Characterization of functionalized multiwalled carbon nanotubes and comparison of their cellular toxicity between HEK 293 cells and zebra fish in vivo.
Carbon nanotubes (CNTs) hold tremendous potential due to their unique and modifiable properties. Their robust biological applications necessitate minimizing their cytotoxicity and increasing the solubilization. In the present manuscript, we have functionalized multiwalled carbon nanotubes (MWCNTs) using defect functionalization methodology to covalently bind carboxy and amino groups on their walls. This functionalization was reassured through fourier-transform infrared spectroscopy (FTIR), energy dispersive x-ray analysis (EDX), elemental and field emission scanning electron microscopy (FE-SEM) analysis. The observations demonstrated that addition of carboxy as well as amino groups on MWCNTs, besides enabling MWCNTs solubilization also significantly ameliorated the cytotoxicity and the oxidative stress in comparison to pristine MWCNTs. It is envisaged that changes in agglomeration of the functionalized MWCNTs and the acquired surface charge is the reason for the reduction of cytotoxicity. Zebra fish embryo model test system employed for in vivo analysis of the MWCNTs showed no significant toxicity on account of any nanoparticle tested pointing towards intrinsic mechanisms in place for deterring the damage in complex organisms. Overall, the observations besides pointing towards functionalized MWCNTs effectiveness towards weakening the toxicity of pristine MWCNTs also caution for extrapolating in vitro data to in vivo observations. The observations further lend credibility for exploiting the zebra fish as a model system for analyzing the effects of MWCNTs functionalization.


Cyanide and azide behave in a similar fashion versus cuprozinc-superoxide dismutase.
The 1H NMR spectra of the cyanide adduct of Cu2Co2-superoxide dismutase have been remeasured at pH 7.5. The exchange rate of CN- is slow on the NMR time scale. The correlation with the spectrum of the unligated enzyme has been established through saturation-transfer techniques of the system in which 50% of the cyanide adduct is formed and through comparison with the spectrum of a Cu2Co2-superoxide dismutase-CN- sample in which the histidines have been deuterium labeled at the position epsilon 1. The similarities between the spectra of the CN- and N-3 derivatives are stressed, in particular with respect to the removal from copper coordination of the same histidine, assigned as His-46.


Genital hypertrophy: a neonatal pseudotumor in females.
A newborn female presented with a perineal and pelvic pseudotumor due to genital hypertrophy. This entity should not be confused with interlabial or cul-de-sac masses that require surgical intervention.


Aerosol jet printing of piezoelectric surface acoustic wave thermometer.
Surface acoustic wave (SAW) devices are a subclass of micro-electromechanical systems (MEMS) that generate an acoustic emission when electrically stimulated. These transducers also work as detectors, converting surface strain into readable electrical signals. Physical properties of the generated SAW are material dependent and influenced by external factors like temperature. By monitoring temperature-dependent scattering parameters a SAW device can function as a thermometer to elucidate substrate temperature. Traditional fabrication of SAW sensors requires labor- and cost- intensive subtractive processes that produce large volumes of hazardous waste. This study utilizes an innovative aerosol jet printer to directly write consistent, high-resolution, silver comb electrodes onto a Y-cut LiNbO3 substrate. The printed, two-port, 20 MHz SAW sensor exhibited excellent linearity and repeatability while being verified as a thermometer from 25 to 200 ∘C. Sensitivities of the printed SAW thermometer are - 96.9 × 1 0 - 6 ∘ C-1 and - 92.0 × 1 0 - 6 ∘ C-1 when operating in pulse-echo mode and pulse-receiver mode, respectively. These results highlight a repeatable path to the additive fabrication of compact high-frequency SAW thermometers.


Relationships between sites of abdominal pain and the organs involved: a prospective observational study.
Abdominal pain is one of the most frequent chief complaints in primary care settings. The aim of the present study was to determine the positive likelihood ratios (PLRs) and negative likelihood ratios (NLRs) of the relationships between the sites of abdominal pain and the organs involved. Prospective observational study. A single tertiary centre, a university hospital in Japan. A total of 2591 new outpatients visited the Department of General Medicine at a university hospital from April 2017 to March 2018. Of these, 326 patients aged ≥20 years with abdominal pain were enrolled. Sites of abdominal pain were classified into 11 categories including nine different abdominal sections, 'generalised abdomen' and 'site-indeterminate'. The PLRs between 'right subcostal' and 'liver and biliary tract'; between 'right subcostal' and 'musculoskeletal' ; between 'epigastric' and 'oesophagus, stomach and duodenum'; between 'right or left flank' and 'urinary tract'; between 'left flank' and 'dermatological'; and between 'mid-lower' and 'intestinal' ranged from 2.17 to 4.14. The PLRs between 'epigastric' and 'urinary tract'; between 'mid-lower' and 'liver and biliary tract'; between 'periumbilical' and 'urinary tract'; and between 'generalised abdomen' and 'oesophagus, stomach and duodenum' were low, ranging from 0.17 to 0.25. The NLR ranged from 0.5 to 1.5, excluding the relationship between 'left flank' and 'dermatological'. The presence of pain at right subcostal, epigastric, right or left flank and mid-lower sites might be useful for identifying the organs involved. Additionally, the presence of pain at mid-lower, epigastric, periumbilical and generalised abdominal sites might be helpful for denying the involvement of some organs. Some sites of abdominal pain can be indicative of the organs involved.Trial registration numberUMIN000037686.


Recent advances in research on Alzheimer's disease in China.
China has the largest number of individuals with dementia worldwide. Alzheimer's disease (AD) is a growing global health issue that seriously threatens human health and quality of life and imposes a significant burden on families and society. To date, no treatment exists that can delay AD progression. This review describes the current understanding of AD in China, including its prevalence, cost burden, diagnosis, and treatment, and summarizes the major advances in AD in China, including government strategies and research. Such findings highlight the need for a brain health action plan to prevent and control AD and to reduce its increasing prevalence and dementia-related costs in China.


Opicapone (Ongentys): A New COMT Inhibitor for the Treatment of Parkinson's Disease.
To describe the safety and efficacy of opicapone, a newly Food and Drug Administration-approved catechol-O-methyltransferase (COMT) inhibitor, as an adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease (PD) experiencing off episodes. A literature search through PubMed and International Pharmaceutical Abstracts (January 2000 to October 2020) was conducted using the following search terms: Ongentys, opicapone, COMT inhibitor, Parkinson's disease, and Parkinson's. Articles selected included those describing preclinical and clinical studies examining the pharmacokinetics, efficacy, and/or safety of opicapone. In preclinical trials, opicapone demonstrated marked S-COMT inhibition, despite its short half-life, while maintaining an acceptable safety and efficacy profile. Results from phase 3 clinical trials further supported the safety and efficacy of opicapone as an adjunct to levodopa. In addition, opicapone, at a dose of 50 mg once daily, was shown to be superior to placebo and noninferior to entacapone in reducing time spent in the off state. Adverse effects commonly reported with opicapone include dyskinesias, constipation, hypotension/syncope, increased blood creatine kinase, and decreased weight. Additional medications, such as COMT inhibitors, become necessary adjunctive treatments as the disease progresses. Compared to other COMT inhibitors currently on the US market, opicapone offers the advantage of once-daily dosing. Opicapone is a safe and effective COMT inhibitor shown to reduce off episodes in patients with PD.


An office-based immunodiagnostic assay for detecting urinary nuclear matrix protein 52 in patients with bladder cancer.
To report the rapid (5 min) and simple detection of a nuclear matrix protein (NMP) in the urine of patients with bladder cancer, using a newly developed office-based dot-enzyme-linked immunosorbent assay (ELISA). Western blot and specific immunoglobulin-G antibody were used to identify the urinary NMP marker. Urine samples from 149 patients with bladder cancer and 72 controls were evaluated using the developed dot-ELISA. The initial responses of 43 patients treated by irradiation were followed using the assay. The NMP marker was identified in the urine of patients with bladder cancer at 52 kDa (NMP-52) by Western blot. The dot-ELISA detected the urinary NMP-52 marker in 92% of patients with squamous cell carcinoma, 98% with transitional cell carcinoma, and all six of those with adenocarcinoma of the bladder, with a specificity of 94%. The positive and negative predictive values (97% and 94%, respectively) and efficiency (96%) of the dot-ELISA were high. In addition, the NMP-52 tumour marker was not detected in the urine of patients who showed a response after radiotherapy. Detecting the urinary NMP-52 marker using dot-ELISA would be helpful in the rapid diagnosis and follow-up of patients with bladder cancer.


