Clinical Validity of hearScreen™ Smartphone Hearing Screening for School Children.
The study aimed to determine the validity of a smartphone hearing screening technology (hearScreen™) compared with conventional screening audiometry in terms of (1) sensitivity and specificity, (2) referral rate, and (3) test time. One thousand and seventy school-age children in grades 1 to 3 (8 ± 1.1 average years) were recruited from five public schools. Children were screened twice, once using conventional audiometry and once with the smartphone hearing screening. Screening was conducted in a counterbalanced sequence, alternating initial screen between conventional or smartphone hearing screening. No statistically significant difference in performance between techniques was noted, with smartphone screening demonstrating equivalent sensitivity (75.0%) and specificity (98.5%) to conventional screening audiometry. While referral rates were lower with the smartphone screening (3.2 vs. 4.6%), it was not significantly different (p > 0.05). Smartphone screening (hearScreen™) was 12.3% faster than conventional screening. Smartphone hearing screening using the hearScreen™ application is accurate and time efficient.


Differences in laterality for recognition of nonverbal material by Japanese and English subjects.
Observed differences in hemispheric dominance of visual function, attributed to culturally based experience of Japanese and American subjects, need systematic exploration.


The effectiveness of miniscrews in the three-dimensional control of a palatal impacted canine: "Canine Only" approach. Case report.
Treatment time and mechanics required to solve palatally impacted canines are usually challenging. Different biomechanics and protocol approaches are available, and among these, the use of skeletal anchorage as reactive unit can be noteworthy. The purpose of this article is to show a treatment of a palatally impacted canine by the means of a double miniscrew and cantilever system only. Two miniscrews with bracket heads were applied in a 16 years old patient; different cantilevers were used to solve the impaction and bring the canine in the right position. Results: the impacted canine was successfully moved into proper position with good three-dimensional control. Both miniscrews worked successfully as anchorage for the entire treatment. The palatally impacted canine was successfully treated utilizing two miniscrews and cantilever approach.


[Occupational and Health Strains of Pensioners with Reduced Earning Capacity Due to Mental or Physical Illnesses - Implications for the Health Care System].
Demographic changes with an increasing number of people receiving pensions and a decreasing number of working people paying into the pension system represent major challenges for the German social security system. In particular, it is important to support people to continue working so that there is no (premature) reduction in their earning capacity and pensioners with reduced earning capacity (disability pensioners) should be helped to return to gainful employment. The aim of this study was to investigate the differing needs of two kinds of disability pensioners, namely those with mental illness and those who were physically ill. A total of 453 persons receiving disability pension because of temporararily reduced earning capacity were interviewed over the telephone. Differences in demographic variables, occupational characteristics before applying for disability pension, and general resources were examined in descriptive analyses and multivariate analyses of variance with post-hoc tests. A third of the sample (33.1%) suffered from mental illness and the rest from somatic disorders. Those with mental illness reported higher perceived mental age, lower work-related self-efficacy, and lower quality of life concerning their mental health. Moreover, they reported higher levels of mental stressors at work. Mentally ill disability pensioners differ considerably from those with somatic illnesses. Accordingly, to promote a return to work, interventions need to target different factors in these two groups.


Immune evader cancer stem cells direct the perspective approaches to cancer immunotherapy.
Exploration of tumor immunity leads to the development of immune checkpoint inhibitors and cell-based immunotherapies which improve the clinical outcomes in several tumor types. However, the poor clinical efficacy of these treatments observed for other tumors could be attributed to the inherent complex tumor microenvironment (TME), cellular heterogeneity, and stemness driven by cancer stem cells (CSCs). CSC-specific characteristics provide the bulk tumor surveillance and resistance to entire eradication upon conventional therapies. CSCs-immune cells crosstalk creates an immunosuppressive TME that reshapes the stemness in tumor cells, resulting in tumor formation and progression. Thus, identifying the immunological features of CSCs could introduce the therapeutic targets with powerful antitumor responses. In this review, we summarized the role of immune cells providing CSCs to evade tumor immunity, and then discussed the intrinsic mechanisms represented by CSCs to promote tumors' resistance to immunotherapies. Then, we outlined potent immunotherapeutic interventions followed by a perspective outlook on the use of nanomedicine-based drug delivery systems for controlled modulation of the immune system.


Health services in Iraq.
After decades of war, sanctions, and occupation, Iraq's health services are struggling to regain lost momentum. Many skilled health workers have moved to other countries, and young graduates continue to leave. In spite of much rebuilding, health infrastructure is not fully restored. National development plans call for a realignment of the health system with primary health care as the basis. Yet the health-care system continues to be centralised and focused on hospitals. These development plans also call for the introduction of private health care as a major force in the health sector, but much needs to be done before policies to support this change are in place. New initiatives include an active programme to match access to health services with the location and needs of the population.


High Frequency of β-Catenin Mutations in Mouse Hepatocellular Carcinomas Induced by a Nongenotoxic Constitutive Androstane Receptor Agonist.
Activation of Wnt/β-catenin signaling is frequent in human and rodent hepatocarcinogenesis. Although in mice the tumor-promoting activity of agonists of constitutive androstane receptor (CAR) occurs by selection of carcinogen-initiated cells harboring β-catenin mutations, the molecular alterations leading to hepatocellular carcinoma (HCC) development by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCP) in the absence of genotoxic injury are unknown. Here, we show that CAR activation per se induced HCC in mice and that 91% of them carried β-catenin point mutations or large in-frame deletions/exon skipping targeting Ctnnb1 exon 3. Point mutations in HCCs induced by TCP alone displayed different nucleotide substitutions compared with those found in HCCs from mice pretreated with diethylnitrosamine. Moreover, unlike those occurring in HCCs from diethylnitrosamine + TCP mice, they did not result in increased expression of β-catenin target genes, such as Glul, Lgr5, Rgn, Lect2, Tbx3, Axin2, and Ccnd1, or nuclear translocation of β-catenin compared with the control liver. Remarkably, in the nontumoral liver tissue, chronic CAR activation led to down-regulation of these genes and to a partial loss of glutamine synthetase-positive hepatocytes. These results show that, although chronic CAR activation per se induces HCCs carrying β-catenin mutations, it concurrently down-regulates the Wnt/β-catenin pathway in nontumoral liver. They also indicate that the relationship between CAR and β-catenin may be profoundly different between normal and neoplastic hepatocytes.


Target product profiles for diagnosis of sepsis: Proposing a new approach for diagnostic innovation.
Sepsis, including neonatal sepsis, remains a prevalent cause of morbidity and mortality in low- and middle-income countries such as India, representing 85 per cent of all sepsis-related deaths globally. Early diagnosis and timely initiation of treatment is challenging due to non-specific clinical manifestations and non-availability of rapid diagnostic tests. There is an urgent need for affordable diagnostics with fast turnaround time catering to the needs of end-users. Target product profiles (TPPs) have been found instrumental in developing 'fit-for-use' diagnostics, thus reducing the time taken to facilitate development and improving diagnosis. Hitherto, no such guidance or criteria has been defined for rapid diagnostics for sepsis/neonatal sepsis. We propose an innovative approach for developing the diagnostics for sepsis screening and diagnosis which can be utilized by diagnostic developers in the country. Thr@ee-round Delphi method, including two online surveys and one virtual consultation, was adopted to define criteria for minimum and optimum attributes of TPPs and build consensus on characteristics. Expert panel (n=23) included infectious disease physicians, public health specialists, clinical microbiologists, virologists, researchers/scientists and technology experts/innovators. We present a three-component product profile for sepsis diagnosis, (i) screening with high sensitivity, (ii) detection of aetiological agent, and (iii) profiling of antimicrobial susceptibility/resistance, in adults and neonates with an option of testing different considerations. An agreement of >75 per cent was achieved for all TPP characteristics by Delphi. These TPPs are tailored to the Indian healthcare settings and can also be extrapolated to other resource-constraint and high-disease burden settings. Diagnostics developed using these TPPs will facilitate utilization of invested resources leading to development of the products that have potential to ease the economic burden on patient and save lives.


Specific JNK inhibition by D-JNKI1 protects Purkinje cells from cell death in Lurcher mutant mouse.
In the Lurcher mutant mouse (+/Lc), Purkinje cells (PCs) selectively die due to the mutation that converts alanine to threonine in the glutamate ionotropic receptor GRID 2, thus resulting in a constitutively leaky cation channel. This intrinsic cell death determines a target-dependent cell death of granule cells and olivary neurons and cerebellum cytoarchitecture is severely disrupted in the adult Lurcher mutant. Although the +/Lc mutant has been widely characterized, less is known about the molecules involved in +/Lc PC death. We, here, used organotypic cerebellar slice cultures from P0 mice to investigate the role of c-jun N-terminal kinase (JNK) in +/Lc PC death by using D-JNKI1 as very specific tool to inhibit its action. Our results showed that D-JNKI1 treatment increased the number of +/Lc PC at 14 DIV of 3.6-fold. Conversely, this specific JNK inhibitor cell permeable peptide did not increase PC number in +/+ treated versus untreated cultures. These results clearly indicate that JNK plays an important role in +/Lc PC mechanism of cell death.


The Influence of Neighborhood Crime on Increases in Physical Activity during a Pilot Physical Activity Intervention in Children.
The purpose of this study was to examine whether neighborhood crime moderated the response (increases in steps) to a pilot intervention to increase physical activity in children. Twenty-seven insufficiently active children aged 6-10 years (mean age = 8.7 years; 56 % female; 59 % African American) were randomly assigned to an intensive intervention group (IIG) or minimal intervention group (MIG). Change in average daily number of steps from baseline was regressed against an index of neighborhood crime in a multilevel repeated-measures model that included a propensity score to reduce confounding. Safer neighborhoods were associated with higher increases in steps during the pilot intervention (interaction p = 0.008). Children in the IIG living in low-crime neighborhoods significantly increased their physical activity (5275 ± 1040 steps/day) while those living in high-crime neighborhoods did not (1118 ± 1007) (p for difference = 0.046). In the IIG, the increase in daily steps was highly correlated with neighborhood crime (r = 0.58, p = 0.04). These findings suggest the need for physical activity interventions to account for participants' environments in their design and/or delivery. To promote healthy behaviors in less-supportive environments, future studies should seek to understand how environments modify intervention response and to identify mediators of the relationship between environment and intervention.


