not differ between interventions. mRNA levels for calpain 2 and calpastatin were upregulated exclusively by eccentric exercise 24 h post-exercise (P < 0.05), with no alteration in expression between bouts. Calpain 1 and calpain 3 mRNA did not change at any specific time point post-exercise for either intervention. Our mRNA results suggest a regulation on the calpain-calpastatin expression response to muscle damaging eccentric exercise, but not concentric exercise. Although a repeated bout effect was demonstrated in terms of muscle function, no immediate support was provided to suggest that regulation of expression of specific system components is involved in the repeated bout adaptation.


Ipsative vs normative interpretation of test scores: a comment on Allen and Foreman's (1976) norms on Edwards Personal Preference Schedule for female Australian therapy students.
A brief review of the literature relating to intra- vs interindividual personality assessment and the lack of logical support for the calculation of T scores using intraindividual data. It concludes with a caution regarding the interpretation of WAIS and MMPI personal profiles which are derived from interindividual scaled scores.


Population pharmacokinetics of piperacillin in critically ill children including those undergoing continuous kidney replacement therapy.
Despite that piperacillin-tazobactam combination is commonly used in critically ill children, increasing evidence suggests that the current dosing schedules are not optimal for these patients. The aim of this work is to develop a population pharmacokinetic model for piperacillin to evaluate the efficacy of standard dosing in children with and without continuous kidney replacement therapy (CKRT) and to propose alternative dosing schemes maximizing target attainment. Four hundred twenty-nine piperacillin concentrations measured in different matrices, obtained from 32 critically ill children (19 without CKRT, 13 with CKRT) receiving 100 mg/kg of piperacillin/tazobactam every 8 hours (increased to 12 hours after the fourth dose) were modelled simultaneously using the population approach with NONMEM 7.4. The percentage of patients with 90% fT > MIC and target attainment (percentage of dosing interval above MIC) were estimated for different intermittent and continuous infusions in the studied population. Piperacillin pharmacokinetic was best described with a two-compartment model. Renal, nonrenal, and hemofilter clearances were found to be influenced by the glomerular filtration rate, height (renal clearance), weight (nonrenal clearance), and filter surface (hemofilter clearance). Only seven (37%) children without CKRT and seven (54%) with CKRT achieved 90% fT > MIC with the current dosing schedule. Of the alternative regimens evaluated, a 24-hour continuous infusion of 200 mg/kg (CKRT) and 300 mg/kg (no CKRT) provided 100% fT > MIC (percent of time free drug remains above the minimum inhibitory concentration) (≤16 mg/L) and target attainments ≥90% across all evaluated MICs. In children with and without CKRT, standard dosing failed to provide an adequate systemic exposure, while prolonged and continuous infusions showed an improved efficacy.


Consumption of an omega-3 fatty acids product, INCELL AAFA, reduced side-effects of CPT-11 (irinotecan) in mice.
INCELL AAFA, an omega-3 polyunsaturated fatty acid product containing a high concentration of long chain fatty acids, was tested for its ability to ameliorate the harmful side effects of CPT-11 chemotherapy including: leukopenia, anaemia, asthenia, weight loss and liver involvement. Four groups of mice were fed an AIN-76 diet modified to contain: 10% w/w corn oil (CO), 0% AAFA; 9% CO, 1% AAFA; 8% CO, 2% AAFA; or 7% CO, 3% AAFA. After 2 weeks on the diets, half of the mice received CPT-11 chemotherapy (60 mg kg(-1) q 4 days, i.v.) the rest of the mice received vehicle for 2 weeks. It was found that 2% AAFA in the diet of the CPT-11 treated mice: decreased apoptotic figures in the duodenal crypts; markedly suppressed the inflammatory eicosanoid, prostaglandin E(2) in the liver; prevented liver hypertrophy; improved white blood cell counts; significantly increased red blood cell counts; decreased numbers of CPT-11 induced immature red blood cell and micronuclei in red blood cells of the peripheral blood; increased eicosapentaenoic acid and docosahexaenoic acid in liver cell membranes and maintained normal grooming behaviour. Thus 2% AAFA in the diet reduced the side effects of CPT-11 treatment in mice.


Suppressing molecular motions for enhanced room-temperature phosphorescence of metal-free organic materials.
Metal-free organic phosphorescent materials are attractive alternatives to the predominantly used organometallic phosphors but are generally dimmer and are relatively rare, as, without heavy-metal atoms, spin-orbit coupling is less efficient and phosphorescence usually cannot compete with radiationless relaxation processes. Here we present a general design rule and a method to effectively reduce radiationless transitions and hence greatly enhance phosphorescence efficiency of metal-free organic materials in a variety of amorphous polymer matrices, based on the restriction of molecular motions in the proximity of embedded phosphors. Covalent cross-linking between phosphors and polymer matrices via Diels-Alder click chemistry is devised as a method. A sharp increase in phosphorescence quantum efficiency is observed in a variety of polymer matrices with this method, which is ca. two to five times higher than that of phosphor-doped polymer systems having no such covalent linkage.