Ten-year clinical outcome of a prospective randomized clinical trial of laparoscopic Nissen versus anterior 180( degrees ) partial fundoplication.
A randomized trial of laparoscopic Nissen fundoplication and anterior 180 degrees partial fundoplication was undertaken to determine whether the anterior procedure might reduce the incidence of dysphagia and other adverse outcomes following surgery for gastro-oesophageal reflux disease. This study evaluated clinical outcomes after 10 years. Some 107 patients were randomized to undergo laparoscopic Nissen or anterior 180 degrees partial fundoplication. Ten-year data were not available for 18 patients. Information was obtained from 89 patients (48 Nissen, 41 anterior fundoplication) using a standard clinical questionnaire that focused on symptoms of reflux, potential postoperative side-effects and overall satisfaction with the outcome of surgery. There were no significant differences between the two groups with regard to reflux symptoms, dysphagia, abdominal bloating, ability to belch and overall satisfaction. Between 5 and 10 years after surgery, revisional surgery was required for reflux in two patients after anterior fundoplication. Two patients had revision after Nissen fundoplication, for reflux and recurrent hiatus hernia. Both laparoscopic anterior 180 degrees partial and Nissen fundoplication are safe, effective and durable at 10 years' follow-up. Most patients are satisfied with the clinical outcome.


CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation.
Hematopoietic stem cells (HSCs) reside at the apex of the hematopoietic differentiation hierarchy and sustain multilineage hematopoiesis. Here, we show that the transcriptional regulator CITED2 is essential for life-long HSC maintenance. While hematopoietic-specific Cited2 deletion has a minor impact on steady-state hematopoiesis, Cited2-deficient HSCs are severely depleted in young mice and fail to expand upon aging. Moreover, although they home normally to the bone marrow, they fail to reconstitute hematopoiesis upon transplantation. Mechanistically, CITED2 is required for expression of key HSC regulators, including GATA2, MCL-1, and PTEN. Hematopoietic-specific expression of anti-apoptotic MCL-1 partially rescues the Cited2-deficient HSC pool and restores their reconstitution potential. To interrogate the Cited2→Pten pathway in HSCs, we generated Cited2;Pten compound heterozygous mice, which had a decreased number of HSCs that failed to reconstitute the HSC compartment. In addition, CITED2 represses multiple pathways whose elevated activity causes HSC exhaustion. Thus, CITED2 promotes pathways necessary for HSC maintenance and suppresses those detrimental to HSC integrity.


Elastic stockings or Tubigrip for ankle sprain: a randomised clinical trial.
Ankle sprains are common and generally believed to be benign and self-limiting. However, a significant proportion of patients with ankle sprains have persistent symptoms for months or even years. The study aimed to evaluate whether elastic stockings improve recovery following ankle sprain. All patients within 72 h of ankle sprain were identified in Accident & Emergency or the Fracture Clinic. Consenting patients, stratified for sex, were randomised to either: (i) Tubigrip or (ii) class II below knee elastic stockings (ESs, Medi UK Ltd.) which were fitted immediately and worn until the patient was pain-free and fully mobile. The deep veins of the injured legs were imaged by duplex Doppler for deep vein thrombosis (DVT) at 4 weeks. Outcome was compared using the American Orthopaedic Foot and Ankle Score (AOFAS) and SF12v2 for quality of life. In the 36 randomised patients, the mean (95% confidence interval (CI)) circumference of the injured ankle treated by ES was 23.5 (23-24)cm initially and 22 (22-23) and 22 (21-22.5)cm at 4 and 8 weeks (p<0.001) compared with 24 (23-25) cm initially and 24 (23-25) and 24 (23-24.5) cm using Tubigrip (p<0.001). By 8 weeks, the mean AOFAS and SF12v2 scores were significantly improved by ES at 99 (8.1) and 119 (118-121) compared with 88 (11) and 102 (99-107) with Tubigrip (p<0.001). Of the 34 duplex images at 4 weeks, none had a DVT. Elastic compression improves recovery following ankle sprain.


Excretion of methimazole in human milk.
It is universally stated that antithyroid drugs are concentrated in human milk and are thus contraindicated during breast-feeding. We recently showed, however, that propylthiouracil (PTU) was not concentrated in milk and a study has now been made of the excretion of another widely used antithyroid drug carbimazole (CMI) in human milk. Methimazole (MMI) in blood and milk from five lactating women was measured after oral administration of CMI 40 mg, which is rapidly and completely transformed to the active antithyroid compound MMI. One hour after CMI, the mean serum-MMI reached 253 microgram/I and the mean concentration of MMI in milk reached 182 microgram/I. MMI was found to be unionized and not to be protein bound in serum, and it occurred in milk in the same concentration as the serum; the mean milk/serum ratio was 0.98. The mean total amount of MMI excreted in milk over 8 h was 34 microgram (SEM +/- 5, n = 5), i.e. 0.14% of the dose administered.


The family and harmonious medical decision making: cherishing an appropriate Confucian moral balance.
This essay illustrates what the Chinese family-based and harmony-oriented model of medical decision making is like as well as how it differs from the modern Western individual-based and autonomy-oriented model in health care practice. The essay discloses the roots of the Chinese model in the Confucian account of the family and the Confucian view of harmony. By responding to a series of questions posed to the Chinese model by modern Western scholars in terms of the basic individualist concerns and values embedded in the modern Western model, we conclude that the Chinese people have justifiable reasons to continue to apply the Chinese model to their contemporary health care and medical practice.


Methods for internal quality control in the mycobacteriology laboratory.
A proposal is given for internal quality control in the mycobacteriology laboratory by continuously monitoring the yields of positive results in microscopy and culture as well as the contamination rates of the culture media. The figures thus obtained can be processed as is customary done in clinical chemistry in order not only to detect deviations, but also to discern whether they are due to chance or whether they indicate a change in the quality of performance. Some examples are given to illustrate the possibilities offered by this control system.


Non-invasive tumor microenvironment evaluation and treatment response prediction in gastric cancer using deep learning radiomics.
The tumor microenvironment (TME) plays a critical role in disease progression and is a key determinant of therapeutic response in cancer patients. Here, we propose a noninvasive approach to predict the TME status from radiological images by combining radiomics and deep learning analyses. Using multi-institution cohorts of 2,686 patients with gastric cancer, we show that the radiological model accurately predicted the TME status and is an independent prognostic factor beyond clinicopathologic variables. The model further predicts the benefit from adjuvant chemotherapy for patients with localized disease. In patients treated with checkpoint blockade immunotherapy, the model predicts clinical response and further improves predictive accuracy when combined with existing biomarkers. Our approach enables noninvasive assessment of the TME, which opens the door for longitudinal monitoring and tracking response to cancer therapy. Given the routine use of radiologic imaging in oncology, our approach can be extended to many other solid tumor types.


Regulation of poly(ADP-ribose) polymerase-1 functions by leukocyte elastase inhibitor/LEI-derived DNase II during caspase-independent apoptosis.
Poly(ADP-ribose) polymerase-1 (PARP-1) is an important regulator of apoptosis. Its over-activation at the onset of apoptosis can inhibit the action of apoptotic endonucleases like caspase-activated DNase and DNAS1L3. Therefore, controlled PARP-1 proteolysis during caspase-dependent apoptosis is considered essential to promote DNA degradation. Yet, little is known about the interplay of PARP-1 and endonucleases that operate during caspase-independent cell death. Here we show that in the long-term cultured HeLa cells which undergo caspase-independent death, PARP-1 co-immunoprecipitates with leukocyte elastase inhibitor-derived DNase II (L-DNase II), an acid DNase implicated in this death pathway and activated by serine proteases. Our results indicate that, despite having putative poly(ADP-ribose)-acceptor sites, LEI/L-DNase II is neither significantly poly(ADP-ribosyl)ated nor inhibited by PARP-1 during caspase-independent apoptosis. Unexpectedly, caspase-independent apoptosis induced by hexa-methylene amiloride, LEI/L-DNase II can activate PARP-1 and promote its auto-poly(ADP-ribosyl)ation, thus inhibiting PARP-1 activity. Moreover, overexpression of LEI blocks the pro-survival effect of PARP-1 in this model of cell death. Our results provide the original evidence for a new mechanism of PARP-1 activity regulation in the caspase-independent death pathway involving LEI/L-DNase II.