Many Faces of TRIM Proteins on the Road from Pluripotency to Neurogenesis.
Tripartite motif (TRIM) proteins participate in numerous biological processes. They are the key players in immune system and are involved in the oncogenesis. Moreover, TRIMs are the highly conserved regulators of developmental pathways in both vertebrates and invertebrates. In particular, numerous data point to the participation of TRIMs in the determination of stem cell fate, as well as in the neurogenesis. TRIMs apply various mechanisms to perform their functions. Their common feature is the ability to ubiquitinate proteins mediated by the Really Interesting New Gene (RING) domain. Different C-terminal domains of TRIMs are involved in DNA and RNA binding, protein/protein interactions, and chromatin-mediated transcriptional regulation. Mutations and alterations of TRIM expression cause significant disturbances in the stem cells' self-renewal and neurogenesis, which result in the various pathologies of the nervous system (neurodegeneration, neuroinflammation, and malignant transformation). This review discusses the diverse molecular mechanisms of participation of TRIMs in stem cell maintenance and self-renewal as well as in neural differentiation processes and neuropathology.


Spironolactone improves endothelial dysfunction in ankylosing spondylitis.
Chronic inflammation in ankylosing spondylitis (AS) is associated with vascular endothelial dysfunction which leads to accelerated atherosclerosis. Accelerated atherosclerosis contributes to premature cardiovascular disease and increased cardiovascular mortality in AS. Spironolactone inhibits the production of proinflammatory cytokines and improves endothelial dysfunction in rheumatoid arthritis. This study aimed to determine the effect of spironolactone in antitumor necrosis factor (TNF)-naive AS patients. Twenty anti-TNF-naive AS patients (M/F = 15/5) with high disease activity (Bath ankylosing spondylitis disease activity index, BASDAI >4) despite treatment with stable doses of conventional disease-modifying antirheumatic drugs were investigated. Inflammatory disease activity (BASDAI and Bath ankylosing spondylitis functional index (BASFI) scores, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels), serum nitrite concentration, and endothelium-dependent and -independent vasodilatation of the brachial artery were measured at baseline and after 12 weeks of therapy with oral spironolactone 2 mg/kg/day. Ten healthy subjects matched for age and sex acted as the control. Flow-mediated dilation (FMD) in AS patients at baseline was significantly impaired compared with healthy control group (p < 0.001). After treatment, FMD improved from 11.3 ± 1.70 to 24.69 ± 2.34% (p < 0.001); nitrite concentration reduced from 7.9 ± 0.28 to 4.79 ± 0.19 μmol/L (p < 0.001); ESR from 33.8 ± 4.38 to 15.13 ± 1.30 mm in the first hour, (p < 0.001); and CRP level from 22.39 ± 3.80 to 6.3 ± 1.29 mg/dL, (p < 0.001). BASDAI and BASFI also reduced significantly (p < 0.001). The study suggests that in AS endothelial dysfunction is a part of the disease process. This is the first study to show that treatment with spironolactone improves both endothelial dysfunction and inflammatory disease activity in AS.


High-frequency transvaginal sonographic examination for the potential malformation assessment of the 9-week to 14-week fetus.
A study was undertaken to evaluate the ability of the high-frequency transvaginal scanning method to consistently image first- and early second-trimester fetal structures, such as body contours, long bones, fingers, face, palate, feet, toes, and the four-chamber view. Ninety-seven low-risk pregnancies were scanned from 9 weeks to 14 menstrual weeks inclusive. Accurate dating was ascertained. The results showed that consistent detection of the respective structures was achieved at the following menstrual ages: sagittal contours at 9 weeks to 10 weeks, long bones at 10 weeks to 11 weeks, fingers at 12 weeks, face and palate at 12 weeks, feet and toes at 13 weeks, and the four-chamber view at 14 weeks. The organs and structures examined could be detected at 9 weeks to 14 weeks inclusive. An increasing number of structure were detected consistently with the increasing menstrual age. The study supports the possibility of searching for specific malformations at or after the menstrual ages mentioned, or performing a more comprehensive malformation evaluation after 13 weeks.


Denaturing gradient gel electrophoresis analysis of bacterial community profiles in the rhizosphere of cry1AC-carrying Brassica rapa subsp. pekinensis.
The effect of genetically modified (GM) Brassica rapa subsp. pekinensis (Chinese cabbage) expressing Bt toxin gene (cry1AC) to the rhizosphere bacterial community was examined using the denaturing gradient gel electrophoresis (DGGE) fingerprinting method. From the visual comparison of the DGGE profiles, there were no significant differences between the profiles of Bt and control rhizosphere in both Suwon and Yesan samples. From the sequence analysis of the individual bands, Sphingomonas sp. of Alphaproteobacteria and several actinobacterial members were identified as the main bacterial taxa in both Suwon and Yesan samples. In the multiple correspondence analysis, no clear separation between Bt and control rhizosphere was seen in both Suwon and Yesan datasets. The profiles of bulk soils were separated from those of rhizosphere. The DGGE fingerprinting analyses indicated that Bt crops did not significantly alter the genetic composition of rhizosphere bacterial communities.


Cu(II)-coumestrol interaction leads to ROS-mediated DNA damage and cell death: a putative mechanism for anticancer activity.
Phytoestrogens have attracted considerable interest as natural alternatives to hormone replacement therapy and their potential as cancer therapeutic agents. Among phytoestrogens, coumestrol has shown multipharmacological properties such as antiinflammatory, neuroprotective, osteoblastic differentiation and anticancer. Though several studies have described anticancer effects of coumestrol, a clear underlying molecular mechanism has not been elucidated. Unlike normal cells, cancer cells contain elevated copper levels that play an integral role in angiogenesis. Copper is an important metal ion associated with the chromatin DNA, particularly with guanine. Thus, targeting copper in cancer cells can serve as effective anticancer strategy. Using human peripheral lymphocytes, we assessed lipid peroxidation, protein carbonylation, reactive oxygen species (ROS) generation, DNA damage and apoptosis by coumestrol in the presence of exogenously added Cu(II) in cells to simulate malignancy-like condition. Results showed that Cu(II)-coumestrol interaction leads to lipid peroxidation and protein carbonylation (markers of oxidative stress), DNA fragmentation and apoptosis in treated lymphocytes. Further, incubation of lymphocytes with ROS scavengers and membrane-permeant copper chelator, neocuproine, resulted in inhibition of DNA damage and apoptosis. This suggests that coumestrol engages in redox cycling of Cu(II) to generate ROS that leads to DNA fragmentation and apoptosis. In conclusion, this is the first report showing that coumestrol targets cellular copper to induce prooxidant death in malignant cells. We believe that such a prooxidant cytotoxic mechanism better explains the anticancer activity of coumestrol. These findings will provide significant insights into the development of new chemical molecules with better copper-chelating and prooxidant properties against cancer cells.


A case of mycosis fungoides after CD30 positive anaplastic large cell lymphoma.
A 55-year-old woman presented with mycosis fungoides (MF) after the total excision of primary cutaneous CD30+ anaplastic large cell lymphoma (ALCL). In the specimens obtained from the nodule of CD30+ ALCL and the plaque lesion of MF, the same pattern of T-cell receptor gene rearragement was detected.


Esophageal dysphagia.
Esophageal dysphagia can arise from a variety of causes such as motility disorders, mechanical and inflammatory diseases. Adequate management includes a detailed history, evaluation with upper endoscopy, barium radiography and manometry. Treatment is usually tailored to the underlying disease process and in some cases, as in inoperable cancer, palliative management may be necessary.


Beta3 subunits promote expression and nicotine-induced up-regulation of human nicotinic alpha6* nicotinic acetylcholine receptors expressed in transfected cell lines.
Nicotinic acetylcholine receptors (AChRs) containing alpha6 subunits are typically found at aminergic nerve endings where they play important roles in nicotine addiction and Parkinson's disease. alpha6* AChRs usually contain beta3 subunits. beta3 subunits are presumed to assemble only in the accessory subunit position within AChRs where they do not participate in forming acetylcholine binding sites. Assembly of subunits in the accessory position may be a critical final step in assembly of mature AChRs. Human alpha6 AChRs subtypes were permanently transfected into human tsA201 human embryonic kidney (HEK) cell lines. alpha6beta2beta3 and alpha6beta4beta3 cell lines were found to express much larger amounts of AChRs and were more sensitive to nicotine-induced increase in the amount of AChRs than were alpha6beta2 or alpha6beta4 cell lines. The increased sensitivity to nicotine-induced up-regulation was due not to a beta3-induced increase in affinity for nicotine but probably to a direct effect on assembly of AChR subunits. HEK cells express only a small amount of mature alpha6beta2 AChRs, but many of these subunits are on the cell surface. This contrasts with Xenopus laevis oocytes, which express a large amount of incorrectly assembled alpha6beta2 subunits that bind cholinergic ligands but form large amorphous intracellular aggregates. Monoclonal antibodies (mAbs) were made to the alpha6 and beta3 subunits to aid in the characterization of these AChRs. The alpha6 mAbs bind to epitopes C-terminal of the extracellular domain. These data demonstrate that both cell type and the accessory subunit beta3 can play important roles in alpha6* AChR expression, stability, and up-regulation by nicotine.


[Influenza A/H1N1v 2009 during pregnancy and breastfeeding: which antiviral to choose?].
Pregnant women are at increased risk of severe complications associated with H1N1 pandemic influenza. Fever and inflammatory syndrome associated with the infection may also be deleterious for the developing fetus. Therefore, early antiviral treatment is recommended. Oseltamivir and zanamivir are the two therapeutic options available indicated in the treatment of H1N1 influenza; however, limited data is published on their use during pregnancy and lactation. In this review, we will focus on the effects of H1N1 during pregnancy and on data safety of antivirals during pregnancy and lactation. Main health authorities recommendations for H1N1 influenza treatment of pregnant women will also be presented.


Acute and Transient Psychotic Disorders: Newer Understanding.
We review the ongoing research in the area of acute and transient psychotic disorders (ATPDs) with regard to their nosology, epidemiology, clinical description, genetics, and neurobiology, examining evidence for distinctiveness or otherwise of ATPDs. We further highlight the lacuna in research in ATPDs. Studies on ATPDs as defined in the ICD 10 have been reported from different parts of the world, more so from the developing countries. There is consistent evidence that there exist a group of ATPDs that occur more commonly among females, are often precipitated by stressful life events or exposure to physiological stresses like fever, child birth, are associated with well-adjusted premorbid personality, and show complete recovery in a short period. Although in some cases of ATPDs, there is symptomatic overlap with schizophrenic symptoms in the acute phase, they follow a completely different course and outcome, exhibit genetic distinctiveness, and do not share genetic relationship with schizophrenias or bipolar affective disorder (BPAD). Comparative studies on neurophysiology and neuroimaging in ATPDs and schizophrenias have demonstrated evidence of hyper arousal and hyper metabolism in ATPDs vs hypo arousal and hypo metabolism as noted in the P300 response and on FDG PET studies, respectively. Immune markers such as IL-6, TNF-alpha, and TGF-beta show higher levels in ATPDs as compared to healthy controls. Findings on the neurobiological mechanisms underlying ATPDs, so far, point towards significant differences from those in schizophrenia or BPAD. Although the studies are few and far between, nevertheless, these point towards the possibility of ATPDs as a distinct entity and underscore the need for pursuing alternate hypothesis such as neuro inflammatory or metabolic. Research on ATPDs is limited due to many reasons including lack of harmony between the ICD and DSM diagnostic systems and clinician biases. Available research data supports the validity of ATPDs as a distinct clinical entity. There is also evidence that ATPDs are different from schizophrenias or BPAD on genetic, neuroimaging, neurophysiological, and immunological markers and require further studies.