Feasibility of robot-assisted modified radical neck dissection by post-auricular facelift approach.
The aim of this study was to evaluate the technical feasibility and safety of robot-assisted modified radical neck dissection (MRND) for head and neck cancer patients with a clinically node-positive neck. The cases of 10 head and neck cancer patients who underwent unilateral therapeutic robot-assisted MRND by post-auricular facelift approach were analyzed. The robot-assisted MRND was completed successfully in all patients without any conversion to conventional neck dissection. The mean number of lymph nodes removed was 36.7±8.6. The mean duration of surgery for robot-assisted MRND was 274±65min (range 175-395min). Transient marginal nerve palsy occurred in two patients and partial necrosis of the skin flap occurred in one patient. In terms of cosmetic satisfaction, 70% of patients were very satisfied or satisfied with postoperative cosmesis. In conclusion, robot-assisted MRND by post-auricular facelift approach is technically feasible and safe in selected patients with head and neck cancer, and yields excellent postoperative cosmesis.


Applications and limitations of laser-assisted angioplasty.
Laser-assisted angioplasty is rapidly evolving into a promising adjunct to or replacement for standard vascular procedures. A protocol was devised to evaluate the technique in a non-selected, consecutive patient population to define the applications and limitations of the technique. In a 12-month period, 358 lower-limb atherosclerotic lesions were treated with laser/balloon angioplasty [percutaneously (52%) or open (48%)] in 206 consecutive patients. Overall, the laser/balloon technique recanalised 234 lesions (65% laser success), judged clinically effective by a greater than 0.15 improvement in the ankle/brachial index and elimination of symptoms. Operative complications included: perforation (15, 4.2%); thrombosis (16, 4.5%); spasm (5, 1.4%); and false aneurysm at the puncture site (7, 2.0%). Of the 124 failures (35%) categorised for analysis, the most common cause was inability to cross the lesion in 20 cases. This experience has identified three significant clinical limitations to successful laser recanalisation: calcification, inadequate distal circulation, and inability to control restenosis/reocclusion (collapsible lesions and accelerated plaque deposition). Further research is needed to determine if thermal injury seriously compromises the safety and long-term outcome of laser-assisted angioplasty.


Occult-blood screening for colorectal carcinoma: the risks.
The evidence that occult-blood (Hemoccult) screening for colorectal carcinoma is beneficial has been examined in a companion paper. No data have yet been published demonstrating actual reductions in morbidity or mortality among patients undergoing the test. In this paper the risks of occult-blood screening are examined. It is shown that significant harm may result from the test's widespread application, due to the need for extensive endoscopic and radiological investigations in persons with a positive result (the vast majority of whom will subsequently be found not to have cancer). Furthermore, the most favorable benefit-risk ratio in Hemoccult screening (i.e., the highest positive predictive value for cancer) is found among persons over 70 years of age. Yet they are generally the least likely of patients screened to undergo treatment if a cancer is found. It is concluded that the risks of occult-blood screening could outweigh the benefits of any age group.


Lacrosse-related injuries in boys and girls treated in U.S. emergency departments, 2000-2016.
Lacrosse is one of the fastest-growing sports in the United States. Its rules regarding permitted contact differ by sex and age. There are no known studies using a nationally representative data set to analyze lacrosse injury patterns over several years by sex and age in the youth population. A retrospective analysis was performed using data from the National Electronic Injury Surveillance System for youth aged 11-18 years who were treated for lacrosse-related injuries in U.S. emergency departments from 2000 to 2016. Based on our review of the case narratives, we created and coded a new injury-mechanism variable. We generated national estimates from 6406 cases. An estimated 206,274 lacrosse-related injuries to youths aged 11-18 years were treated in U.S. emergency departments from 2000 to 2016. The rate of injuries per 10,000 significantly increased from 1.9 in 2000 to a peak of 5.3 in 2012 (p < 0.0001), followed by a significant decrease to 3.4 in 2016 (p = 0.020). Injury mechanism, body part injured, and diagnosis differed by sex. Boys were 1.62 times (95% confidence interval (95%CI): 1.25-2.09) more likely than girls to be injured by player-to-player contact. Girls were 2.21 times (95%CI: 1.96-2.49) more likely than boys to have non-contact injuries. Overall, as age increased, the percentage of injuries from lacrosse sticks decreased and player-to-player contact increased. Despite additional protective regulations in the sport, lacrosse is an important source of injury where we continue to see differences by sex and age. This study supports the continuation, modification, and addition of rules aimed at reducing lacrosse injury risk.