Seasonal effect on steroids in blood plasma and seminal plasma of boars.
Unconjugated testosterone (T), 5a-androst-16-en-3-one (delta-16), dihydrotestosterone (DHT), unconjugated (u Oe) and conjugated oestrogens (c Oe) were determined weekly in the peripheral blood plasma and seminal plasma of 8 boars for a period of 15 months. Four of the boars were kept under natural daylength fluctuations (8-17 h), and 4 boars on a light programme which shifted these fluctuations by half a year. In peripheral plasma of all boars the highest concentrations were found for c Oe (17 ng/ml) followed by delta-16 (7.3), T (2.2) DHT (0.75) and u Oe (0.24). In seminal plasma of all boars (with an average volume of 172 ml) the highest concentrations were again found for c Oe (5.9 ng/ml) followed by delta-16 (1.1), u Oe (0.73), T (0.28) and DHT (0.1). This shows that u Oe reach higher concentrations in seminal plasma than in blood plasma. In boars under the influence of natural daylight steroids fluctuated with season. Maximum concentrations were present from October till December. Minimum concentrations were about 1/10 of the maximum concentrations. All steroids measured in blood and semen were similarly affected and all were highly correlated. In boars on an artificial light programme the off-season depression during the summer was completely restored. This indicates that daylight fluctuations are the main reason for seasonal changes of testicular function in the domestic boar.


[Removal of thrombus associated with ablation of atrial fibrillation -- the role of intracardiac echocardiography].
Lef atrial thrombus formation during ablation of atrial fibrillation carries the risk of thrombo-embolic complications. We describe a case of a 55 year old male in whom thrombus formation was detected by intracardiac echocardiography. Thrombus was safely removed by aspiration into transseptal sheath.


A Plasmodium falciparum GLURP-MSP3 chimeric protein; expression in Lactococcus lactis, immunogenicity and induction of biologically active antibodies.
Plasmodium falciparum malaria is a major cause of morbidity and mortality worldwide. To evaluate the efficacy of a possible vaccine antigen against P. falciparum infection, a fusion protein, derived from P. falciparum Glutamate-rich protein (GLURP) genetically coupled to P. falciparum Merozoite surface protein 3 (MSP3) was produced in Lactococcus lactis as a secreted recombinant GLURP-MSP3 fusion protein. The hybrid protein was purified to homogeneity by ion exchange and hydrophobic-interaction chromatography and its composition was verified by MALDI MS, SDS/PAGE and Western blotting with antibodies against antigenic components of GLURP and MSP3. Mice immunized with the hybrid protein produced higher levels of both GLURP- and MSP3-specific antibodies than mice immunized with either GLURP, MSP3 or a mix of both. The protective potential of the hybrid protein was also demonstrated by in vitro parasite-growth inhibition of mouse anti-GLURP-MSP3 IgG antibodies in a monocyte-dependent manner. These results indicate that the GLURP-MSP3 hybrid could be a valuable strategy for future P. falciparum vaccine development.


Ontogeny of the immune system in carp (Cyprinus carpio L.). The appearance of antigenic determinants on lymphoid cells detected by mouse anti-carp thymocyte monoclonal antibodies.
Mouse anti-carp thymocyte monoclonal antibodies were used to investigate the appearance of lymphoid cell determinants in young carp. Determinants detected by clone WCT 4 were present on thymocytes as soon as the thymus was visible histologically, day 4 after fertilization (a.f.) at 21 degrees C, but WCT 4-positive lymphocytes were not present in the pronephros until day 7 a.f.. In contrast, determinants detected by monoclonal antibodies from clones WCT 8 and WCT 10 appeared on thymocytes from day 7 a.f. at 21 degrees C, and WCT 8-positive and WCT 10-positive lymphocytes were not detected in the pronephros until days 16 and 12 a.f., respectively. These results are discussed in relation to the appearance of determinants detected by anti-carp serum immunoglobulin antisera.


A systematic review of meta-analyses assessing the validity of tumour response endpoints as surrogates for progression-free or overall survival in cancer.
Tumour response endpoints, such as overall response rate (ORR) and complete response (CR), are increasingly used in cancer trials. However, the validity of response-based surrogates is unclear. This systematic review summarises meta-analyses assessing the association between response-based outcomes and overall survival (OS), progression-free survival (PFS) or time-to-progression (TTP). Five databases were searched to March 2019. Meta-analyses reporting correlation or regression between response-based outcomes and OS, PFS or TTP were summarised. The systematic review included 63 studies across 20 cancer types, most commonly non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer. The strength of association between ORR or CR and either PFS or OS varied widely between and within studies, with no clear pattern by cancer type. The association between ORR and OS appeared weaker and more variable than that between ORR and PFS, both for associations between absolute endpoints and associations between treatment effects. This systematic review suggests that response-based endpoints, such as ORR and CR, may not be reliable surrogates for PFS or OS. Where it is necessary to use tumour response to predict treatment effects on survival outcomes, it is important to fully reflect all statistical uncertainty in the surrogate relationship.


Structure and regulation of the BsYetJ calcium channel in lipid nanodiscs.
BsYetJ is a bacterial homolog of transmembrane BAX inhibitor-1 motif-containing 6 (TMBIM6) membrane protein that plays a key role in the control of calcium homeostasis. However, the BsYetJ (or TMBIM6) structure embedded in a lipid bilayer is uncharacterized, let alone the molecular mechanism of the calcium transport activity. Herein, we report structures of BsYetJ in lipid nanodiscs identified by double electron-electron resonance spectroscopy. Our results reveal that BsYetJ in lipid nanodiscs is structurally different from those crystallized in detergents. We show that BsYetJ conformation is pH-sensitive in apo state (lacking calcium), whereas in a calcium-containing solution it is stuck in an intermediate, inert to pH changes. Only when the transmembrane calcium gradient is established can the calcium-release activity of holo-BsYetJ occur and be mediated by pH-dependent conformational changes, suggesting a dual gating mechanism. Conformational substates involved in the process and a key residue D171 relevant to the gating of calcium are identified. Our study suggests that BsYetJ/TMBIM6 is a pH-dependent, voltage-gated calcium channel.


Probiotic nasal spray development by spray drying.
The upper respiratory tract (URT) is the main entrance point for many viral and bacterial pathogens, and URT infections are among the most common infections in the world. Recent evidences by our own group and others imply the importance of lactobacilli as gatekeepers of a healthy URT. However, the benefits of putting health-promoting microbes or potential probiotics, such as these URT lactobacilli, in function of URT disease control and prevention is underestimated, among others because of the absence of adequate formulation modalities. Therefore, this study entails important aspects in probiotic nasal spray development with a novel URT-derived probiotic strain by spray drying. We report quantitative and qualitative analysis of several spray-dried formulations, i.e. powders for reconstitution, based on disaccharide or sugar alcohol combinations with a polymer, including their long-term stability. Four formulations with the highest survival of >109 (Colony Forming Units) CFU/g after 28 weeks were further examined upon reconstitution which confirmed sufficiency of one bottle/dosage form during 7 days and rheological properties of shear-thinning. Tests also demonstrated maintained viability and cell morphology overall upon spraying through a nasal spray bottle in all 4 formulations. Lastly, application suitability in terms of high adherence to Calu-3 cells and antimicrobial activity against common URT pathogens was demonstrated and was not impacted neither by powder production process nor by spraying of reconstituted powder through a nasal spray device.


Mutagenic effect and mutation spectrum induced by 3H decay in the 8th position of DNA purine bases in Saccharomyces cerevisiae.
Lethal and mutagenic effects and the mutation spectrum induced by 3H decay in the 8th position of adenine and guanine in yeast DNA have been studied. For haploid cells labelled with [8-3H]deoxyadenosinemonophosphate (8-3H-A) and [8-3H]deoxyguanosinemonophosphate (8-3H-G), the lethal efficiencies were determined as (3.0 +/- 0.8) X 10(-3) decay-1 and (3.8 +/- 0.6) X 10(-3) decay-1, respectively, and the mutagenic efficiencies as (5.7 +/- 1.1) X 10(-8) decay-1 and (8.7 +/- 1.4) X 10(-8) decay-1, respectively. The lethal effect of [8-3H]purines may be explained as being due to internal beta-irradiation. In contrast, the local effect of 3H-transmutation was twice as mutagenic as beta-irradiation when the induction of forward gene mutations was examined. Within the spectrum of mutations induced by 8-3H-G, a preference for GC----AT transitions was observed.