Single-cell profiling of vascular endothelial cells reveals progressive organ-specific vulnerabilities during obesity.
Obesity promotes diverse pathologies, including atherosclerosis and dementia, which frequently involve vascular defects and endothelial cell (EC) dysfunction. Each organ has distinct EC subtypes, but whether ECs are differentially affected by obesity is unknown. Here we use single-cell RNA sequencing to analyze transcriptomes of ~375,000 ECs from seven organs in male mice at progressive stages of obesity to identify organ-specific vulnerabilities. We find that obesity deregulates gene expression networks, including lipid handling, metabolic pathways and AP1 transcription factor and inflammatory signaling, in an organ- and EC-subtype-specific manner. The transcriptomic aberrations worsen with sustained obesity and are only partially mitigated by dietary intervention and weight loss. For example, dietary intervention substantially attenuates dysregulation of liver, but not kidney, EC transcriptomes. Through integration with human genome-wide association study data, we further identify a subset of vascular disease risk genes that are induced by obesity. Our work catalogs the impact of obesity on the endothelium, constitutes a useful resource and reveals leads for investigation as potential therapeutic targets.


Targeted Replacement of HSF1 Phosphorylation Sites at S303/S307 with Alanine Residues in Mice Increases Cell Proliferation and Drug Resistance.
Mammalian heat shock factor HSF1 transcriptional activity is controlled by a multitude of phosphorylations that occur under physiological conditions or following exposure of cells to a variety of stresses. One set of HSF1 phosphorylation is on serine 303 and serine 307 (S303/S307). These HSF1 phosphorylation sites are known to repress its transcriptional activity. Here, we describe a knock-in mouse model where these two serine residues were replaced by alanine residues and have determined the impact of these mutations on cellular proliferation and drug resistance. Our previous study using this mouse model indicated the susceptibility of the mutant mice to become obese with age due to an increase in basal levels of heat shock proteins (HSPs) and chronic inflammation. Since HSF1 transcriptional activity is increased in many tumor types, this mouse model may be a useful tool for studies related to cellular transformation and cancer.


Chronic estrogen treatment modifies insulin-induced insulin resistance and hypertension in ovariectomized rats.
Gender differences have been found in the development of hypertension. The role of estrogen in the association between hyperinsulinemia/insulin resistance and hypertension was investigated in an insulin-induced, insulin-resistant, and hypertensive model. Ovariectomized or sham operated female Wistar rats were chronically treated with insulin and/or estrogen via subcutaneous implants (insulin, 2 U/day; 17beta-estradiol 0.5 mg/pellet, 60-day release). Systolic blood pressure was monitored at weeks 0, 3, and 6. At week 7, an oral glucose tolerance test was performed. Ovariectomy resulted in the development of insulin resistance and blood pressure elevation in chronically insulin-treated female rats. Chronic estrogen treatment prevented the elevation in blood pressure and the development of insulin resistance. The results indicate that chronic estrogen treatment modifies the insulin-induced hypertension by increasing insulin sensitivity in ovariectomized rats.


An update on T-2 toxin and its modified forms: metabolism, immunotoxicity mechanism, and human exposure assessment.
T-2 toxin is the most toxic trichothecene mycotoxin, and it exerts potent toxic effects, including immunotoxicity, neurotoxicity, and reproductive toxicity. Recently, several novel metabolites, including 3',4'-dihydroxy-T-2 toxin and 4',4'-dihydroxy-T-2 toxin, have been uncovered. The enzymes CYP3A4 and carboxylesterase contribute to T-2 toxin metabolism, with 3'-hydroxy-T-2 toxin and HT-2 toxin as the corresponding primary products. Modified forms of T-2 toxin, including T-2-3-glucoside, exert their immunotoxic effects by signaling through JAK/STAT but not MAPK. T-2-3-glucoside results from hydrolyzation of the corresponding parent mycotoxin and other metabolites by the intestinal microbiota, which leads to enhanced toxicity. Increasing evidence has shown that autophagy, hypoxia-inducible factors, and exosomes are involved in T-2 toxin-induced immunotoxicity. Autophagy promotes the immunosuppression induced by T-2 toxin, and a complex crosstalk between apoptosis and autophagy exists. Very recently, "immune evasion" activity was reported to be associated with this toxin; this activity is initiated inside cells and allows pathogens to escape the host immune response. Moreover, T-2 toxin has the potential to trigger hypoxia in cells, which is related to activation of hypoxia-inducible factor and the release of exosomes, leading to immunotoxicity. Based on the data from a series of human exposure studies, free T-2 toxin, HT-2 toxin, and HT-2-4-glucuronide should be considered human T-2 toxin biomarkers in the urine. The present review focuses on novel findings related to the metabolism, immunotoxicity, and human exposure assessment of T-2 toxin and its modified forms. In particular, the immunotoxicity mechanisms of T-2 toxin and the toxicity mechanism of its modified form, as well as human T-2 toxin biomarkers, are discussed. This work will contribute to an improved understanding of the immunotoxicity mechanism of T-2 toxin and its modified forms.


Evaluation of the use of high-efficacy treatments (HETs) in patients with relapsing-remitting multiple sclerosis in Argentina.
Disease-modifying therapies (DMTs) in multiple sclerosis (MS) can be classified according to the efficacy in which they prevent inflammatory activity. To date, there are limited data regarding the use of high-efficacy treatments (HETs) in Latin America (LATAM). We aimed to analyze the use of HETs in Argentina, focusing on the clinical and sociodemographic characteristics of the patients who use these treatments and the changes in the trend of use over the years. A retrospective cohort study was done using the Argentina MS patient registry, RelevarEM. Patients diagnosed with relapsing-remitting MS (RRMS) according to validated diagnostic criteria and under treatment with natalizumab, alemtuzumab, cladribine, rituximab or ocrelizumab were included. Out of 2450 RRMS patients under a DMT, 462 (19%) were on HETs. One third of those patients (35%) received HETs as the first treatment. The most frequent reason for switching to HETs was treatment failure to previous DMT (77%). The time from MS diagnosis to the first HET in treatment-naive patients was less than one year (IQR: 0-1 year) and in treatment-experienced patients it was 5 years (IQR: 3-9 years). Between 2015 and 2017 (P1), 729 patients included in RelevarEM started a new treatment, of which 85 (11.65%) were HETs. Between 2018 and 2020 (P2), 961 patients included in RelevarEM started a new treatment, of which 284 (29.55%) were HETs. When comparing P2 with P1, a significant increase in the use of HETs was observed (p < 0.01). The most frequently used HETs were alemtuzumab (50.59%) in P1, and cladribine (45.20%) in P2. The demographic and clinical characteristics of patients under HET in Argentina were identified. Based on a real-world setting, we found a significant trend towards and a rapid increase in the use of HETs in clinical practice in patients with RRMS.


Applying a subtraction technique to minimize cochlear implant artifact with soundfield and direct audio input stimulations.
We explored the feasibility of a subtraction technique described by Friesen and Picton to remove the cochlear implant (CI) artifact to long duration stimuli in the soundfield and using direct input all through the participant's preferred MAP. Friesen and Picton previously explored this technique by recording cortical potentials in four CI users with 1000 pulse per second (pps) stimuli, bypassing the speech processor. Cortical auditory evoked potentials (N1-P2) to 1000 Hz tones were recorded from a post-lingually deafened adult with three different stimulus presentation setups: soundfield to processor T-mic (SF), soundfield to lapel mic (SF-LM), and direct input (DI). Stimuli were presented at 65 dB SPL(A). The SF setup required stabilizing the head to minimize changes in magnitude for the CI artifact. The SF-LM and DI setups did not require head stabilization, but were evaluated as alternatives to the SF setup. Clear N1-P2 responses were obtained with comparable waveform morphologies, amplitudes, and latencies despite some differences in the magnitude of the CI artifact for the different stimulus presentation setups. The results of this study demonstrate that subtraction technique is feasible for recording N1-P2 responses in CI users, though further studies are needed for the three stimulation setups.


Skeletal metastases.
This article discusses the role of imaging in the evaluation of patients with known or suspected malignancies. The radionuclide skeletal scintigram is the most sensitive imaging method for screening the skeleton for metastatic disease but is inherently nonspecific. Standard radiography provides useful correlative information and often confirms the presence of malignancy when characteristic lytic or blastic lesions are seen. Newer modalities such as CT and MR do not have a primary role in detecting skeletal metastases but may reveal lesions incidentally.


Mildly acidic pH selects for chain elongation to caproic acid over alternative pathways during lactic acid fermentation.
Carbohydrate-rich waste streams can be used for bioproduction of medium-chain carboxylic acids (MCCA) such as caproic acid. The carbohydrates in these streams can be converted to lactic acid as the initial fermentation product, which can then be fermented to MCCA by chain elongation. In this process, chain elongators compete for lactic acid with other bacterial groups that, for instance, ferment lactic acid to propionic and acetic acid. Understanding the drivers that control the competition between these two pathways is essential to maximizing MCCA production. This study aimed to investigate the competition between chain elongating and propionic acid producing organisms as a function of operational pH. Operation of long-term lactic acid fermenting reactors with varying pH values showed that pH values above 6 resulted in a propionic acid producing community dominated by Veillonella and Aminobacterium. At pH values below 6, the community moved towards chain elongation, with communities dominated by Caproiciproducens. Short-term incubations showed that rates of lactic acid consumption were strongly reduced at pH below 6 (7.7 ± 1.2 mM lactic acid·h-1 at pH 6.5; 0.74 ± 0.33 mM lactic acid·h-1 at pH 5.5). Similar to observations in long-term reactors, when a chain elongating community adapted to pH 5.5 was used for short-term incubations at pH 6.5, propionic acid was the dominant product. The results of this study show that pH below 6 stimulate lactic acid chain elongators through kinetic effects, and potentially improved energetics, providing a tool for microbial management of MCCA-producing systems.