Interferon-beta-1b slows progression of atrophy in RRMS: Three-year follow-up in NAb- and NAb+ patients.
To determine the effect of interferon-beta-1b (IFNbeta-1b) treatment on total contrast-enhancing lesions (CEL), white matter lesion load (WMLL), and cerebral atrophy (CA) in patients with relapsing-remitting multiple sclerosis (RRMS) using serial monthly MRI. An open-label baseline-vs-treatment crossover trial was conducted with 30 RRMS patients monitored during a 6-month baseline and up to 36 months on treatment with IFNbeta-1b. Monthly MRI exams and neurologic exams using the Expanded Disability Status Scale (EDSS) were performed. The percentage changes from baseline for years 1, 2, and 3 on IFNbeta-1b were as follows: brain volume (BV) = -1.35, -1.48, and -1.68%; CEL = -76.5, -60.1, and -54.7%; WMLL = -12.2, -9.8, and -10.4%. There was no difference in the BV, CEL, or WMLL for between-year comparisons, and the decrease in BV from year 1 to years 2 and 3 was less than the change from baseline to year 1. EDSS did increase (p < 0.001) when comparing the last 3 months of baseline (2.8 +/- 2.1) and the last 3 months on IFNbeta-1b (3.6 +/- 2.1). Eleven patients developed neutralizing antibody (NAb) during the study. The effect of IFNbeta-1b on CEL and WMLL was significantly reduced in NAb+ patients compared with NAb- patients (p < 0.003). IFNbeta-1b decreases contrast-enhancing lesions and white matter lesion load over 3 years on therapy and slows the progression in cerebral atrophy during years 2 and 3.


Using Data on Survival with Idiopathic Pulmonary Fibrosis to Estimate Survival with Other Types of Progressive Fibrosis Interstitial Lung Disease: A Bayesian Framework.
Among the various types of progressive fibrosing interstitial lung diseases (PF-ILDs), substantial survival data exist for idiopathic pulmonary fibrosis (IPF) but not for other types. This hinders evidence-based decisions about treatment and management, as well as the economic modelling needed to justify research into new treatments and reimbursement approvals. Given the clinical similarities between IPF and other PF-ILDs, we reasoned that patient survival data from four major IPF trials could be used to estimate long-term survival in other PF-ILDs. We used propensity score matching to match patients with IPF taking either nintedanib or placebo in the TOMORROW, INPULSIS-1, INPULSIS-2 and INPULSIS-ON trials to patients with PF-ILDs other than IPF in the INBUILD trial. Seven models were fitted to the survival data for the matched patients with IPF, and the three best-fitting models were used to generate informative priors in a Bayesian framework to extrapolate patient survival of the INBUILD population. After propensity score matching, the analysis included data from 1099 patients with IPF (640 nintedanib patients; 459 placebo patients) and 654 patients with other PF-ILDs (326 nintedanib patients; 328 placebo patients). Gamma, log-logistic and Weibull models best fit the survival of the matched patients with IPF. All three models led to consistent Bayesian estimates of survival for the matched patients with other PF-ILDs, with median rates of overall survival ranging from 6.34 to 6.50 years after starting nintedanib. The corresponding control group survival estimates were 3.42 to 3.76 years. We provide the first estimates of long-term overall survival for patients with PF-ILDs other than IPF, and our analysis suggests that nintedanib may prolong their survival. Our Bayesian approach to estimating survival of one disease based on clinical trial data from a similar disease may help inform economic modelling of rare, orphan and newly defined disorders.


Methods in heart rate variability analysis: which tachogram should we choose?
We investigated the practical impact of the representation of the cardiac rhythm--the cardiotachogram--on two elementary spectral indexes in heart rate variability analysis: the low-frequency (0.07-0.14 Hz) and high-frequency (0.14-0.40 Hz) powers. Five commonly used tachograms (inter-beat interval function/series, counts, instantaneous heart rate function/series) were compared. Measurements were done on seven volunteers in the supine and standing positions. Ratios, and their deviations from 100%, of alternative power values were calculated. Mean low-frequency and high-frequency ratio deviations ranged from 0 to 5% and from 6 to 37%. The spectrum of counts yielded on average more (15-37%) high-frequency power. Spectra were incomparable without normalization of the tachogram with respect to heart rate. In conclusion, (i) the choice of a particular spectrum may lead to differing conclusions on the vagal contribution to heart rate variability and (ii) inconclusive results from studies using different tachogram variants can partly be due to the omission of normalization.


An algorithm for estimation and correction of anisotropic magnification distortion of cryo-EM images without need of pre-calibration.
Anisotropic magnification distortion of TEM images (mainly the elliptic distortion) has been recently found as a potential resolution-limiting factor in single particle 3-D reconstruction. Elliptic distortions of ∼1-3% have been reported for multiple microscopes under low magnification settings (e.g., 18,000×), which significantly limited the achievable resolution of single particle 3-D reconstruction, especially for large particles. Here we report a generic algorithm that formulates the distortion correction problem as a generalized 2-D alignment task and estimates the distortion parameters directly from the particle images. Unlike the present pre-calibration methods, our computational method is applicable to all datasets collected at a broad range of magnifications using any microscope without need of additional experimental measurements. Moreover, the per-micrograph and/or per-particle level elliptic distortion estimation in our method could resolve potential distortion variations within a cryo-EM dataset, and further improve the 3-D reconstructions relative to constant-value correction by the pre-calibration methods. With successful applications to multiple datasets and cross-validation with the pre-calibration method, we have demonstrated the validity and robustness of our algorithm in estimating the distortion; correction of the elliptic distortion significantly improved the achievable resolutions by ∼1-3 folds and enabled 3-D reconstructions of multiple viral structures at 2.4-2.6Å resolutions. The resolution limits with elliptic distortion and the amounts of resolution improvements with distortion correction were found to strongly correlate with the product of the particle size and the amount of distortion, which can help assess if elliptic distortion is a major resolution limiting factor for single particle cryo-EM projects.