Protective effect of enzymatic hydrolysates from seahorse (Hippocampus abdominalis) against H2O2-mediated human umbilical vein endothelial cell injury.
Oxidative stress-mediated endothelial dysfunction and LDL oxidation have been implicated in the pathogenesis of atherosclerosis. Thus, the protection of the endothelial cells against oxidative stress-mediated injury and the inhibition of LDL oxidation by the use of antioxidants are a good strategy against atherosclerosis development. Here, we investigated the protective effect and the inhibition of LDL oxidation of seahorse H. abdominalia hydrolysates by Alcalase (SHAH). SHAH showed higher antioxidant activities by measuring DPPH, ABTS+, and ORAC assays than the other hydrolysates. SHAH reduced the formation of thiobarbituric acid reactive substance in Cu2+-induced LDL oxidation. In human umbilical vein endothelial cell (HUVEC), SHAH ameliorated H2O2-mediated HUVEC injury through the restoration of antioxidant enzyme activities and glutathione. In addition, SHAH inhibited HUVEC apoptosis through the down-regulation of caspase-3 and p53 and the increase bcl-2/bax ratio. These results suggested that seahorse H. abdominalia could be developed as potential agents for atherosclerosis.


Long-term results with the Gn-RH analogue, buserelin, in metastatic prostate cancer.
LH-RH analogues have come into use to suppress the synthesis of testosterone by the testes and to induce palliation in advanced prostate cancer. Twenty-one patients were treated with buserelin (Hoe 766), and 19 were evaluable. Stages of disease were D1-D2. Seventeen patients responded to treatment, 3 patients are still in partial response, and 16 underwent progression. The median time to progression was 12 months (range, 3-36), and the median follow-up time was 10 months (mean, 25.4; range, 5-48).


Technique of using the St. Jude aortic connector with the radial artery.
We present a technique for the use of St. Jude Aortic Connector System with the radial artery. This technique will allow surgeons, who prefer the radial artery to the vein, to use this approach whenever feasible.


Effect of dipyrone and thalidomide alone and in combination on STZ-induced diabetic neuropathic pain.
Diabetic neuropathy is recognized as one of the most common complications of chronic diabetes, but its pathophysiological mechanism is complex and yet to be completely explored. Monotherapy with conventional analgesics fails to provide adequate pain relief in peripheral diabetic neuropathy. There are a number of evidence suggesting that tumor necrosis factor (TNF-α) plays an important role in the pathogenesis of peripheral diabetic neuropathy. TNF-α up-regulation activates nuclear factor κB, which further up-regulates cyclooxygenase (COX)-2 leading to altered prostaglandin profile. Inhibition of TNF-α and COX-2 provides beneficial effect on diabetic neuropathy by decreasing the oxidative stress level and by preventing neuronal hypersensitivity due to an increased prostaglandin level. The present study was designed to assess the effect of dipyrone and thalidomide on streptozotocin (STZ)-induced neuropathic pain behavior in rats. STZ 50 mg/kg, i.p. was administered to induce experimental diabetes in the rats. Three weeks following STZ, dipyrone (300 and 600 mg/kg, i.p.) and thalidomide (25 and 50 mg/kg, i.p.) alone and subeffective dose combination of dipyrone and thalidomide (300 and 25 mg/kg(-1), i.p.) administered daily for 2 weeks significantly attenuated thermal hyperalgesia, mechanical allodynia, and formalin-induced phase-2 flinching response. Moreover, the subeffective dose combination of dipyrone and thalidomide and preemptive treatment with thalidomide (50 mg/kg) reduces oxidative stress in diabetic rats. In conclusion, the combination of subeffective dose of dipyrone and thalidomide prevented the development and maintenance of experimental diabetic neuropathy. The combination of thalidomide (TNF-α inhibitor) and dipyrone (COX inhibitor) may be used as a potential therapeutic agent for the treatment of diabetic neuropathy.


Spontaneous closure of non-cavernous sinus dural arteriovenous fistulas: A case series and systematic review of the literature.
To report 9 new cases of non-cavernous sinus dural arteriovenous fistulas (NCS-DAVFs) that closed spontaneously and systematically review reports of other cases in the literature. We performed a retrospective analysis of 9 cases from 2 institutions of NCS-DAVFs that closed spontaneously. Using PubMed and Scopus in accordance with the PRISMA guidelines, we systematically reviewed English language articles about NCS-DAVFs showing spontaneous closure. Review of the cases from 2 institutions identified 9 cases of NCS-DAVFs showing spontaneous closure in follow-up magnetic resonance angiography (MRA), and the systematic review of the literature yielded an additional 38 cases, which had been diagnosed by repeated arteriography. Collectively, the patients included 23 men and 24 women with a mean age of 54 years. The shunts were located in the transverse-sigmoid sinus in 24 cases (51%), anterior condylar confluence in 11, and other locations in 12. Based on the venous drainage pattern on arteriography, 27 cases (57%) were classified as low-risk NCS-DAVF (without cortical venous reflux) and 17 were classified as high-risk NCS-DAVF (with cortical venous reflux). Shunt closure was observed within 3 months in 17 cases (36%). Extrinsic predisposing factors for shunt closure were detected in 14 cases (30%). These included angiography in 7 cases, sinus recanalization in 4, development of sinus occlusion in 2, and sinus compression by a newly developed hematoma in 1. Spontaneous closures of NCS-DAVFs can occur for both high- and low-risk types. One-third of these closures occur within 3 months.


Spatio-temporal pattern and associate factors of intestinal infectious diseases in Zhejiang Province, China, 2008-2021: a Bayesian modeling study.
Despite significant progress in sanitation status and public health awareness, intestinal infectious diseases (IID) have caused a serious disease burden in China. Little was known about the spatio-temporal pattern of IID at the county level in Zhejiang. Therefore, a spatio-temporal modelling study to identify high-risk regions of IID incidence and potential risk factors was conducted. Reported cases of notifiable IID from 2008 to 2021 were obtained from the China Information System for Disease Control and Prevention. Moran's I index and the local indicators of spatial association (LISA) were calculated using Geoda software to identify the spatial autocorrelation and high-risk areas of IID incidence. Bayesian hierarchical model was used to explore socioeconomic and climate factors affecting IID incidence inequities from spatial and temporal perspectives. From 2008 to 2021, a total of 101 cholera, 55,298 bacterial dysentery, 131 amoebic dysentery, 5297 typhoid, 2102 paratyphoid, 27,947 HEV, 1,695,925 hand, foot and mouth disease (HFMD), and 1,505,797 other infectious diarrhea (OID) cases were reported in Zhejiang Province. The hot spots for bacterial dysentery, OID, and HEV incidence were found mainly in Hangzhou, while high-high cluster regions for incidence of enteric fever and HFMD were mainly located in Ningbo. The Bayesian model showed that Areas with a high proportion of males had a lower risk of BD and enteric fever. People under the age of 18 may have a higher risk of IID. High urbanization rate was a protective factor against HFMD (RR = 0.91, 95% CI: 0.88, 0.94), but was a risk factor for HEV (RR = 1.06, 95% CI: 1.01-1.10). BD risk (RR = 1.14, 95% CI: 1.10-1.18) and enteric fever risk (RR = 1.18, 95% CI:1.10-1.27) seemed higher in areas with high GDP per capita. The greater the population density, the higher the risk of BD (RR = 1.29, 95% CI: 1.23-1.36), enteric fever (RR = 1.12, 95% CI: 1.00-1.25), and HEV (RR = 1.15, 95% CI: 1.09-1.21). Among climate variables, higher temperature was associated with a higher risk of BD (RR = 1.32, 95% CI: 1.23-1.41), enteric fever (RR = 1.41, 95% CI: 1.33-1.50), and HFMD (RR = 1.22, 95% CI: 1.08-1.38), and with lower risk of HEV (RR = 0.83, 95% CI: 0.78-0.89). Precipitation was positively correlated with enteric fever (RR = 1.04, 95% CI: 1.00-1.08), HFMD (RR = 1.03, 95% CI: 1.00-1.06), and HEV (RR = 1.05, 95% CI: 1.03-1.08). Higher HFMD risk was also associated with increasing relative humidity (RR = 1.20, 95% CI: 1.16-1.24) and lower wind velocity (RR = 0.88, 95% CI: 0.84-0.92). There was significant spatial clustering of IID incidence in Zhejiang Province from 2008 to 2021. Spatio-temporal patterns of IID risk could be largely explained by socioeconomic and meteorological factors. Preventive measures and enhanced monitoring should be taken in some high-risk counties in Hangzhou city and Ningbo city.