[Early treatment with Nd:YAG laser for Valsalva retinopathy: results of five cases and literature review].
According to the literature, the treatment of retinopathy of Valsalva (VR) by laser is recommended when the macular hemorrhage has not regressed after 3 weeks. We report five cases of VR treated early (≤ 24 hours) by Nd:YAG laser membranotomy (LM). Clinical examination was performed before and after LM (D1, D7, M1, M3 and M6). Optical coherence tomography (OCT) analysis was performed to determine the precise location of the macular hemorrhage. Good visual recovery was obtained early by LM with a stable outcome at 6 months. The hemorrhage was located under the internal limiting membrane (ILM) and posterior hyaloid in two patients and only under the ILM in three patients. The literature review and our study confirm the good functional results for patients treated by LM for VR. Furthermore, very few side effects are reported with this type of treatment compared with the natural course of the disease, which may certainly regress spontaneously, but carries a risk of secondary preretinal fibrosis. However, to obtain optimal efficacy, the treatment should be carried out as soon as possible, in order to avoid clotting of the hematoma, preventing any subsequent evacuation by laser. LM for VR is an effective, safe and inexpensive technique compared to the surgical management of these patients presenting with a persistant premacular hematoma after a period of observation.


Dual-energy snap-shot perfusion CT in suspect pulmonary nodules and masses and for lung cancer staging.
Dual energy computed tomography (DECT) has proven its clinical usefulness for improved tissue characterization within the past years. In thoracic oncology, DECT can be used to differentiate between benign and malignant pulmonary nodules and masses. In patients with known lung cancer, DECT can add incremental functional information to staging scans, therapeutic response evaluation, as well as to the assessment of lung function. This review aims to give an overview on the current clinical utilities of DECT of the chest, its multiple post-processing applications and dose saving options. Furthermore, this review highlights promising applications of DECT that merit implementation in future clinical routine.


Lactobacillus improves the effects of prednisone on autoimmune hepatitis via gut microbiota-mediated follicular helper T cells.
Autoimmune hepatitis (AIH) is a chronic, immune-mediated liver dysfunction. The gut microbiota and T follicular helper (Tfh) cells play critical roles in the immunopathogenesis and progression of AIH. We aimed to investigate the effect of gut microbiota combined with prednisone therapy on Tfh cell response in AIH. Samples from AIH patients and mouse model of experimental autoimmune hepatitis (EAH) were analyzed using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, flow cytometry, and hematoxylin-eosin staining to determine the role of gut microbiota on AIH. Lactobacillus significantly increased the levels of Bacteroides fragilis, Clostridium, Clostridium leptum, Bifidobacterium, and Lactobacillus and significantly enhanced the suppressive effects of prednisone on the levels of AIH clinical indexes in AIH patients. Lactobacillus exerts the same prptective effects as prednisone in EAH mice and enhanced the effects of prednisone. Lactobacillus also reinforced the inhibitory effects of prednisone on the levels of serum IL-21 and the proportions of Tfh cells in peripheral blood mononuclear cells. Mechanistically, prednisone and Lactobacillus regulated Tfh cell response in EAH mice in an MyD88/NF-κB pathway-dependent manner. Our results suggested a therapeutic potential of Lactobacillus in the prednisone-combined treatment of AIH. Video Abstract.


Variation of insect attracting odor in endophytic Epichloë fungi: phylogenetic constrains versus host influence.
Odor is a key trait for pollinator attraction in flowering plants, and many studies have investigated odor evolution in the light of pollinator selection by emphasizing the importance of the plant phylogenetic history. By contrast, little is known on the evolution of odors in fungus-insect interactions. In this study, profiles of three volatile compounds that are emitted by grass-inhabiting Epichloë fungi (Clavicipitaceae, Ascomycota) and that have a confirmed or likely role in the attraction of gamete-transferring Botanophila flies were investigated. We collected headspace samples from stromata of six European Epichloë species (including various host races) that originated from different locations in Switzerland, France, Poland, and UK for conducting gas chromatography analyses. Odor profiles exhibited considerable variation, but profiles of most species overlapped and did not discriminate at the species level. The exception was Epichloë festucae, which had a profile dominated by methyl (Z)-3-methyldodec-2-enoate. Based on an Epichloë phylogeny, there was some hierarchical structuring regarding levels of chokol K, another confirmed Botanophila attractant. However, patterns of odor profiles appeared to be largely dependant on particular Epichloë-host associations. The observed variation may be the result of complex selective pressures imposed by Botanophila gametic vectors, local environment, and mycoparasites.


Elevated levels of secretory immunoglobulin A (sIgA) in urinary tract infections.
Urinary secretory IgA (sIgA), an immunoglobulin synthesized locally in mucosal surface is an important immunological defense in preventing bacterial adherence to periurethral epithelia and uroepithelia. Therefore attempts were made to measure secretory IgA in the urine of children with urinary tract infections (UTI), by using sIgA specific ELISA. Fresh or unprocessed urine samples from healthy donors (children and adults N=10 each), 68 children and 17 Adults with UTI were tested for the presence of sIgA. The level of sIgA in 10 healthy normal children was 2.7 +/- 0.94 ug/ml and that in 10 healthy adults was 5.2 +/- 0.73 ug/ml. Children with UTI showed highly elevated levels of sIgA amounting to 279 +/- 80 ug/ml (p<0.001). It was interesting to note that 96% of children and 76% of adults with UTI had sIgA level significantly above that of +/- 2SD of respective controls (287 +/- 99 and 80 +/- 48 ug/ml respectively). On culturing the urine obtained from these children the colonies identified were E. coil about 46%, Klebsiella about 24% and Pseudomonas about 24%. The sIgA antibody from urine samples assessed by indirect immunoflourescense. specifically reacted with the respective organism. Taken together the results show that the presence of sIgA not only correlated with the UTI in children as well in adults but sIgA seems to be directed to the infective agent and can also be used to identify the type of infection. Thus measurement of urine antibody levels may provide an alternative marker of host responses to infection, which can be used either as a simple screening test or could be useful to assist alongwith other tests in establishing a diagnosis.


Management of paediatric post-tonsillectomy bleeds - does everyone need observation?
The management of patients who present with a post-tonsillectomy bleed (PTB) who are not actively haemorrhaging is contentious. In our institution, those without an active bleed are admitted for a period of observation, due to the theoretical risk of further bleeding. This paper aims to review PTB admissions to ascertain the risk of rebleeding while under observation and to identify whether there is a low-risk group who can be safely discharged without observation. Review of current literature. Retrospective chart review of all patients who presented to Perth Children's Hospital between February 2018 and February 2022 with a PTB. Exclusion criteria included primary PTB, known blood dyscrasias and patients >16 years of age. A total of 826 presentations of secondary PTB (sPTB) were reviewed, with 752 admitted for a period of observation. Twenty-two (2.9%) patients rebled while under observation, with 17 managed operatively. The average age of patients who rebled was 6.2 years and they presented at an average 7.14 post-operative days. The median time to rebleed was 4.4 h. Four patients with no oropharyngeal clot at presentation subsequently re-bled (0.53%) while under observation, with 2 (0.26%) managed surgically. In patients observed with an oropharyngeal clot at presentation 18 (3.1%) rebled, with 15 (2.6%) managed operatively. Patients presenting with a sPTB have a low risk of rebleeding while under observation. Patients with a normal oropharyngeal examination at presentation have a very low risk of rebleed and should be considered for early discharge if they meet other low risk criteria. Patients who present with an oropharyngeal clot can be safely observed with a low risk of further bleeding. Patients who rebleed while under observation should have a trial of conservative management if clinically appropriate.


The Association Between PNPLA2 Methylation in Peripheral Blood and Early-Stage Lung Cancer in a Case-Control Study.
Lung cancer (LC) brings great burden to the society worldwide. Exploring novel biomarkers in vitro for the early detection of LC would be of great importance. We measured DNA methylation levels of 21 CpG sites within Patatin-like phospholipase domain containing 2 (PNPLA2) gene in the peripheral blood of 168 early-stage LC cases (94.0% LC at stage I) and 187 age- and gender-matched cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression adjusted for covariates. Non-parametric tests were applied for the comparisons of stratified groups. Hypomethylation of PNPLA2_CpG_8,10 and hypermethylation of PNPLA2_CpG_9 were correlated to the early-stage LC with the ORs of 1.44 (95% CI: 1.06-1.96, P = 0.018) and 0.82 (95% CI: 0.69-0.98, P = 0.029), respectively. The associations were still significant for the very early-stage LC patients (stage I). Further gender- and age-stratified analyses indicated that the association between hypomethylation of PNPLA2_CpG_8,10 and LC existed only in females and in subjects younger than 55 years. In addition, the association between LC and hypermethylation of PNPLA2_CpG_6 and PNPLA2_CpG_9 was also observed in the younger population. Taken together, our study has proved the hypothesis that the altered methylation in the peripheral blood may be correlated with the burden of cancer at an early stage. Here, we find a novel association between blood-based aberrant PNPLA2 methylation and LC at a very early stage and particularly for women at a younger age.


A role for platelet-activating factor in endothelin-1-induced rat mesangial cell proliferation.
Endothelin-1 stimulated the release of bioassayable platelet-activating factor-like material and the incorporation of acetate to PAF in rat mesangial cells, in a dose-dependent manner, with an EC50 of about 10(-9) M. Endothelin-1 also stimulated dose dependently [3H]thymidine incorporation into DNA, protein synthesis and cell growth. The platelet-activating factor antagonists BN-52021 (10(-5) M), and alprazolam (10(-5) M), reduced significantly endothelin-1-stimulated thymidine incorporation into DNA, protein synthesis and cell growth. Platelet-activating factor also stimulated significantly thymidine incorporation into DNA, cell proliferation and protein synthesis. In conclusion, the present results suggest that endothelin-1 induces mesangial cell proliferation through a mechanism involving among others, synthesis and release of platelet-activating factor by these cells.


Longitudinal course of salivary cortisol in post-traumatic stress disorder.
In chronic post-traumatic stress disorder (PTSD) lowered cortisol secretion and hypersuppression to dexamethasone has been described repeatedly. However, so far no longitudinal data on the natural course or on the effect of therapy are available. We measured basal and post-dexamethasone morning salivary cortisol in a drug-free patient with chronic PTSD (DSM-IV) monthly for nearly 2 years and assessed PTSD and depressive symptoms. Salivary cortisol decreased dramatically 3 months after the traumatic event and in the further course showed an inverse relation to fluctuating but gradually improving PTSD symptoms. Post-dexa-methasone cortisol was suppressed below the detection limit early after trauma and rose again more than 1 year post-trauma. Both the potential renormalization of low cortisol levels in improving chronic PTSD and the putative vulnerability to develop PTSD in subjects with increased dexamethasone suppression need further research.