Aberrant DNA-PKcs and ERGIC1 expression may be involved in initiation of gastric cancer.
To investigate the molecular mechanisms of gastric carcinogenesis. We used label-free quantification technology integrated with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to identify differentially expressed proteins in 160 specimens of normal gastric mucosa, gastric mucosa with mild dysplasia, moderate dysplasia, severe dysplasia, and early mucosal gastric cancer (GC) collected at the Second Hospital of Lanzhou University from 2010 to 2015. Immunohistochemistry was used to verify the differentially expressed proteins detected by LC-MS/MS. With a threshold of a 1.2-fold change and a P-value < 0.05 between mild dysplasia, moderate dysplasia, severe dysplasia or early mucosal GC and matched normal gastric mucosa tissues, proteomic analysis identified 365 significantly differentially expressed proteins. ERGIC1 expression decreased, while DNA-PKcs expression increased gradually along with different stages of GC initiation based on the tendency of fold change. The expression patterns of ERGIC1 and DNA-PKcs revealed by immunohistochemistry were consistent with the LC-MS/MS results. The results suggest that aberrant ERGIC1 and DNA-PKcs expression may be involved in GC initiation.


Cancer Stem Complex, Not a Cancer Stem Cell, Is the Driver of Cancer Evolution.
Here, we put forward the hypothesis on the mechanism of functioning of cancer stem cells, provided that they exist. The hypothesis is based on the following postulates. 1) Paracrine exchange between cancer and stromal cells is efficient only if they are in a close contact and form a synapse-like cleft between them for the cell-cell crosstalk. The concentration of paracrine signaling molecules in the cleft is high because of the cleft small volume. 2) Cancer stem cells per se do not exist. Instead, there are cancer stem complexes formed by cancer cells tightly bound to stromal cells (portable niches) that exchange paracrine signals. 3) Cancer stem complex is a complex system with newly emerged properties, such as a stemness and resistance to external impacts, including therapeutic interventions. 4) The stemness manifests itself as the ability of cancer cells within the complex to divide asymmetrically: one daughter cell remains in the complex forming a renewed stem complex, whereas the other daughter cell detaches from the complex and transforms in a non-stem cell capable of differentiation. 5) An increased resistance of a cancer stem complex is due to the integration of its intrinsic defense systems through the exchange of paracrine signals, i.e., represents a microresistance at the cell level. 6) Cancer stem complexes can stochastically dissociate with the formation of non-stem cancer cells. Partially differentiated non-stem cancer cells are able to stochastically bind to the stromal component, dedifferentiate under the action of paracrine signals, and form new cancer stem complexes. Therefore, a tumor is a flexible system existing in the pseudo-equilibrium state. Such systems comply with the Le Chatelier's principle stating that an equilibrium system under the action of external factors activates the processes antagonistic to the changes (homeostasis). This promotes tumor resistance at the level of cell populations, i.e., the macroresistance. 7) The portable niche travels with the cancer cell during metastasis. We propose a general therapeutic strategy targeting the contacts between cancer and stromal cells. The disruption of these contacts should lead to the destruction of cancer stem complexes and elimination of tumors.


Sieve-Like interface built by ZnO porous sheets towards stable zinc anodes.
Zn-based electrochemical energy storage (EES) systems are plagued by the uncontrollable generation of dendritic zinc and side reactions on zinc anodes. Herein, we report a ZnO porous sheets-assembled sieve-like interface to stabilize zinc anodes. Specifically, ZnO porous sheets are synthesized through the thermal decomposition of basic zinc sulfate nanoflakes and then served as an artificial zinc anode-electrolyte interface. Benefiting from the sieve-like interface formed by the ZnO porous sheets, Zn2+ flux is effectively homogenized during the zinc plating process and thus zinc dendrite growth is restricted. Meanwhile, the corrosion behavior of zinc anodes is alleviated thanks to the hydrophobic feature of the ZnO porous sheets. As a result, the electrochemical properties of zinc anodes are notably optimized under the protection of such a sieve-like interface. Cycling life evaluated at 1 mA cm-2 of the zinc anodes is prolonged from less than 100 h for bare zinc anodes to 2800 h for the protected zinc anodes (Zn@ZnO), and even at 5 mA cm-2, the latter ones can operate normally for 400 h. As expected, the cycling life of VO2//Zn@ZnO zinc-ion batteries is greatly increased, achieving 90% capacity retention after 1000 cycles at 5 A g-1 and activated carbon fiber//Zn@ZnO zinc-ion hybrid supercapacitors possess 96% capacity retention after 10,000 cycles at 1 A g-1. This work provides a promising approach for improving the electrochemical stability of the Zn-based EES system.