Prospective 1-year follow-up study comparing joint prosthesis with tendon interposition arthroplasty in treatment of trapeziometacarpal osteoarthritis.
Osteoarthritis of the thumb basal joint is a common and disabling condition. This clinical follow-up study compares the efficacy of total basal joint replacement surgery with that of tendon interposition arthroplasty. Ninety-eight patients (mean age, 60 years +/- 1) with severe trapeziometacarpal joint osteoarthritis (Eaton-Littler stage 2.4 +/- 0.1) were included in this prospective follow-up study. Based on written and verbal information, the patients could choose either a cementless, unconstrained, hydroxyapatite-coated trapeziometacarpal joint prosthesis or abductor pollicis longus tendon interposition arthroplasty. Clinical outcome parameters were determined preoperatively and at 3, 6, and 12 months postoperatively. Furthermore, osteo-integration and osteo-fixation of the implants were radiologically analyzed after 12 months. Joint replacement surgery resulted in faster and better pain relief, stronger grip functions, improved range of motion, and faster convalescence than did tendon interposition arthroplasty. After 12 months, patients with joint prostheses had regained the same strength and range of motion as in the asymptomatic contralateral thumb. After 12 months, osteolysis had developed in the vicinity of 2 cups, but there were no signs of implant loosening. The prosthesis surgery was not associated with more complications than occurred with tendon interposition arthroplasty. This study demonstrates that patients with joint prostheses achieve faster convalescence with better patient comfort and improved strength and range of motion without any increased risk of complications than do patients treated with tendon interposition arthroplasty at 1-year follow up. However, a randomized clinical trial with long-term follow-up is required.


Expression and localization of pannexin-1 hemichannels in human colon in health and disease.
Pannexin-1 (Panx1) proteins can function as channels for adenosine triphosphate (ATP) release, but there have been limited studies investigating their potential role in the human intestine. The aim of this study was to characterize Panx1 expression and distribution in the human colon and its potential involvement in inflammatory bowel diseases (IBD). Human colon segments were dissected into mucosa and muscularis layers, and evaluated for Panx1 expression by real-time PCR and Western blotting. Immunohistochemistry was conducted to localize the cellular distribution of Panx1 in intact tissues. In the colonic muscularis of ulcerative colitis (UC), Panx1 mRNA expression showed a 3.5-fold reduction compared with control (P = 0.0015), but no change was seen in UC mucosa. In contrast, down-regulation of Panx1 mRNA was observed in both muscularis and mucosa of Crohn's disease (CD), showing a 2.7- and 1.8-fold reduction, respectively (P < 0.05). There was reduced Panx1 protein expression in CD muscularis, but no change in CD mucosa, UC muscularis, or UC mucosa. Pannexin-1 immunoreactivity was mainly localized to enteric ganglia, blood vessel endothelium, erythrocytes, epithelial cells, and goblet cells. Inflammatory bowel disease samples showed a similar overall pattern of Panx1 staining, but in UC myenteric ganglia, there was a significant reduction in Panx1 immunoreactivity. Significant Panx1 positive leukocyte infiltrations were seen at the sites of inflammation. The presence of Panx1 in the colon and changes to its distribution in disease suggests that Panx1 channels may play an important role in mediating gut function and in IBD pathophysiology.


SLWE-Net: An improved lightweight U-Net for Sargassum extraction from GOCI images.
The Sargassum bloom has severely impacted the ecological environment of the East China Sea and the Yellow Sea, causing significant economic losses. In recent years, deep learning has seen extensive development due to its outstanding feature extraction capabilities. However, the deep learning process typically involves a large number of parameters and computations. To address this issue, this paper proposes a lightweight deep learning network based on the U-Net framework, called SLWE-NET, which uses lightweight modules to replace the feature extraction modules in U-Net. In this experiment, SLWE-Net performed the best in both extraction accuracy and model lightweight. Compared to the formal U-Net, the number of parameters decreased by 65.83 %, the model size reduced from 94.97 MB to 32.51 MB, and the mIoU increased to 93.81 %. Therefore, the method proposed in this paper is beneficial for Sargassum extraction and provides a basis for operational monitoring.


Whole saliva proteases: development of methods for determination of origins.
1) Recognition and characterization of protease activities present in saliva by PAGE examination of substrate protein cleavage patterns appears possible. 2) BSA proteolysis by whole saliva is not due to activities present in the major gland secretions and may be due, in part, to the oral microflora.


Understanding silibinin's modes of action against HCV using viral kinetic modeling.
Legalon® SIL (SIL) is a chemically hydrophilized version of silibinin that has exhibited high antiviral effectiveness against hepatitis C virus (HCV). Its main mode of action (MOA) remains unclear, with contradicting in vitro studies supporting either suppression of entry and cell-to-cell spread or suppression of viral RNA synthesis as the main MOA. We sought to provide new insights into SIL's MOA in HCV genotype-1/4 patients receiving intravenous SIL monotherapy for 7 days via mathematical modeling. Changes in HCV RNA in 25 patients receiving 10, 15, or 20mg/kg/day of SIL were analyzed and modeled using viral kinetic methods. In 15 patients, the virus declined in a biphasic manner, in which a sharp drop between days 0 and 2 was followed by a slower second phase of decline. In 10 patients, the initial decline was weaker and the virus declined in a single phase over the 7-day period. The blocking production effectiveness, ε, was dose-dependent with mean ε=0.49 and 0.89 in the 10 or 15 and 20mg/kg/day dosing groups, respectively (p=0.02). The effectiveness of blocking viral infection, η, was estimated as 0.60 with no significant differences across dosing groups. For all patients, the mean rate of viral load decline measured between days 2 and 7 was high (0.3 log(10)IU/ml/day), i.e., 4-fold higher than typically observed during the 2nd phase of (pegylated)-interferon-α±ribavirin treatment. Modeling HCV kinetics in vivo suggests that SIL may block both viral infection and viral production/release with its main dose-dependent effect being blocking viral production/release.


NetBID2 provides comprehensive hidden driver analysis.
Many signaling and other genes known as "hidden" drivers may not be genetically or epigenetically altered or differentially expressed at the mRNA or protein levels, but, rather, drive a phenotype such as tumorigenesis via post-translational modification or other mechanisms. However, conventional approaches based on genomics or differential expression are limited in exposing such hidden drivers. Here, we present a comprehensive algorithm and toolkit NetBID2 (data-driven network-based Bayesian inference of drivers, version 2), which reverse-engineers context-specific interactomes and integrates network activity inferred from large-scale multi-omics data, empowering the identification of hidden drivers that could not be detected by traditional analyses. NetBID2 has substantially re-engineered the previous prototype version by providing versatile data visualization and sophisticated statistical analyses, which strongly facilitate researchers for result interpretation through end-to-end multi-omics data analysis. We demonstrate the power of NetBID2 using three hidden driver examples. We deploy NetBID2 Viewer, Runner, and Cloud apps with 145 context-specific gene regulatory and signaling networks across normal tissues and paediatric and adult cancers to facilitate end-to-end analysis, real-time interactive visualization and cloud-based data sharing. NetBID2 is freely available at https://jyyulab.github.io/NetBID .


Association between antiphospholipid antibodies and factor Bb in lupus nephritis patients with glomerular microthrombosis.
The mechanism of glomerular microthrombosis (GMT) in patients with lupus nephritis (LN) is largely unknown. The aim of this study is to investigate the association between antiphospholipid antibodies (aPLs) and factor Bb in LN patients with GMT. Patients with biopsy-proven LN hospitalized from July 2015 to July 2018 in our hospital were selected for this study. Levels of lupus anticoagulant (LAC), anticardiolipin antibodies (aCLs), anti-β2-glycoprotein I (anti-β2-GPI) antibodies and factor Bb were measured, and other clinical and pathological data were also obtained during the same period before renal biopsy. A total of 25 LN patients with GMT and 76 LN patients without GMT were included in this study. In LN patients with GMT, the presence of anti-β2GPI and LAC were both significantly higher than in those without GMT (P < .001 and P = .039, respectively). The level of factor Bb was also higher in LN patients with GMT than in those without GMT (P = .021). In the correlation analysis, Bb level was positively correlated with serum creatinine (r = 0.28, P = .014), activity index (r = 0.24, P = .021) GMT (r = 0.65, P < .001) and IgG-anti-β2GPI (r = 0.771, P < .001). Our work suggests that aPLs, especially IgG-anti-β2GPI, may play a role in the progress of GMT, and this process might involve alternative complement activation.