Theoretically unveiling the effect of solvent polarities on ESDPT mechanisms and photophysical properties of hydroxyanthraquinones.
In this work, we were devoted to explore the effect of solvent polarities on the excited-state intramolecular proton transfer (ESIPT) process of 1-acetamido-4-hydroxyanthraquinone (AcHAQ) in three different polarity solvents (acetonitrile, chloroform, and cyclohexane) based on the density functional theory (DFT) and time-dependent DFT (TD-DFT) methods, and thereby regulating the distribution ratio between the dual excited-state isomers (enol and keto). The calculated geometrical parameters and infrared (IR) vibrational spectra have confirmed the excited-state intramolecular hydrogen bond (IHB) strengthening mechanism. Natural bond orbital (NBO) population analysis indicates that the intramolecular charge transfer (ICT) around IHBs has enhanced IHB, thereby triggering the ESIPT reaction. In addition, results obtained from the scanned potential energy curve (PEC) manifest that ESIPT process prefers to occur along the O3-H2…O1 IHB and energy barriers corresponding to the proton transfer in ACN are the lowest among all the studied solvents.


Update on Management Recommendations for Advanced Cutaneous Squamous Cell Carcinoma.
Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, the incidence of which has risen over the last years. Although cSCC rarely metastasizes, early detection and treatment of primary tumours are critical to limit progression and local invasion. Several prognostic factors related to patients' clinicopathologic profile and tumour features have been identified as high-risk markers and included in the stratification scales, but their association with regional control or survival is uncertain. Therefore, decision-making on the diagnosis and management of cSCC should be made based on each individual patient's characteristics. Recent advances in non-invasive imaging techniques and molecular testing have enhanced clinical diagnostic accuracy. Surgical excision is the mainstay of local treatment, whereas radiotherapy (RT) is recommended for patients with inoperable disease or in specific circumstances. Novel systemic treatments including immunotherapies and targeted therapies have changed the therapeutic landscape for cSCC. The anti-PD-1 agent cemiplimab is currently the only FDA/EMA-approved first-line therapy for patients with locally advanced or metastatic cSCC who are not candidates for curative surgery or RT. Given the likelihood of recurrence and the increased risk of developing multiple cSCC, close follow-up should be performed during the first years of treatment and continued long-term surveillance is warranted.


Pronated oblique view in assessing proximal scaphoid articular cannulated screw penetration.
Volar and percutaneous techniques of screw fixation for scaphoid fractures usually do not involve direct visualization of the dorsoproximal scaphoid articular surface. Intra-articular screw penetration may be overlooked if the proper fluoroscopic views are not obtained. The hypothesis of this study is that the pronated oblique fluoroscopic view of the scaphoid is the most sensitive in detecting dorsal articular screw penetration of the scaphoid when compared with other views. A 3.6-mm Steinmann pin was inserted along the central axis of the scaphoid using an open dorsal technique in 10 embalmed cadaver wrists. The pin was then withdrawn from the palmar side until it was flush with the dorsal articular surface of the scaphoid. Five fluoroscopic views of the wrist were then obtained by rotating the forearm, keeping the image beam parallel to the floor: (1) anteroposterior, (2) supinated lateral, (3) pronated lateral, (4) 60 degrees supinated oblique (60 degrees supinated from wrist neutral), and (5) 60 degrees pronated oblique (60 degrees pronated from wrist neutral). The Steinmann pin was then allowed to visually protrude proximally from the articular surface in 0.5-mm increments, and all views were repeated. The view in which articular violation was first observed was recorded, as was the corresponding amount of pin protrusion. The pronated oblique was the fluoroscopic view in which articular penetration was first observed in all 10 specimens before it was evident on the other views. The amount of pin penetrating the articular surface before it was detected on the other views was 1 mm in 6 wrists and 2 mm in 4 wrists. Statistical analysis using Fischer's exact test was performed to determine whether the radiographic projection had an effect on the determination of articular penetration. The pronated oblique view was the first view to demonstrate articular penetration, with an average radiographically measured articular penetration of 1.4 mm +/- 0.5. This study confirms our hypothesis that the pronated oblique view is the most important fluoroscopic image to obtain when evaluating penetration of the proximal scaphoid articular surface.


Lead phytotoxicity in soils and nutrient solutions is related to lead induced phosphorus deficiency.
This study was set up to relate lead (Pb) bioavailability with its toxicity to plants in soils. Tomato and barley seedlings were grown in six different PbCl(2) spiked soils (pH: 4.7-7.4; eCEC: 4.2-41.7 cmol(c)/kg). Soils were leached and pH corrected after spiking to exclude confounding factors. Plant growth was halved at 1600-6500 mg Pb/kg soil for tomato and at 1900-8300 mg Pb/kg soil for barley. These soil Pb threshold were unrelated to soil pH, organic carbon, texture or eCEC and neither soil solution Pb nor Pb(2+) ion activity adequately explained Pb toxicity among soils. Shoot phosphorus (P) concentrations significantly decreased with increasing soil Pb concentrations. Tomato grown in hydroponics at either varying P supply or at increasing Pb (equal initial P) illustrated that shoot P explained growth response in both scenarios. The results suggest that Pb toxicity is partially related to Pb induced P deficiency, likely due to lead phosphate precipitation.


Repression of autophagy leads to acrosome biogenesis disruption caused by a sub-chronic oral administration of polystyrene nanoparticles.
As a new widespread contaminant, nanoplastics (NPs) pose a potential risk to human health. Nevertheless, the adverse effects of NPs on the male reproductive system are poorly understood. In this study, we aimed to determine the effects of polystyrene nanoplastics (PS-NPs) (50 nm) on sperm quality, with a focus on the acrosome defects. After 35 days of intragastric administration, sperm quality was decreased and testicular structures were impaired in mice exposed to PS-NPs in both the medium (1.0 mg/kg) and high dose (10 mg/kg) groups. No significant changes were observed in the low dose (0.2 mg/kg) group. Meanwhile, acrosome parameters including acrosome integrity and acrosome reaction were decreased after the administration of PS-NPs. These findings were consistent with the disruption of acrosome biogenesis, as identified by the changed testicular ultrastructure. Additionally, the findings were further validated using seven marker genes (Gba2, Pick1, Gopc, Hrb, Zpbp1, Spaca1 and Dpy19l2) essential for acrosome formation, which showed that two of these genes (Gopc and Dpy19l2) were significantly down-regulated. Moreover, repressed autophagy was observed in the testes of PS-NPs-exposed mice based on autophagy-related protein expression. This phenomenon was further verified in GC-2spd cells treated with PS-NPs (50 μg/mL, 100 μg/mL, 200 μg/mL for 24 h). The potential role of autophagy in such acrosome defects was explored by using the autophagy inhibitor 3-methyladenine (3-MA), autophagy activator rapamycin or beclin-1 siRNA. The results showed that Golgi-associated vesicle disorganization was exacerbated with the 3-MA and beclin-1 siRNA pretreatments, but decreased with the rapamycin pretreatment, and the expression of GOPC and DPY19L2 was also altered. These results indicated that autophagy might be involved in the PS-NPs-induced acrosome lesions based on the regulation of two key acrosome-formation proteins, GOPC and DPY19L2. Altogether, our results will provide new insights into the PS-NPs-induced male reproductive impairment.


Stabilizing iron single atoms with electrospun hollow carbon nanofibers as self-standing air-electrodes for long-time Zn - air batteries.
Developing iron-based single-atom catalysts (Fe SACs) with low cost, high activity and stability is vital for commercialising sustainable energy technologies. However, accurately controlling and identifying structure-activity relationships of Fe SACs remains a significant challenge. Herein, we report Fe/N co-doped carbon nanofiber membranes with highly exposed Fe-N4 sites (Fe/NCNFs), synthesized by electrospinning and pyrolysis. The three-dimensional (3D) hierarchical structure and atomically dispersed pyrrole-type Fe (III)-N4 active sites provide the as-prepared catalyst with a positive half-wave potential of 0.87 V and an ultralow Tafel slope of 53 mV dec-1. As an air cathode catalyst for liquid Zn - air batteries, it delivers a high open-circuit voltage (1.474 V), a large peak power density (190 mW cm-2) and a high durability of 2000 cycles at 5 mA cm-2. As a self-standing air cathode, the as-assembled solid-state Zn - air batteries also show stable cycling with a small discharge/charge voltage gap of 0.65 V, indicating great prospects for developing portable zinc - air batteries.


Histone deacetylase inhibitor: antineoplastic agent and radiation modulator.
Inhibitors of histone deacetylases (HDACs) have emerged as a new class of anticancer agents based on their actions in cancer cell growth and cell cycle arrest, terminal differentiation, and apoptosis. Previously, we rationally designed and developed a new class of hydroxamide- and mercaptoacetamide-bearing HDAC inhibitors. A subset of these inhibitors exhibited chemo-radiation sensitizing properties in various human cancer cells. Furthermore, some HDAC inhibitors protected normal cells from radiation-induced damage and extended the survival of mice following total body exposure to lethal dose radiation. Pathological analyses revealed that intestinal and bone marrow cellularities recovered significantly from radiation-induced damage by structural compartments restoration, suggesting the mechanism of action of these HDAC inhibitors. These findings support the hypothesis that epigenetic regulation may play a crucial role in the functional recovery of normal tissues from radiation injuries.


Effect of an invasive strategy on in-hospital outcome and one-year mortality in women with non-ST-elevation myocardial infarction.
Subgroup analyses from randomized studies show inconsistent results regarding an early invasive approach in women with non-ST-elevation myocardial infarction (NSTEMI). We sought to investigate the impact of an invasive strategy in clinical practice, analyzing data from the German Acute Coronary Syndromes registry (ACOS). Overall 1986 consecutive women were enrolled in the registry between June 2000 and November 2002 and were divided into two groups: 1215 (61.2%) underwent coronary angiography, 771 (38.8%) received conservative treatment. In the invasive group percutaneous coronary intervention was performed in 40.7% within 48 h and in 16.4% after 48 h, whereas 8.3% underwent coronary artery bypass grafting within hospital stay. In-hospital death (3.2% vs 10.5%, p<0.0001), in-hospital death/myocardial infarction (MI) (7.1% vs 14.9%, p<0.0001) and one-year death (8.1% vs 24%) occurred significantly less often in patients with invasive strategy. After adjustment of the confounding factors in the propensity score analysis the invasive strategy showed no significant benefit for in-hospital death (OR 0.86, 95% CI 0.51-1.44) or death/MI (OR 0.70, 95% CI 0.47-1.04) but remained superior for mortality (OR 0.47, 95% CI 0.3-0.7) and death/MI one year after discharge (OR 0.47, 95% CI 0.33-0.68). In clinical practice women presenting with NSTEMI have a long-term benefit from an invasive therapeutic strategy with a significant reduction in mortality as well as the composite endpoint of death/MI.