The psychological and mental impact of coronavirus disease 2019 (COVID-19) on medical staff and general public - A systematic review and meta-analysis.
The coronavirus disease 2019 (COVID-19) pandemic has caused enormous psychological impact worldwide. We conducted a systematic review and meta-analysis on the psychological and mental impact of COVID-19 among healthcare workers, the general population, and patients with higher COVID-19 risk published between 1 Nov 2019 to 25 May 2020. We conducted literature research using Embase, PubMed, Google scholar and WHO COVID-19 databases. Among the initial search of 9207 studies, 62 studies with 162,639 participants from 17 countries were included in the review. The pooled prevalence of anxiety and depression was 33% (95% confidence interval: 28%-38%) and 28% (23%-32%), respectively. The prevalence of anxiety and depression was the highest among patients with pre-existing conditions and COVID-19 infection (56% [39%-73%] and 55% [48%-62%]), and it was similar between healthcare workers and the general public. Studies from China, Italy, Turkey, Spain and Iran reported higher-than-pooled prevalence among healthcare workers and the general public. Common risk factors included being women, being nurses, having lower socioeconomic status, having high risks of contracting COVID-19, and social isolation. Protective factors included having sufficient medical resources, up-to-date and accurate information, and taking precautionary measures. In conclusion, psychological interventions targeting high-risk populations with heavy psychological distress are in urgent need.


Platform- and label-free detection of lead ions in environmental and laboratory samples using G-quadraplex probes by circular dichroism spectroscopy.
Guanine-rich quadruplex (G-QD) are formed by conversion of nucleotides with specific sequences by stabilization of positively charged K+ or Na+. These G-QD structures differentially absorb two-directional (right- and left-handed) circularly polarized light, which can discriminate the parallel or anti-parallel structures of G-QDs. In this study, G-QDs stabilized by Pb2+ were analyzed by a circular dichroism (CD) spectroscopy to determine Pb2+ concentration in water samples. Thrombin aptamer (TBA), PS2.M, human telomeric DNA (HTG), AGRO 100, and telomeric related sequence (T2) were studied to verify their applicability as probes for platform- and label-free detection of Pb2+ in environmental as well as laboratory samples. Among these nucleotides, TBA and PS2.M exhibited higher binding constants for Pb2+, 1.20-2.04 × 106/M at and 4.58 × 104-1.09 × 105/M at 100 micromolar and 100 mM K+ concentration, respectively. They also exhibited excellent selectivity for Pb2+ than for Al3+, Cu2+, Ni2+, Fe3+, Co2+, and Cr2+. When Pb2+ was spiked into an effluent sample from a wastewater treatment plant (WWTP), its existence was detected by CD spectroscopy following a simple addition of TBA or PS2.M. By the addition of TBA and PS2.M, the Pb2+ signals were observed in effluent samples over 0.5 micromolar (100 ppb) concentration. Furthermore, PS2.M caused a Pb2+-specific absorption band in the effluent sample without spiking of Pb2+, and could be induced to G-QD structure by the background Pb2+ concentration in the effluent, 0.159 micromolar concentration (3.30 ppb). Taken together, we propose that TBA and PS2.M are applicable as platform- and label-free detection probes for monitoring Pb2+ in environmental samples such as discharged effluent from local WWTPs, using CD spectroscopy.


Melatonin-vorinostat hybrid ligands show higher histone deacetylase and cancer cell growth inhibition than vorinostat.
Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the approved histone deacetylase (HDAC) inhibitor vorinostat, using melatonin's amide side chain (3a-e), its indolic nitrogen (5a-d), and its ether oxygen (7a-d) as attachment points. Several hybrid ligands showed higher potency thanvorinostat in both HDAC inhibition and cellular assays on different cultured cancer cell lines. In the most potent HDAC1 and HDAC6 inhibitors, 3e, 5c, and 7c, the hydroxamic acid moiety of vorinostat is linked to melatonin through a hexamethylene spacer. Hybrid ligands 5c and 7c were also found to be potent growth inhibitors of MCF-7, PC-3M-Luc, and HL-60 cancer cell lines. As these compounds showed only weak agonist activity at melatonin MT1 receptors, the findings indicate that their anticancer actions are driven by HDAC inhibition.


Degradation of seventeen contaminants of emerging concern in municipal wastewater effluents by sonochemical advanced oxidation processes.
The simultaneous degradation of seventeen emerging concern pollutants in effluent from the municipal wastewater treatment plant (MWTP) of Bogotá-Colombia was studied using high frequency ultrasound (375 kHz). The considered compounds in the effluent corresponded to pharmaceuticals (diclofenac, carbamazepine, venlafaxine, ciprofloxacin, norfloxacin, valsartan, losartan, irbesartan, sulfamethoxazole, clarithromycin, azithromycin, erythromycin, metronidazole, trimethoprim and clindamycin); cocaine and its major metabolite benzoylecgonine. Due to limitation of the MWTP for the pollutants elimination, ultrasound was applied to remove these compounds. Interestingly, ultrasonic physical action led to releasing of ciprofloxacin, norfloxacin, diclofenac and sulfamethoxazole from suspended solids, whereas the chemical effects induced degradation of the rest of compounds. For the latter ones, an interesting correlation between the sonodegradation and arithmetic multiplication between hydrophobicity and concentration of pollutants was established. Afterwards, the sonochemical process was complemented with ferrous ions (sono-Fenton), ferrous ions plus light (sono-photo-Fenton) or ferrous ions plus light in presence of oxalic acid (sono-photo-Fenton/oxalic acid). Additionally, to clarify fundamental aspects of the different systems, individual treatments in distilled water of a model pollutant (valsartan) were performed. The complemented processes significantly enhanced all compounds degradation, following the order: sono-photo-Fenton/oxalic acid > sono-photo-Fenton ∼ sono-Fenton > sonochemistry. The Fe2+ addition improved the pollutants elimination by generation of more hydroxyl radicals in the solution bulk. Meanwhile, oxalic acid avoided Fe3+ precipitation favoring the iron catalytic cycle. Thus, the work demonstrates the high potentiality of the sono-photo-Fenton/oxalic acid system for the pollutants elimination in real-world wastewater matrices.