Neighborhood Deprivation and Association With Neonatal Intensive Care Unit Mortality and Morbidity for Extremely Premature Infants.
Socioeconomic status affects pregnancy and neurodevelopment, but its association with hospital outcomes among premature infants is unknown. The Area Deprivation Index (ADI) is a validated measure of neighborhood disadvantage that uses US Census Bureau data on income, educational level, employment, and housing quality. To determine whether ADI is associated with neonatal intensive care unit (NICU) mortality and morbidity in extremely premature infants. This retrospective cohort study was performed at 4 level IV NICUs in the US Northeast, Mid-Atlantic, Midwest, and South regions. Non-Hispanic White and Black infants with gestational age of less than 29 weeks and born between January 1, 2012, and December 31, 2020, were included in the analysis. Addresses were converted to census blocks, identified by Federal Information Processing Series codes, to link residences to national ADI percentiles. ADI, race, birth weight, sex, and outborn status. In the primary outcome, the association between ADI and NICU mortality was analyzed using bayesian logistic regression adjusted for race, birth weight, outborn status, and sex. Risk factors were considered significant if the 95% credible intervals excluded zero. In the secondary outcome, the association between ADI and NICU morbidities, including late-onset sepsis, necrotizing enterocolitis (NEC), and severe intraventricular hemorrhage (IVH), were also analyzed. A total of 2765 infants with a mean (SD) gestational age of 25.6 (1.7) weeks and mean (SD) birth weight of 805 (241) g were included in the analysis. Of these, 1391 (50.3%) were boys, 1325 (47.9%) reported Black maternal race, 498 (18.0%) died before NICU discharge, 692 (25.0%) developed sepsis or NEC, and 353 (12.8%) had severe IVH. In univariate analysis, higher median ADI was found among Black compared with White infants (77 [IQR, 45-93] vs 57 [IQR, 32-77]; P < .001), those who died before NICU discharge vs survived (71 [IQR, 45-89] vs 64 [IQR, 36-86]), those with late-onset sepsis or NEC vs those without (68 [IQR, 41-88] vs 64 [IQR, 35-86]), and those with severe IVH vs those without (69 [IQR, 44-90] vs 64 [IQR, 36-86]). In a multivariable bayesian logistic regression model, lower birth weight, higher ADI, and male sex were risk factors for mortality (95% credible intervals excluded zero), while Black race and outborn status were not. The ADI was also identified as a risk factor for sepsis or NEC and severe IVH. The findings of this cohort study of extremely preterm infants admitted to 4 NICUs in different US geographic regions suggest that ADI was a risk factor for mortality and morbidity after adjusting for multiple covariates.


A case for the role of memory consolidation in speech-motor learning.
This review will explore the role of memory consolidation in speech-motor learning. Existing frameworks of speech-motor control account for the protracted time course of building the speech-motor representation. These perspectives converge on the speech-motor representation as a multimodal unit that is comprised of auditory, motor, and linguistic information. Less is known regarding the memory mechanisms that support the emergence of a generalized speech-motor unit from instances of speech production. Here, we consider the broader learning and memory consolidation literature and how it may apply to speech-motor learning. We discuss findings from relevant domains on the stabilization, enhancement, and generalization of learned information. Based on this literature, we provide our predictions for the division of labor between conscious and unconscious memory systems in speech-motor learning, and the subsequent effects of time and sleep to memory consolidation. We identify both the methodological challenges, as well as the practical importance, of advancing this work empirically. This discussion provides a foundation for building a memory-based framework for speech-motor learning.


Psychosocial distress and the quality of life of cancer patients in two health facilities in Cameroon.
Psychosocial distress interferes with the ability to cope effectively with cancer, its physical symptoms and treatment. This in turn leads to poor outcomes in patients. The aim of this study was to assess the level of psychosocial distress, emotional distress and the quality of life of cancer patients in two health facilities in Cameroon. This study used a cross-sectional hospital-based design. The study was carried out over a period of three months from July-September 2020. The sample size was 120 cancer patients. A consecutive sampling technique was used to select participants. Three validated questionnaires were used: DT, HADS and EORTC QLQ-C30 to assess, psychosocial distress, emotional distress and quality of life respectively. Results were presented using descriptive (frequency, percentage, mean) and inferential statistics (Chi square, Pearson's correlation, ANOVA). Data were analysed with SPSS version 21. All statistics were considered significant at an alpha value set at 0.05 level. The majority of patients 83 (69.2%) presented with clinically significant distress, with financial difficulties 87 (72.5%), fatigue 83 (69.2%), transportation 73 (60.8%) and difficulties with work/school 69(57.5%) being the most reported problems. Fifty nine (50.0%) and 56(47.5%) had moderate to severe anxiety and depression symptoms respectively. Overall on HADS, 67 patients (56.8%) presented with emotional distress. The quality of life was fair, with a mean of 52.4 ± 21.3.There was a statistically significant negative relationship (P < 0.0001), between psychosocial distress and quality of life of patients. Cancer patients suffer from psychosocial distress, which has a negative relationship on their quality of life. It is important that healthcare professionals working in these settings, assess psychosocial distress early in patients with cancer to improve the quality of care and enhance quality of life.


Spontaneous renocolic fistula secondary to calculous pyonephrosis.
A rare case of spontaneous renocolic fistula is described, and the literature is reviewed.


Post-translational isoprenylation of cellular proteins is altered in response to mevalonate availability.
Cells incorporate isoprenoid products derived from mevalonate (MVA) into several unique proteins. The aim of this study was to delineate the effects of blocking MVA synthesis on the covalent isoprenylation of these proteins in murine erythroleukemia cells. Inhibition of protein synthesis with cycloheximide prevented the incorporation of [3H]MVA into proteins, suggesting that isoprenylation normally occurs immediately after synthesis of the polypeptides. However, incubation of cells with lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, for as little as 1 h prior to addition of cycloheximide rendered the isoprenylation step insensitive to cycloheximide. Lovastatin had no apparent effect on the stability of the isoprenylated proteins, but the development of cycloheximide insensitivity during the lovastatin preincubation was dependent on synthesis of new protein during that period. Addition of 50-200 microM MVA to the culture medium eliminated the effects of preincubation with lovastatin. Preincubation of cells with 25-hydroxycholesterol, which suppresses the synthesis and enhances the degradation of HMG-CoA reductase but is not a competitive enzyme inhibitor, did not induce cycloheximide-insensitivity of the isoprenylation reaction. The results suggest that blocking MVA synthesis with lovastatin causes a rapid depletion of isoprenoid groups available for protein modification. Consequently, there is an accumulation of non-isoprenylated substrate proteins. Shifts in the ratio of modified vs. unmodified proteins in response to MVA availability may have implications for the changes in cell morphology, cell proliferation and HMG-CoA reductase gene expression that occur when cells are subjected to MVA deprivation.


Radiotherapy of spontaneous carotid-cavernous sinus fistulas.
Between 1984 and 1986, 7 patients with spontaneous carotid-cavernous fistulas (CCF) were treated by radiotherapy delivering 3,000 cGy (200 cGy, 5 times per week) to the sellar region. Improvements of clinical signs and symptoms were seen in all patients within 6 months of treatment. During a follow-up period of 7 to 35 months, 6 patients remained in good clinical condition and only one patient developed a recurrence. As an adverse effect, one patient developed early menopause, but no other side-effects or complications were seen. Radiotherapy should be considered in patients with spontaneous CCF, when CCF are seen in middle-high aged patients and progressive without relief of symptoms.


Intratumoral injection of IL-12-encoding mRNA targeted to CSFR1 and PD-L1 exerts potent anti-tumor effects without substantial systemic exposure.
IL-12 is a potent cytokine for cancer immunotherapy. However, its systemic delivery as a recombinant protein has shown unacceptable toxicity in the clinic. Currently, the intratumoral injection of IL-12-encoding mRNA or DNA to avoid such side effects is being evaluated in clinical trials. In this study, we aimed to improve this strategy by further favoring IL-12 tethering to the tumor. We generated in vitro transcribed mRNAs encoding murine single-chain IL-12 fused to diabodies binding to CSF1R and/or PD-L1. These targeted molecules are expressed in the tumor microenvironment, especially on myeloid cells. The binding capacity of chimeric constructs and the bioactivity of IL-12 were demonstrated in vitro and in vivo. Doses as low as 0.5 μg IL-12-encoding mRNA achieved potent antitumor effects in subcutaneously injected B16-OVA and MC38 tumors. Treatment delivery was associated with increases in IL-12p70 and IFN-γ levels in circulation. Fusion of IL-12 to the diabodies exerted comparable efficacy against bilateral tumor models. However, it achieved tethering to myeloid cells infiltrating the tumor, resulting in nearly undetectable systemic levels of IL-12 and IFN-γ. Overall, tethering IL-12 to intratumoral myeloid cells in the mRNA-transferred tumors achieves similar efficacy while reducing the dangerous systemic bioavailability of IL-12.