Same-Day Yttrium-90 Radioembolization: Feasibility with Resin Microspheres.
To evaluate the feasibility of a same-day yttrium-90 (90Y) radioembolization protocol with resin microspheres (including pretreatment angiography, lung shunt fraction [LSF] determination, and radioembolization) for the treatment of hepatocellular carcinoma (HCC) and liver metastases. All same-day radioembolization procedures performed over 1 y (February 2017 to January 2018) were included in this single-institutional retrospective analysis, in which 34 procedures were performed in 26 patients (median age, 63 y; 13 women), 19 with liver metastases and 7 with HCC. Yttrium-90 treatment activities were calculated by body surface area method. Tumor imaging response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for liver metastases and modified RECIST for HCC. Clinical side effects and adverse events were graded per Common Terminology Criteria for Adverse Events version 4.0. All planned cases were technically successful, and no cases were canceled for elevated LSF or vascular anatomic reasons. Pretreatment angiography modified the planned 90Y treatment activity in 1 case in which vascular anatomy required a lobar-dose split into 2 for segmental infusions. In 18% of cases, patients were briefly admitted after the procedure for observation or symptom management. Imaging evaluation of initial efficacy at 1 month demonstrated partial response in 25% and stable disease in 67% of patients with liver metastases and partial/complete response in 43% and stable disease in 14% of patients with HCC. Grade ≥ 3 adverse events occurred in 6% of cases, with no systemic therapy-limiting toxicities. The mean total procedure time was 4.2 hours. A same-day 90Y radioembolization protocol with resin microspheres is feasible in select patients, which can expedite cancer therapy.


Arthroscopic Treatment of Calcific Tendinitis of Gemellus Superior and Gemellus Inferior: A Case Report and Literature Review.
Tendon calcification is a common disease, and it could happen in the tendons of the shoulder, wrist, etc. However, tendon calcification in the superior and inferior gemellus is rare, and in this region is likely to be misdiagnosed. Here, our case report first reported a 53-year-old female patient with an unusual case of calcific tendinitis of the gemellus superior and gemellus inferior muscles. The patient presented with severe pain in the right hip and lower extremities, not relieved using nonsteroidal anti-inflammatory drugs (NSAIDs). The preoperative physical examination indicated an abnormality in the hip joint. Preoperative imaging confirmed the results of the physical examination and showed a right hip lesion. We did not make a definite diagnosis preoperatively but considered that the patient might have an osteochondroma. However, surgical findings indicated that the lesion was not in the hip capsule on subsequent arthroscopic surgery, which suggested that the preoperative diagnosis might be wrong. We opened the posterior capsule and found a "toothpaste-like" lesion in the superior and inferior gemellus muscles' tendon. We thought this might be the calcified tendon. Then the arthroscopic surgery was finished to remove the lesion, and the removed tissue was sent to the pathology department for pathological examination. The pathological report confirmed the diagnosis of the calcified tendon. Postoperative follow-up was conducted. The effect of the operation was noticeable. Postoperative symptoms were relieved. Calcification of the tendons of the superior and inferior gemellus muscles can be easily misdiagnosed, and the disease can be treated minimally with arthroscopy.


Nonclinical challenges of Indian dermatology - cities vs. villages, poverty, and lack of awareness.
As India shines in its enviable achievements, one after the other in rapid succession, it also invites criticism from visitors for what they witness. It is imperative to delve deeper to fathom the realities of the predominantly rural India with its poverty and lack of awareness which are stumbling blocks and are major pitfalls in the practice of dermatology. The urban-rural divide, the phenomenon of migration, poverty, lack of awareness all affect practice of dermatology in this country. These are battles that have no ready answers. However a deeper understanding of the ground reality is a worthwhile exercise for the increasing tribe of international dermatologists who like to explore "cross cultural dermatology".


Medical Humanities Education and Its Influence on Students' Outcomes in Taiwan: A Systematic Review.
Medical education has emphasized the importance of integrating medical humanities training into the curriculum to benefit medical and nursing students' future practice, featuring in the list of national funding priorities for healthcare education research in Taiwan for many years. However, the extent to which this drive has resulted in medical humanities training, what rationales underpin its inclusion, and its efficacy is largely unknown. This study aims to address these issues across medical humanities programs within the Taiwanese context. We conducted a systematic review. Inclusion criteria included studies in English or Mandarin reporting outcomes of medical humanities courses in healthcare education settings in Taiwan between 2000 and 2019. We searched across five electronic databases (PubMed, Embase, ERIC, PsycInfo, Web of Science), following PRISMA guidelines. The Best Evidence Medical Education (BEME) Global Scale and Kirkpatrick Levels are used for identifying the strength of evidence. 17 articles were extracted from the 134 identified. Intrinsic and instrumental rationales for the inclusion of medical humanities education were common, compared with epistemological-based and critical-based approaches. Several positive impacts were identified in relation to participation including modification of attitudes, knowledge, and skills. However, the highest level (i.e., unequivocal) of evidence characterized by effects on students' behaviors or ongoing interaction with colleagues and patients is lacking. Findings suggest that although medical humanities education is widely implemented in Taiwan, no clear consensus has been reached regarding the rationale for inclusion or how it is localized from Western to Asian contexts. Future research still needs to explore the long-term impact of medical humanities education for medical and nursing students and its impact on patient care. https://www.crd.york.ac.uk/PROSPERO, identifier: CRD42019123967.


Exogenous 24-epibrassinolide boosts plant growth under alkaline stress from physiological and transcriptomic perspectives: The case of broomcorn millet (Panicum miliaceum L.).
Land alkalization is an abiotic stress that affects global sustainable agricultural development and the balance of natural ecosystems. In this study, two broomcorn millet cultivars, T289 (alkaline-tolerant) and S223 (alkaline-sensitive), were selected to investigate the response of broomcorn millet to alkaline stress and the role of brassinolide (BR) in alkaline tolerance. Phenotypes, physiologies, and transcriptomes of T289 and S223 plants under only alkaline stress (AS) and alkaline stress with BR (AB) were compared. The results showed that alkaline stress inhibited growth, promoted the accumulation of soluble sugars and malondialdehyde, enhanced electrolyte leakage, and destroyed the integrity of broomcorn millet stomata. In contrast, BR lessened the negative effects of alkaline stress on plants. Transcriptome sequencing analysis showed that relative to control groups (CK, nutrient solution), in AS groups, 21,113 and 12,151 differentially expressed genes (DEGs) were identified in S223 and T289, respectively. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed various terms and pathways related to metabolism. Compared to S223, alkaline stress strongly activated the brassinosteroid biosynthesis pathway in T289. Conversely, ARF, TF, and TCH4, associated with cell growth and elongation, were inhibited by alkaline stress in S223. Moreover, alkaline stress induced the activation of the mitogen-activated protein kinase (MAPK) pathway, the abscisic acid signaling pathway that initiates stomatal closure, as well as the starch and sucrose metabolism. The EG and BGL genes, which are associated with cellulose degradation, were notably activated. BR enhanced alkaline tolerance, thereby alleviating the transcriptional responses of the two cultivars. Cultivar T289 is better in alkalized regions. Taken together, these results reveal how broomcorn millet responds to alkaline stress and BR mitigates alkaline stress, thus promoting agriculture in alkalized regions.


Novel Nexus with NFκB, β-catenin, and RB1 empowers PSMD10/Gankyrin to counteract TNF-α induced apoptosis establishing its oncogenic role.
NFκB is a critical rapid-acting transcription factor that protects cancer cells from programmed cell death induced by stress or therapy. While NFκB works in nexus with non-classical oncoproteins such as STAT3 and AKT under a variety of conditions, it is a major antiapoptotic factor activated by TNF-α of the tumor microenvironment. Therefore, it is surprising that PSMD10, an oncoprotein overexpressed in several cancers and a marker of poor prognosis, is reported to inhibit the NFκB pathway. In this study, we explore the role of PSMD10 in cancer cells exposed to TNF-α. We screen several breast and colon cancer cell lines and select SW480, a colon cancer cell line highly resistant to TNF-α, and demonstrate that PSMD10 knockdown sensitizes these cells to TNF-α induced cell death. One of the mechanisms involves transcriptional regulation of β-catenin and RB1, two key colon cancer cell specific anti-apoptotic factors. Surprisingly, we find that PSMD10 is required for optimal phosphorylation and transcriptional activation of NFκB (RELA). Thus, upon PSMD10 knockdown, there is significant downregulation of anti-apoptotic NFκB target genes TNFAIP3 (A20), BIRC2 (cIAP1), BIRC3 (cIAP2), and XIAP. Our study, for the first time, shows that PSMD10 is required for the activation of the pro-survival arm via NFκB transcriptional activation to prevent cancer cells from succumbing to TNF-induced cell death. In addition by transcriptional regulation of two major antiapoptotic players RB1 and β-catenin, PSMD10 proves to be a coveted oncoprotein with a key role in tumorigenesis.


Misdiagnosis of a Cardiac Angiosarcoma During the COVID-19 Pandemic.
The final months of 2019 saw the emergence of a new pandemic termed "COVID-19". Since then, this infection and its complications have been the priority of healthcare providers, with many symptoms attributed to its early and late presentations. Thus far, other diseases, even fatal situations, have been overlooked or misdiagnosed due to the attribution of patient symptoms to the presence of COVID-19 infection. We herein present a case of cardiac angiosarcoma in a young boy who had previously become infected with COVID-19 about two months earlier. Given the history of infection, the initial approach was post-COVID-19 myopericarditis management. However, the patient's condition worsened, necessitating reevaluation via multimodalities with higher precision. Ultimately, the patient was diagnosed with a cardiac tumor. This article seeks to underscore the significance of taking heed of other diseases and fatal conditions during the COVID-19 pandemic with an emphasis on avoiding misdiagnosing other diseases.