Glaucoma masqueraders: Diagnosis by spectral domain optical coherence tomography.
Advances in optic nerve and retinal imaging have dramatically changed the care of glaucoma patients, complementing the importance of the clinical exam of the optic nerve and automated perimetry in making the diagnosis of glaucoma. Computerized imaging, however, does not replace the clinical exam, as there can be overlap in the appearance of non-glaucomatous optic neuropathies with glaucoma. The spectral domain optic coherence tomography (SD-OCT) images of five patients with non-glaucomatous optic nerve pathology are presented. The first patient had bilateral temporal thinning on OCT imaging and subsequent positive syphilis testing. The second patient had a glaucomatous-appearing inferior arcuate scotoma and associated superior thinning on OCT; these findings were due to buried optic nerve head drusen, clearly appreciated on OCT of the optic nerve head. Bilateral diffuse macular thinning, with preservation of the superior and inferior fiber bundles, was seen in the third patient, who had multiple sclerosis, with no clinical history of optic neuritis. Dense and marked thinning of a macular half, respecting the horizontal meridian, is seen in two patients, one patient with non-arteritic anterior ischemic optic neuropathy and lastly, in a patient with hemi-retinal vein occlusion. SD-OCT of the optic nerve and retina complements the essential clinical examination of patients with glaucomatous and non-glaucomatous optic neuropathies.


Oxidized thioredoxin-1 restrains the NLRP1 inflammasome.
The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1) binds to NLRP1. We found that oxidized TRX1 associates with the NACHT-LRR region of NLRP1 in an ATP-dependent process, forming a stable complex that restrains inflammasome activation. Consistent with these findings, patient-derived and ATPase-inactivating mutations in the NACHT-LRR region that cause hyperactive inflammasome formation interfere with TRX1 binding. Overall, this work strongly suggests that reductive stress, the cellular perturbation that will eliminate oxidized TRX1 and abrogate the TRX1-NLRP1 interaction, is a danger signal that activates the NLRP1 inflammasome.


Probing the interaction of a new synthesized CdTe quantum dots with human serum albumin and bovine serum albumin by spectroscopic methods.
A novel CdTe quantum dots (QDs) were prepared in aqueous phase via a facile method. At first, poly (acrylic amide) grafted onto sodium alginate (PAAm-g-SA) were successfully synthesized and then TGA capped CdTe QDs (CdTe-TGA QDs) were embed into it. The prepared CdTe-PAAm-g-SA QDs were optimized and characterized by transmission electron microscopy (TEM), thermo-gravimetric (TG) analysis, Fourier transform infrared (FT-IR), UV-vis and fluorescence spectroscopy. The characterization results indicated that CdTe-TGA QDs, with particles size of 2.90 nm, were uniformly dispersed on the chains of PAAm-g-SA biopolymer. CdTe-PAAm-g-SA QDs also exhibited excellent UV-vis absorption and high fluorescence intensity. To explore biological behavior of CdTe-PAAm-g-SA QDs, the interactions between CdTe-PAAm-g-SA QDs and human serum albumin (HSA) (or bovine serum albumin (BSA)) were investigated by cyclic voltammetry, FT-IR, UV-vis, and fluorescence spectroscopic. The results confirmed the formation of CdTe-PAAm-g-SA QDs-HSA (or BSA) complex with high binding affinities. The thermodynamic parameters (ΔG<0, ΔH<0 and ΔS<0) were indicated that binding reaction was spontaneous and van der Waals interactions and hydrogen-bond interactions played a major role in stabilizing the CdTe-PAAm-g-SA QDs-HSA (or BSA) complexes. The binding distance between CdTe-PAAm-g-SA QDs and HSA (or BSA)) was calculated about 1.37 nm and 1.27 nm, respectively, according to Forster non-radiative energy transfer theory (FRET). Analyzing FT-IR spectra showed that the formation of QDs-HSA and QDs-BSA complexes led to conformational changes of the HSA and BSA proteins. All these experimental results clarified the effective transportation and elimination of CdTe-PAAm-g-SA QDs in the body by binding to HSA and BSA, which could be a useful guideline for the estimation of QDs as a drug carrier.