An update on the role of human dendritic cells in patients with atopic dermatitis.
Dendritic cells (DCs) are without a doubt important key skin cells that connect information from the environment with the innate and adaptive immune system. Their function is decisive for the initiation and inhibition of immune responses, and therefore they play a central role for both the healthy and diseased states of the skin. The type, maturation stage, and function of DCs, as well as the micromilieu in which they are located and their contact with cellular partners in the surrounding area, are important cofactors that direct maintenance of immune homeostasis or breakout of inflammatory reactions in patients with chronic inflammatory skin diseases, such as atopic dermatitis. Thus better knowledge about the exact proinflammatory and anti-inflammatory properties of DCs in patients with atopic dermatitis and the disease-specific roles of DC subtypes would allow us to target these important immune cells with versatile functions for therapeutic purpose.


Chronic renal failure in methylmalonic acidaemia.
The renal function of 12 patients with non vitamin B12 responsive methylmalonic acidaemia has been investigated. Eight patients had reduced glomerular filtration rates, but the plasma creatinine concentration was only raised in those with values of less than 40 ml/min per 1.73 m2 surface area. The reduction in glomerular filtration was a function of the age and the severity of the disease. Plasma urate concentrations were increased in four patients but this may be secondary to the renal disease rather than its cause.


Self-Assembled Vanadium Oxide Nanoflakes for p-Type Ammonia Sensors at Room Temperature.
VO₂(B), VO₂(M), and V₂O₅ are the most famous compounds in the vanadium oxide family. Here, their gas-sensing properties were investigated and compared. VO₂(B) nanoflakes were first self-assembled via a hydrothermal method, and then VO₂(M) and V₂O₅ nanoflakes were obtained after a heat-phase transformation in nitrogen and air, respectively. Their microstructures were evaluated using X-ray diffraction and scanning and transmission electron microscopies, respectively. Gas sensing measurements indicated that VO₂(M) nanoflakes were gas-insensitive, while both VO₂(B) and V₂O₅ nanoflakes were highly selective to ammonia at room temperature. As ammonia sensors, both VO₂(B) and V₂O₅ nanoflakes showed abnormal p-type sensing characteristics, although vanadium oxides are generally considered as n-type semiconductors. Moreover, V₂O₅ nanoflakes exhibited superior ammonia sensing performance compared to VO₂(B) nanoflakes, with one order of magnitude higher sensitivity, a shorter response time of 14⁻22 s, and a shorter recovery time of 14⁻20 s. These characteristics showed the excellent potential of V₂O₅ nanostructures as ammonia sensors.


Interaction of reproductive tract infections with estrogen exposure on breast cancer risk and prognosis.
Reproductive tract infections influenced a series of inflammatory processes which involved in the development of breast cancer, while the processes were largely affected by estrogen. The present study aimed to explore the associations of breast cancer risk and prognosis with reproductive tract infections and the modification effects of estrogen exposure. We collected history of reproductive tract infections, menstruation and reproduction from 1003 cases and 1107 controls and a cohort of 4264 breast cancer patients during 2008-2018 in Guangzhou, China. We used logistic regression model to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for risk; Cox model was applied to estimate the hazard ratios (HRs) and 95% CIs for progression-free survival (PFS) and overall survival (OS). It was found that previous reproductive tract infections were negatively associated with breast cancer risk (OR = 0.80, 95%CI, 0.65-0.98), particularly for patients with more menstrual cycles (OR = 0.74, 95%CI, 0.57-0.96). Patients with previous reproductive tract infections experienced better OS (HR = 0.61; 95% CI, 0.40-0.94) and PFS (HR = 0.84; 95% CI, 0.65-1.09). This protective effect on PFS was only found in patients with more menstrual cycles (HR = 0.52, 95% CI:0.34-0.79, Pinteraction = 0.015). The findings suggested that reproductive tract infections may be protective for the initiation and development of breast cancer, particularly for women with a longer interval of lifetime estrogen exposure.


Pupil-BLAH-metry: cognitive effort in speech planning reflected by pupil dilation.
In reading research, a longstanding question is whether any stages of lexical processing require central attention, and whether such potential demands are frequency-sensitive. In the present study, we examined the allocation of cognitive effort in lexical processing by examining pupil dilations and naming latencies in a modified delayed naming procedure. In this dual-task/change procedure, participants read words and waited for various delays before being signaled to issue a response. On most trials (80%), participants issued a standard naming response. On the remaining trials, they were cued to abandon the original speech plan, saying "blah" instead, thereby equating production across different words. Using feature-matched low- and high-frequency words, we observed the differences in pupil dilations as a function of word frequency. Indeed, frequency-sensitive cognitive demands were seen in word processing, even after naming responses were issued. The results suggest that word perception and/or speech planning requires the frequency-sensitive allocation of cognitive resources.


Diminished Protective Effects of Household Income on Internalizing Symptoms among African American than European American Pre-Adolescents.
To investigate the differential role of race on the effect of household income on pre-adolescents' internalizing symptoms in a national sample of U.S. pre-adolescents. This is a cross-sectional study that used data from the Adolescent Brain Cognitive Development (ABCD) study. Wave 1 ABCD data included 5,913 adolescents between ages 9 and 10 years old. The independent variable was household income. The primary outcome was internalizing symptoms measured by the teacher report of the Brief Problem Monitor (BPM) scale. Overall, high household income was associated with lower levels of pre-adolescents internalizing symptoms. Race showed statistically significant interaction with household income on pre-adolescents' internalizing symptoms, controlling for all confounders, indicating weaker protective effect of high household income on internalizing symptoms for African American than European pre-adolescents. High household income is a more salient protective factor against internalizing symptoms of socially privileged European American pre-adolescents than of historically marginalized African Americans pre-adolescents. Elimination of internalizing behavioral gaps across racial groups requires more than equalizing socioeconomic status. Future research should study the moderating role of institutional and structural racism experienced by African American families across all income levels. Such research may explain why pre-adolescent African Americans with high household income remain at high risk of internalizing symptoms.


Life cycle greenhouse gases emissions from high-speed rail in Spain: The case of the Madrid - Toledo line.
The Madrid - Toledo high-speed rail (HSR) line is 74.5 km long, has an average speed of 140 km/h and a maximum speed of 270 km/h. It averages almost 104 million passenger-kilometres travelled and has a utilisation rate (passengers per available seats) of 0.75 as of 2019. This study analyses the life cycle greenhouse gases (GHG) emissions of the Madrid - Toledo HSR line using the life cycle assessment methodology, taking into consideration the stages of construction, maintenance and operation for the infrastructure, as well as the manufacturing, maintenance and operation stages for trains. The most significant stage is infrastructure construction, which accounts for an average 75 % emissions, followed by train operation, with an average 18.2 %. The results highlight several environmental benefits of the deployment of the line, as after 40 years of operation there will be an average 21 % reduction in GHG emissions for passenger mobility between Madrid and Toledo compared to the case where no HSR line was built. Moreover, the line's GHG emissions are offset between 19 and 23 years after starting operation, mainly due to the emissions avoided by passengers switching to a carbon-friendlier mode of transportation in terms of operation, and the adoption of a 100 % renewable energy mix for the operation of trains since 2019. These findings point to opportunities for improving the life cycle GHG emissions of high-speed rail lines, such as increasing the occupancy of trains by applying new pricing policies and investing in intermodal infrastructures to achieve higher modal shift rates, promoting proximity criteria for the supply of raw materials during the infrastructure construction stage and improving the maintenance stage to prolong the lifetime of the infrastructure, thus deferring life cycle emissions for longer.


Human tumour--lymphocyte interaction in vitro. V. Comparison of the reactivity of tumour-infiltrating, blood and lymph-node lymphocytes with autologous tumour cells.
Lymphocytes prepared from the blood, tumour-draining lymph node and tumour were tested for immune reactivity with freshly isolated autologous tumour cells from biopsies. Reactivity was assessed by the autologous tumour stimulation assay and by lymphocytotoxicity. Activity was found in 6/11 blood preparations, 7/10 lymph nodes and 1/7 tumour-infiltrating lymphocytes in tumour stimulation assays and in 6/19 blood, 8/18 lymph-node and 5/20 tumour-infiltrating lymphocytes in cytotoxicity assays. Tests with material from patients with nasopharyngeal carcinoma showed a higher frequency of cytotoxicity in the tumour-infiltrating lymphocytes than in other solid tumours. There was a correlation between results of the two assays when performed on the same preparations and between the levels of reactivity in lymph node and blood from the same patient. Cytotoxicity in the lymph nodes showed specificity in that cells from a long-term culture (K562) known to be sensitive to natural killer activity and from allogeneic tumour biopsies were only rarely damaged. Cytotoxicity against K562 was more frequently determined in blood lymphocytes. Tumour-infiltrating lymphocytes were non-reactive in patients when the blood and lymph-node lymphocytes were active.