Effects of gender on hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, and LDL receptor in hereditary analbuminemia.
Hypoalbuminemia is accompanied by hypercholesterolemia in both nephrotic syndrome and hereditary analbuminemia. Hypercholesterolemia is more severe in the female than in the male Nagase analbuminemic rats (NAR). The sex difference in plasma cholesterol diminishes after ovariectomy (OVX) and reappears after estrogen replacement in the NAR. The molecular mechanism responsible for the sex difference in severity of hypercholesterolemia in NAR is not known and was investigated here. To this end, hepatic hydroxylmethylglutaryl (HMG)-CoA reductase, cholesterol 7alpha-hydroxylase, and LDL receptor were determined in male, female, and OVX female NAR and Sprague-Dawley (SD) rats. Plasma cholesterol, triglycerides, and hepatic HMG-CoA reductase activities were greater in both female and male NAR than in SD rats. This was coupled with upregulation of cholesterol 7alpha-hydroxylase in both male and female NAR compared with SD controls. LDL receptor in male NAR was similar to that in male SD rats but was significantly reduced in female NAR. OVX partially, but significantly, reduced plasma cholesterol and triglyceride levels in female NAR. This was coupled with a significant rise in hepatic cholesterol 7alpha-hydroxylase and a modest increase in hepatic LDL receptor. In contrast, OVX resulted in a mild elevation of plasma cholesterol and no significant changes in total hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, or LDL receptor in female SD rats. Thus the greater severity of hypercholesterolemia in the female NAR appears to be due, in part, to a combination of the constrained compensatory upregulation of cholesterol 7alpha-hydroxylase and LDL receptor deficiency.


A mutation in CHN-1/CHIP suppresses muscle degeneration in Caenorhabditis elegans.
Duchenne muscular dystrophy (DMD) is one of the most severe X-linked, inherited diseases of childhood, characterized by progressive muscle wasting and weakness as the consequence of mutations in the dystrophin gene. The protein encoded by dystrophin is a huge cytosolic protein that links the intracellular F-actin filaments to the members of the dystrophin-glycoprotein-complex (DGC). Dystrophin deficiency results in the absence or reduction of complex components that are degraded through an unknown pathway. We show here that muscle degeneration in a Caenorhabditis elegans DMD model is efficiently reduced by downregulation of chn-1, encoding the homologue of the human E3/E4 ubiquitylation enzyme CHIP. A deletion mutant of chn-1 delays the cell death of body-wall muscle cells and improves the motility of animals carrying mutations in dystrophin and MyoD. Elimination of chn-1 function in the musculature, but not in the nervous system, is sufficient for this effect, and can be phenocopied by proteasome inhibitor treatment. This suggests a critical role of CHIP/CHN-1-mediated ubiquitylation in the control of muscle wasting and degeneration and identifies a potential new drug target for the treatment of this disease.


A novel approach for the biosynthesis of silver nanoparticles using the defensive gland extracts of the beetle, Luprops tristis Fabricius.
Discovering novel natural resources for the biological synthesis of metal nanoparticles is one of the two key challenges facing by the field of nanoparticle synthesis. The second challenge is a lack of information on the chemical components needed for the biological synthesis and the chemical mechanism involved in the metal nanoparticles synthesis. In the current study, microwave-assisted silver nanoparticle (AgNP) synthesis employing the defensive gland extract of Mupli beetle, Luprops tristis Fabricius (Order: Coleoptera; Family: Tenebrionidae), addresses these two challenges. This study was conducted without killing the experimental insect. Earlier studies in our laboratory showed the presence of the phenolic compounds, 2,3-dimethyl-1,4-benzoquinone, 1,3-dihydroxy-2-methylbenzene, and 2,5-dimethylhydroquinone in the defensive gland extract of L. tristis. The results of the current study show that the phenolic compounds in the defensive gland extract of the beetle has the ability to reduce silver ions into AgNPs and also acts as a good capping and stabilizing agent. A possible mechanism for the reduction of silver nitrate (AgNO3) into AgNPs is suggested. The synthesized AgNPs were characterized by Ultraviolet-Visible (UV-Vis) spectroscopy, Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy energy-dispersive X-ray (SEM-EDX) analysis and high-resolution transmission electron microscopic (HR-TEM) techniques. The stability of biologically synthesized nanoparticles was studied by zeta potential analysis. The TEM analysis confirmed that AgNPs are well dispersed and almost round shaped. The average size of nanoparticle ranges from 10 to 20 nm. EDX analysis showed that silver is the prominent metal present in the nanomaterial solution. The AgNPs synthesized have antibacterial property against both Staphylococcus aureus and Escherichia coli. Radical scavenging (DPPH) assay was used to determine the antioxidant activity of the AgNPs. AgNPs exhibited anticancer activity in a cytotoxicity experiment against Dalton's lymphoma ascites (DLA) cell line.


MR-Clust: clustering of genetic variants in Mendelian randomization with similar causal estimates.
Mendelian randomization is an epidemiological technique that uses genetic variants as instrumental variables to estimate the causal effect of a risk factor on an outcome. We consider a scenario in which causal estimates based on each variant in turn differ more strongly than expected by chance alone, but the variants can be divided into distinct clusters, such that all variants in the cluster have similar causal estimates. This scenario is likely to occur when there are several distinct causal mechanisms by which a risk factor influences an outcome with different magnitudes of causal effect. We have developed an algorithm MR-Clust that finds such clusters of variants, and so can identify variants that reflect distinct causal mechanisms. Two features of our clustering algorithm are that it accounts for differential uncertainty in the causal estimates, and it includes 'null' and 'junk' clusters, to provide protection against the detection of spurious clusters. Our algorithm correctly detected the number of clusters in a simulation analysis, outperforming methods that either do not account for uncertainty or do not include null and junk clusters. In an applied example considering the effect of blood pressure on coronary artery disease risk, the method detected four clusters of genetic variants. A post hoc hypothesis-generating search suggested that variants in the cluster with a negative effect of blood pressure on coronary artery disease risk were more strongly related to trunk fat percentage and other adiposity measures than variants not in this cluster. MR-Clust can be downloaded from https://github.com/cnfoley/mrclust. Supplementary data are available at Bioinformatics online.


Cerebrospinal fluid rhinorrhea and intraventricular pneumocephalus due to intermittent shunt obstruction.
Cerebrospinal fluid rhinorrhea and intraventricular pneumocephalus occurred in an adolescent with aqueduct stenosis whose ventriculoperitoneal shunt occluded repeatedly due to a faulty on-off control. The possible mechanisms are discussed, the urgency of treatment is stressed, and the risk of pneumocephalus when a shunt is used to treat cerebrospinal fluid rhinorrhea is pointed out.


Effect of a textured insole on balance and gait symmetry.
Asymmetry of standing balance and gait is common in individuals with neurological disorders, and achieving symmetrical stance and gait is an important goal of rehabilitation. The purpose of this study was to investigate the effect of a novel discomfort-induced approach (that is based on using a single textured insole) on the alteration in the symmetry of gait and balance. Eleven healthy subjects (6 females and 5 males, mean age of 28.0 ± 4.1 years) were tested using the Computerized Dynamic Posturography and GaitRite systems when standing or walking while wearing standard footwear with the textured insole positioned either in the left or in the right shoe, and without the insole. Significant immediate effect of the textured insole was seen in the outcome measures of static (weight bearing) and dynamic (weight symmetry index, strength symmetry) balance tests (p < 0.05) as well as in gait symmetry (single support and swing phases) (p < 0.05). The results of the study indicate that a textured insole can significantly modify the symmetry of stance and gait in healthy individuals. Pilot data from individuals with stroke also showed a reduction in the asymmetry of gait when walking with the single textured insole in the shoe on the unaffected side. This outcome provides support for future studies on the efficacy of the textured insole in minimizing asymmetry of gait and posture in individuals in need.


Mechanisms underlying the protective potential of alpha-tocopherol (vitamin E) against haloperidol-associated neurotoxicity.
The undesired side-effects of haloperidol treatment include a number of extrapyramidal side-effects which have been proposed to result from drug-induced damage to the basal ganglia. The drug also causes irregular movements and locomotor patterns in experimental animals. Here we show that haloperidol treatment in rats is associated with increases in the expression of p53 and the ratio of pro-apoptotic (Bax) to anti-apoptotic (Bcl-2/Bcl-x(L)) proteins in the hippocampus and caudate putamen (CPu). In addition, haloperidol induces the DNA binding activity of the redox-sensitive nuclear factor-kappa B (NF-kappaB) and concomitantly upregulates the levels of the phosphorylated form of IkappaBalpha protein in vivo. Similar responses are observed when a mouse hippocampal cell line (HT-22) is treated with haloperidol and/or vitamin E. Interestingly, all of these biochemical effects of haloperidol are significantly attenuated when animals or cultured cells are pretreated with alpha-tocopherol (vitamin E). Consistent with this, vitamin E is demonstrated to substantially reduce the haloperidol-induced impairment of locomotor activity in rats. Collectively, the data indicate the usefulness of vitamin E as an adjunct to haloperidol treatment and provide initial clues about the underlying molecular mechanisms involved in these effects.


In vivo activity of 11beta-hydroxysteroid dehydrogenase type 1 and free fatty acid-induced insulin resistance.
Free fatty acids (FFAs) induce hepatic insulin resistance and enhance hepatic gluconeogenesis. Glucocorticoids (GCs) also stimulate hepatic gluconeogenesis. The aim of this study was to investigate whether the FFA-induced hepatic insulin resistance is mediated by increased activity of hepatic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), accompanied by elevated hepatic cortisol levels. Following a 10-h overnight fast, six healthy male volunteers were investigated. A euglycaemic hyperinsulinaemic clamp was performed during lipid or saline infusion. To assess hepatic 11beta-HSD1 activity, plasma cortisol levels were measured after oral administration of cortisone acetate during lipid or saline infusion. In addition, 11beta-HSD activities were determined in vivo by calculating the urinary ratios of GC metabolites. Lipid infusion increased FFAs (5.41 +/- 1.00 vs. 0.48 +/- 0.20 mmol/l; P < 0.005) and significantly increased insulin resistance [glucose infusion rate (GIR) 6.02 +/- 2.60 vs. 4.08 +/- 2.15 mg/kg/min; P < 0.005]. After lipid and saline infusions no changes in 11beta-HSD1 activity were found, neither by changes in cortisone acetate to cortisol conversion nor by differences in urinary free cortisol (UFF) or cortisone (UFE), 5beta-tetrahydrocortisol (THF), 5alpha-THF, cortisone (THE), UFF/UFE and (5alpha-THF + THF)/THE ratios. We found no change in hepatic and whole-body 11beta-HSD1 activity during acute FFA-induced insulin resistance. Further studies are necessary to clarify whether 11beta-HSD1 in muscle and adipose tissue is influenced by FFAs and whether 11beta-HSD1 is involved in other conditions of insulin resistance.