Amino acid sequence homology between ligands and their receptors: potential identification of binding sites.
Mice were immunized with alpha-bungarotoxin (BGT), a nearly irreversible antagonist of the acetylcholine receptor (AChR), to produce monoclonal antibodies (Mabs). One of the Mabs (JMC2.7) bound not only to BGT, but to the AChR as well. To understand the molecular basis for this novel cross-reaction, the amino acid sequences of these proteins were searched for areas of similarity which might constitute the shared epitope. A number of short segments of sequence homology were found, one of them representing the BGT-binding site of the AChR. Because a portion of BGT resembles that part of the AChR that binds toxin, the self-binding of BGT was evaluated. As shown here, BGT binds specifically to itself to form dimers. In order to extend these observations, other ligand-receptor pairs were examined for sequence homology. The sodium channel and alpha-scorpion toxins were found to have distinct areas of similarity, as do interleukin 2 (IL-2) and the IL-2 receptor. As a general principle, we propose that peptide ligands and their receptors may often share amino acid sequence homology. In fact, the sites of interaction between two proteins may largely be determined by these regions of similarity.


Genetic and hereditary aspects of childhood obesity.
Genetic factors are involved in the regulation of body weight and in determining individual responses to environmental factors such as diet and exercise. The identification and characterization of monogenic obesity syndromes have led to an improved understanding of the precise nature of the inherited component of severe obesity and has had undoubted medical benefits, whilst helping to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. For individuals at highest risk of the complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for one disorder, congenital leptin deficiency.


The silent ductus arteriosus.
Preterm infants at risk of developing a patent ductus arteriosus were followed sequentially by physical examination, echocardiographic determinations of the LA/AO ratio, and chest roentgenograms. The results show that a significant number of infants who have no clinical signs or symptoms of a PDA have large left-to-right shunts. The presence of this shunt was suggested by acute increase in left atrial size by ECHO determination and confirmed by retrograde single-film aortography. Clinical signs and symptoms often developed several days after documentation of the left-to-right shunt.


Calcium requirement and calcium therapy.
The mean calcium requirement of normal adults has been estimated from 212 calcium balances on 84 normal subjects and found to be 578 mg. The calcium allowance required to ensure that 95% of normal adults are in calcium balance is about 900 mg. Calcium requirement is relatively higher than that of phosphorus or magnesium because plasma calcium--and therefore urine calcium--is maintained at the expense of the skeleton in the presence of calcium deficiency, whereas plasma phosphate and magnesium--and therefore urine phosphate and magnesium--fall on phosphorus and magnesium deficient diets. Calcium requirement appears to rise at the menopause, and postmenopausal bone loss can be reduced by calcium supplements. In postmenopausal osteoporosis, the severe negative calcium balance can be corrected by giving calcium or calcium and vitamin D, but vitamin D alone is not beneficial. Similarly, bone loss, height loss and further vertebral compression can be reduced by calcium or calcium and vitamin D but not by vitamin D alone.


Comment on "Ultrapotassic magmatism in the heyday of the Variscan Orogeny: the story of the Třebíč Pluton, the largest durbachitic body in the Bohemian Massif" by Janoušek et al.
This comment addresses the incorrect treatment and presentation of data from laser ablation ICP-MS U-Pb age determinations of two samples of the Třebíč Pluton. This results in inaccurate ages and error assessment, invalidating the age interpretations of the authors. To corroborate our arguments, new high-precision chemical abrasion ID-TIMS data are presented that unequivocally define the emplacement age of the Třebíč pluton.


Intentional overdose with insulin: prognostic factors and toxicokinetic/toxicodynamic profiles.
Prognostic factors in intentional insulin self-poisoning and the significance of plasma insulin levels are unclear. We therefore conducted this study to investigate prognostic factors in insulin poisoning, in relation to the value of plasma insulin concentration. We conducted a prospective study, and used logistic regression to explore prognostic factors and modelling to investigate toxicokinetic/toxicodynamic relationships. Twenty-five patients (14 female and 11 male; median [25th to 75th percentiles] age 46 [36 to 58] years) were included. On presentation, the Glasgow Coma Scale score was 9 (4 to 14) and the capillary glucose concentration was 1.4 (1.1 to 2.3) mmol/l. The plasma insulin concentration was 197 (161 to 1,566) mIU/l and the cumulative amount of glucose infused was 301 (184 to 1,056) g. Four patients developed sequelae resulting in two deaths. Delay to therapy in excess of 6 hours (odds ratio 60.0, 95% confidence interval 2.9 to 1,236.7) and ventilation for longer than 48 hours (odds ratio 28.5, 95% confidence interval 1.9 to 420.6) were identified as independent prognostic factors. Toxicokinetic/toxicodynamic relationships between glucose infusion rates and insulin concentrations fit the maximum measured glucose infusion rate (Emax) model (Emax 29.5 [17.5 to 41.1] g/hour, concentration associated with the half-maximum glucose infusion rate [EC50] 46 [35 to 161] mIU/l, and R2 range 0.70 to 0.98; n = 6). Intentional insulin overdose is rare. Assessment of prognosis relies on clinical findings. The observed plasma insulin EC50 is 46 mIU/l.