Investigation of Triangle Terthiophene and Hydroxyphenylbenzothiazole Configured Fluorescent Dye with a Triple Bond Bridge.
A photochromic dye was constructed by incorporation of a carbon-carbon triple bond spaced triangle terthiophene skeleton and hydroxyphenylbenzothiazole. Regular photochromic behavior was investigated with alternated UV (254 nm) and visible light (≥ 400 nm) irradiation. The color of dye in solution can be cycled between pink and colorless. Additionally, the dye solution strongly fluoresces in THF with the absolute quantum yield (QY) being 0.56. When irradiation with 254 nm light, the emissive solution can be effectively quenched to photo-stationary sate (Φ = 0.05). An emission "on-off" cycle could be established based on the UV/visible light irradiation cycle. The photochromic dye also exhibits good photo- and thermal-stability at room temperature. The emission decay profile indicates typical single component character with the fluorescence lifetime being 6.68 ns. The emission color was determined by the CIE 1931 coordinates of x = 0.14, y = 0.25 in the blue region.


Energetic heavy ions overcome tumor radioresistance caused by overexpression of Bcl-2.
Overexpression of Bcl-2 is frequent in human cancers and has been associated with radioresistance. Here we investigated the potential impact of heavy ions on Bcl-2 overexpressing tumors. Bcl-2 cells (Bcl-2 overexpressing HeLa cells) and Neo cells (neomycin resistant gene-expressing HeLa cells) exposed to gamma-rays or heavy ions were assessed for the clonogenic survival, apoptosis and cell cycle distribution. Whereas Bcl-2 cells were more resistant to gamma-rays (0.2keV/microm) and helium ions (16.2keV/microm) than Neo cells, heavy ions (76.3-1610keV/microm) yielded similar survival regardless of Bcl-2 overexpression. Carbon ions (108keV/microm) decreased the difference in the apoptotic incidence between Bcl-2 and Neo cells, and prolonged G(2)/M arrest that occurred more extensively in Bcl-2 cells than in Neo cells. High-LET heavy ions overcome tumor radioresistance caused by Bcl-2 overexpression, which may be explained at least in part by the enhanced apoptotic response and prolonged G(2)/M arrest. Thus, heavy-ion therapy may be a promising modality for Bcl-2 overexpressing radioresistant tumors.


Using the "final-on-four" concept to deliver an immediate metal-resin implant-fixed complete dental prosthesis.
In traditional dental implant therapy, the time between implant placement and delivery of the definitive prosthesis can be long and uncomfortable for a patient wearing a conventional removable denture on an atrophied ridge. New clinical protocols, often with tilted implants, are being used to immediately restore mandibular implants with interim restorations, thus shortening the patient's return to function. However, these conversion type interim restorations do not decrease the time to definitive prosthetic rehabilitation. The Ohio State University (OSU) developed an immediate load surgical and prosthetic protocol to compensate for the disadvantages of previous techniques. With this protocol, a custom, definitive, screw-retained metal-resin fixed prosthesis can be delivered 2 to 4 days postoperatively and has been described using 5 implants. This clinical report presents the OSU immediate loading protocol, combined with a tilted implant technique, for the fabrication of a mandibular metal-resin implant fixed complete dental prosthesis (MRIFCDP) in 3 days postoperatively and with only 4 implants. Replacing the mandibular dentition with an immediate load-fixed metal-resin prosthesis by means of the "final-on-four" technique resulted in a custom, definitive, and functional restorative solution immediately after surgery.


Cytokine-gene-modified tumor vaccination intensified by a streptococcal preparation OK-432.
Vaccinations with tumor cells engineered to express certain cytokines have been demonstrated to induce potent and specific antitumor immunity. In our previous report, we carried out a comparative study on the ability of cytokine-gene-modified tumor vaccines to induce host immune responses, and found that irradiated tumor cells, genetically modified to secrete granulocyte/macrophage-colony-stimulating factor (GM-CSF tumor vaccine), were the most potent stimulators of systemic antitumor immunity. In this report, using the experimental tumor models in which the GM-CSF tumor vaccine was less effective in immunopotentiation, we found that the combined use of a biological response modifier (BRM) OK-432 remarkably enhanced the antitumor activity induced by the GM-CSF tumor vaccine. These data indicate the possible role of a BRM such as OK-432 to intensify further the specific tumor vaccination therapy.


[The validity and reliability of the Spanish version of the Severe Cognitive Impairment Profile (SCIP) for the cognitive assessment of persons with advanced stages of Alzheimer's disease].
Few validated tools exist in Spanish for conducting a precise assessment of the cognitive functioning of persons with advanced dementia. This population is a challenge due to the large number of persons who reach these states and owing to the complexity of the care that they require. This study presents a validated Spanish version of an instrument, the Severe Cognitive Impairment Profile (SCIP), which allows assessment of the cognitive functioning of persons with advanced Alzheimer's disease. We conducted a cross-sectional study with 133 subjects (29 males and 104 females; mean age: 81.61 ± 7.41 years) diagnosed with Alzheimer's disease in moderate to very severe stages, according to the Global Deterioration Scale (GDS 5-7). The following were performed: discrimination analyses of the items, a study of the internal consistency and interrater reliability and test-retest. Likewise, the factorial structure and the validity of the instrument were also tested. Only 1% of the 160 items on the scale were found to be non-discriminatory. The internal consistency of the scale is adequate, as is the interrater and the test-retest reliability. As regards the validity of the construct, the correlation with the mini-mental state examination is 0.74 (p < 0.01) and significant differences are found between the SCIP and the three levels of the GDS that were analysed. The factorial structure of the scales shows the existence of a single factor that accounts for 66.12% of the variance. The SCIP scale is a useful, reliable and valid instrument for the exhaustive evaluation in Spanish of the cognitive functions of persons with dementia in moderate to very severe states.


Multiplexed protein analysis using antibody microarrays and label-based detection.
This chapter describes methods for the production and use of antibody microarrays. The experimental methods are divided into three sections. The first gives information relating to the preparation and handling of antibodies and the production of microarrays. The second relates to the preparation of the samples, from either blood, tissue, or cell lysates. The third section describes methods for using the samples on antibody microarrays. Two related detection methods are described in which the proteins of a sample to be analyzed are labeled with a tag to allow detection after capture on antibody microarrays.


[Experimental and clinical studies on application of vitamin A to cancer treatment].
Retinol-type vitamin A enhances cytocidal effect of several anticancer agents or radiation in in vitro as well as in vivo. We describe therapeutic effect fo a combination therapy of vitamin A and other agents which has been applied to cancer patients since 1972. We also discuss a possible role of vitamin A in the efficient synergistic effect.


E.s.r. study of the alkaline degradation of disaccharides in methyl sulfoxide.
The degradation of a series of deoxy sugars and disaccharides in methyl sulfoxide-tetrabutylammonium hydroxide has been studied by e.s.r. spectroscopy. The generation of radicals and the types of radical formed are dependent on the anomeric configuration of non-reducing moieties and on the positions of the linkages and deoxy groups. Mechanisms for the pathways of degradation are proposed.


Chronic access to endoneurial space using an arterial autograft.
A technique for direct chronic infusion of compounds onto peripheral axons has been investigated in the rat sciatic nerve. A 2 cm segment of the femoral artery was removed and one end inserted into the endoneurial space of the contralateral peroneal nerve fascicle of the same animal. The other end of the artery was connected to a catheter system to allow infusion into the endoneurium, thus bypassing the barrier that the perineurium presents to hydrophilic compounds. The patency of this arterial access system was evaluated by the ability of 20 microliters of 2% lidocaine to inhibit the toe-spreading reflex. The results of the study were that the infusion system remained operational for 3-7 days after transplantation. There were histologic changes in the nerve but there were no functional deficits due to the surgery. Although a long-term endoneurial infusion was not achieved, the limited access time to the axons might be long enough for applications such as the delivery of nerve growth factors to injured nerve.


Examining the knowledge, attitude and use of research by nurses.
This study sought to determine the knowledge, attitudes and use of research by nurses. There is little evidence about whether nurses are aware of using research and how much research they use in their clinical practice. Using a descriptive design, 347 registered and Enrolled Nurses completed the Edmonton Research Orientation Survey. Senior Nurse Managers were more likely to have a positive attitude towards research, and completion of university subjects on nursing research was significant in determining attitude and knowledge of research. All nurses, regardless of position identified barriers to performing research. Nurses require specific research education, clinical nursing leadership and work environments conducive to ensure practice is evidenced-based. A positive attitude towards research by Senior Nurse Managers has the potential to influence other nurses in establishing an active nursing research culture and promote evidence-based practice in the workplace.


Interactions of triiodothyronine, insulin and dexamethasone on the binding of human LDL to rat hepatocytes in monolayer culture.
Rat hepatocytes were maintained for the first 24 h in culture in the presence of 10% (v/v) newborn calf serum and then for a further 16 h in serum-free medium containing 2 g bovine serum albumin per litre. The presence of 1-100 nM triiodothyronine (T3) in the second incubation significantly increased binding of human 125I-LDL to the LDL receptor. Unlike insulin, T3 was unable to reverse the decrease in binding brought about by dexamethasone. The increased binding to the LDL receptor produced by insulin and T3 was additive. We conclude that T3, insulin and glucocorticoids may play important roles in regulating plasma LDL concentrations by direct effect on LDL uptake by the liver.


Anatomic repair of anomalies of ventriculo-arterial connection (REV). Results of a new technique in cases associated with pulmonary outflow tract obstruction.
From November 1980 to November 1986, 63 patients aged 4 months to 13 years (mean 3.4 years) underwent repair of anomalies of ventriculo-arterial connection with ventricular septal defect and pulmonary outflow tract obstruction, using a technique (REV) first described by us in 1982. The selection of patients was based on preoperative criteria, namely the measurement of the distance between the tricuspid and the semilunar valves. These measurements enabled us to select from patients with an abnormal ventriculo-arterial connection, those in whom the anomaly could be repaired by intra-ventricular partition alone. In the remaining cases, REV was indicated in the presence of pulmonary stenosis. The principles of the technique are: (1) resection of the infundibular septum creating a large, direct and subarterial communication between the left ventricle and the aorta; (2) construction of a straight left ventricle to aorta tunnel by intraventricular partition; (3) direct anastomosis of the pulmonary trunk to the right ventricle. There were 12 hospital deaths (19%). The mean follow-up was 32 months. One patient died suddenly 1 year after repair. Six patients required reoperation. All survivors are in NYHA class I, except for 3 patients who are in class II. No stenosis of the left ventricular outflow tract was found but 5 patients had a significant pressure gradient at the pulmonary outflow tract level. Our present experience suggests that in properly selected patients, REV allows anatomic repair in a wide variety of anomalies of the ventriculo-arterial connection associated with VSD and pulmonary outflow tract obstruction with an acceptable rate of mortality and morbidity.