Apontic directly activates hedgehog and cyclin E for proper organ growth and patterning.
Hedgehog (Hh) signaling pathway and Cyclin E are key players in cell proliferation and organ development. Hyperactivation of hh and cyclin E has been linked to several types of cancer. However, coordination of the expression of hh and cyclin E was not well understood. Here we show that an evolutionarily conserved transcription factor Apontic (Apt) directly activates hh and cyclin E through its binding site in the promoter regions of hh and cyclin E. This Apt-dependent proper expression of hh and cyclin E is required for cell proliferation and development of the Drosophila wing. Furthermore, Fibrinogen silencer-binding protein (FSBP), a mammalian homolog of Apt, also positively regulates Sonic hh (Shh), Desert hh (Dhh), Cyclin E1 (CCNE1) and Cyclin E2 (CCNE2) in cultured human cells, suggesting evolutionary conservation of the mechanism. Apt-mediated expression of hh and cyclin E can direct proliferation of Hh-expressing cells and simultaneous growth, patterning and differentiation of Hh-recipient cells. The discovery of the simultaneous expression of Hh and principal cell-cycle regulator Cyclin E by Apt implicates insight into the mechanism by which deregulated hh and cyclin E promotes tumor formation.


Designated "no smoking" areas provide from partial to no protection from environmental tobacco smoke.
To determine the efficacy of designated "no smoking" areas in the hospitality industry as a means of providing protection from environmental tobacco smoke (ETS), and whether certain design features assist in achieving this end. In the greater metropolitan region of Sydney, a representative group of 17 social and gaming clubs, licensed to serve alcoholic beverages and in which, apart from designated areas, smoking occurs, agreed to participate. In each establishment, simultaneous single measurements of atmospheric nicotine, particulate matter (10 microm; PM10) and carbon dioxide (CO2) levels were measured in a general use area and in a designated "no smoking" area during times of normal operation, together with the levels in outdoor air (PM10 and CO2 only). Analyses were made of these data to assess the extent to which persons using the "no smoking" areas were protected from exposure to ETS. By comparison with levels in general use areas, nicotine and particulate matter levels were significantly less in the "no smoking" areas, but were still readily detectable at higher than ambient levels. For nicotine, mean (SD) levels were 100.5 (45.3) microg/m3 in the areas where smoking occurred and 41.3 (16.1) microg/m3 in the "no smoking" areas. Corresponding PM10 levels were 460 (196) microg/m3 and 210 (210) microg/m3, while outdoor levels were 61 (23) microg/m3. The reduction in pollutants achieved through a separate room being designated "no smoking" was only marginally better than the reduction achieved when a "no smoking" area was contiguous with a smoking area. CO2 levels were relatively uninformative. Provision of designated "no smoking" areas in licensed (gaming) clubs in New South Wales, Australia, provides, at best, partial protection from ETS-typically about a 50% reduction in exposure. The protection afforded is less than users might reasonably have understood and is not comparable with protection afforded by prohibiting smoking on the premises.


Respiratory complications of gastrointestinal diseases.
Further advances in the ability to diagnose GER disease by use of ambulatory pH monitoring have unveiled a host of extraesophageal manifestations of GERD. These include pulmonary symptoms of asthma, recurrent pneumonia, cough or bronchitis, and infant apnea. Many of these symptoms may be the sole presentations of GER in these patients. It is important that the clinician is aware of these atypical presentations of GERD. The expanding use of ambulatory pH monitoring is helping to clarify the underlying pathophysiology of these disorders as well as to improve the ability to diagnose the atypical manifestations of GERD.


Establishment and depletion of the ovarian reserve: physiology and impact of environmental chemicals.
The reproductive life span in women starts at puberty and ends at menopause, following the exhaustion of the follicle stockpile termed the ovarian reserve. Increasing data from experimental animal models and epidemiological studies indicate that exposure to a number of ubiquitously distributed reproductively toxic environmental chemicals (RTECs) can contribute to earlier menopause and even premature ovarian failure. However, the causative relationship between environmental chemical exposure and earlier menopause in women remains poorly understood. The present work, is an attempt to review the current evidence regarding the effects of RTECs on the main ovarian activities in mammals, focusing on how such compounds can affect the ovarian reserve at any stages of ovarian development. We found that in rodents, strong evidence exists that in utero, neonatal, prepubescent and even adult exposure to RTECs leads to impaired functioning of the ovary and a shortening of the reproductive lifespan. Regarding human, data from cross-sectional surveys suggest that human exposure to certain environmental chemicals can compromise a woman's reproductive health and in some cases, correlate with earlier menopause. In conclusion, evidences exist that exposure to RTECs can compromise a woman's reproductive health. However, human exposures may date back to the developmental stage, while the adverse effects are usually diagnosed decades later, thus making it difficult to determine the association between RTECs exposure and human reproductive health. Therefore, epidemiological surveys and more experimental investigation on humans, or alternatively primates, are needed to determine the direct and indirect effects caused by RTECs exposure on the ovary function, and to characterize their action mechanisms.