Heart failure readmission reductions during the COVID-19 pandemic.
Behaviors, treatments, and self-management strategies used by patients and caregivers at home.


Melatonin alleviates cadmium toxicity by reducing nitric oxide accumulation and IRT1 expression in Chinese cabbage seedlings.
Melatonin (MT) is reported as a kind of phytohormone, exerts various biological activities, mediating plant growth and development and responding to abiotic stresses. In the present research, we examined the possibility that MT could involve in the alleviation of cadmium (Cd) toxicity by reducing the accumulation of nitric oxide (NO). The research indicated that the addition of MT significantly increased the biomass and photosynthetic parameters of plants compared with the control treated under Cd stress. Besides, we found that compared with the control treatment, MT also reduced the level of Cd-induced nitric oxide, and at the same time, the enzyme activity related to NO synthesis and the expression of related genes were decreased. In addition, MT treatment significantly reduced the Cd content in Chinese cabbage seedlings compared with the control, which was partially reversed by the addition of SNP (NO donor). PTIO (NO scavenger) addition could reduce the Cd content when seedlings were exposed to Cd stress. At the same time, compared with the Cd stress, the concentration of Cd in MT-treated plants decreased significantly, and the expression levels of related transport genes IRT1 also decreased significantly. Taken together, these results further support the idea that under the stress of Cd, NO increases the expression of IRT1, thus further increasing the absorption of Cd and aggravating the stress of Cd in plants, while exogenously added MT can inhibit the synthesis of NO, reduce the content of Cd, and alleviate the stress caused by Cd.


Associations between motorized transport access, out-of-home activities, and life-space mobility in older adults in Japan.
Motorized transport access and out-of-home activities are two potential correlates of Life-space mobility (LSM), a common research topic in mobility studies of older adults. These correlates remain mostly unexplored in previous literature and relating them with LSM can reveal directions for improving the LSM of older adults. The associations between motorized transport access, out-of-home activities, and LSM were examined using data from 1,333 older adults (mean age = 70.63) living in 15 cities and towns in Japan. LSM was assessed using composite life-space assessment (LSA) scores. Motorized transport access was measured using dummies showing whether a person had car access (divided into five levels) and used public transport (bus and railway), and out-of-home activities were measured using the number of various activities that were conducted during the most recent weekday and weekend day. Generalized linear models were used to assess the associations. The sample was dominated by males (74.42%), with more than half of the sample had their own cars. On average, each respondent had four activities during two survey days, and shopping was the most common activity. The results showed that owning a car and using railway, as well as various activities were associated with increased composite LSA scores, whereas no cars or only shared cars in home were associated with decreased composite LSA scores. However, these associations differed between males and females. In this study, different levels of motorized transport access and different types of out-of-home activities were found to associate differently with composite LSA scores. Based on these findings, we suggest that policymakers should provide more transport access, pay more attention to the LSM of older adults with high clinics/hospital activities, and trigger more shopping and daily leisure activities for older adults to improve the LSM of this population.


Consent for dental therapy in severely ill patients.
Delirium, dementia, or depression is frequently seen in association with severe medical illness. Usually transient, it is precipitated by the stress of systemic illness and the medications used to treat the underlying disease. Unrecognized, it may invalidate the informed consent required for the provision of emergency dental care services.


ST segment elevation in one lead: a case report.
We describe an unusual finding in an electrocardiogram showing ST-segment elevation not related to coronary artery stenosis, pericarditis, bundle branch block, or other well known disorders. A 60-year-old African American woman admitted for elective coronary artery bypass graft surgery. A temporary pacemaker with pacing wires was placed intraoperatively for prevention and treatment of postoperative bradyarrhythmia. One day following uneventful surgery, her electrocardiogram demonstrated marked ST segment elevation confined to lead V(6). These changes were comparable to tracings obtained from direct epicardial electrocardiogram, due to contact between the V(6) electrode and the temporary pacemaker ventricular lead wire. Current-of-injury patterns are represented on surface electrocardiogram by deviations of the ST segment from the isoelectric baseline. The pacing wire causes direct localized epicardial current-of-injury, affecting the action potential and the resting membrane potentials of cardiomyocytes. Our case report demonstrates epicardial current-of-injury pattern obtained via surface rather than epicardial electrocardiogram, with surface leads as surrogates of epicardial tracing. Measurement of ST-segment shifts from the epicardial electrocardiogram has been shown to provide a more sensitive measurement of ischemia when compared to surface precordial ECG.


Left ventricular thrombus incidence and behavior studied by serial two-dimensional echocardiography in acute anterior myocardial infarction: left ventricular wall motion, systemic embolism and oral anticoagulation.
Serial two-dimensional echocardiography was performed to detect left ventricular thrombus in 92 consecutive patients with a confirmed first acute anterior myocardial infarction. Thirty left ventricular thrombi were diagnosed in these 92 patients. The cumulative percent of identified thrombus in each echocardiographic examination in the surviving patients was 27% at less than 24 h; 57% at 48 to 72 h; 75% at 1 week and 96% at 2 weeks. The thrombus shape was defined as mural in 53% and protruding in 47% of patients. Systemic embolism (stroke) was noted during hospitalization in two patients with a protruding thrombus. At 12 weeks of follow-up, patients with thrombus had poorer (and almost unchanged from baseline) global left ventricular function as expressed by wall motion score compared with that of patients without thrombus, who exhibited significant improvement. Global left ventricular wall motion in patients with persisting or resolved thrombus was similar during follow-up. Apical wall motion worsened in 70% of the patients with persisting thrombus and in 25% of the patients with resolved thrombus (p less than 0.1). In the 22 surviving patients with thrombus, resolution or change in thrombus shape or size was noted in 14 of the 15 patients receiving anticoagulant therapy and in 4 of the 7 untreated patients. Six of the 18 patients with an early- (48 to 72 h) and none of the 12 patients with a later-formed thrombus died. Maximal serum enzyme levels, percent with Killip functional class III to IV and left ventricular wall motion score were higher in the patients with an early- than in those with a later-formed thrombus.(ABSTRACT TRUNCATED AT 250 WORDS)


Controversies in neuroimmunology: multiple sclerosis, vaccination, SARS-CoV-2 and other dilemas
Neuroimmunology is a discipline that increasingly broadens its horizons in the understanding of neurological diseases. At the same time, and in front of the pathophysiological links of neurological diseases and immunology, specific diagnostic and therapeutic approaches have been proposed. Despite the important advances in this discipline, there are multiple dilemmas that concern and filter into clinical practice. This article presents 15 controversies and a discussion about them, which are built with the most up-to-date evidence available. The topics included in this review are: steroid decline in relapses of multiple sclerosis; therapeutic recommendations in MS in light of the SARS-CoV-2 pandemic; evidence of vaccination in multiple sclerosis and other demyelinating diseases; overview current situation of isolated clinical and radiological syndrome; therapeutic failure in multiple sclerosis, as well as criteria for suspension of disease-modifying therapies; evidence of the management of mild relapses in multiple sclerosis; recommendations for prophylaxis against Strongyloides stercolaris; usefulness of a second course of immunoglobulin in the Guillain-Barré syndrome; criteria to differentiate an acute-onset inflammatory demyelinating chronic polyneuropathy versus Guillain-Barré syndrome; and, the utility of angiotensin-converting enzyme in neurosarcoidosis. In each of the controversies, the general problem is presented, and specific recommendations are offered that can be adopted in daily clinical practice.


Reducing Phthalate, Paraben, and Phenol Exposure from Personal Care Products in Adolescent Girls: Findings from the HERMOSA Intervention Study.
Personal care products are a source of exposure to potentially endocrine-disrupting chemicals such as phthalates, parabens, triclosan, and benzophenone-3 (BP-3) for adolescent girls. We enrolled 100 Latina girls in a youth-led, community-based participatory research intervention study to determine whether using personal care products whose labels stated they did not contain these chemicals for 3 days could lower urinary concentrations. Pre- and postintervention urine samples were analyzed for phthalate metabolites, parabens, triclosan, and BP-3 using high-performance liquid chromatography/tandem mass spectrometry. Urinary concentrations of mono-ethyl phthalate (MEP) decreased by 27.4% (95% CI: -39.3, -13.2) on average over the 3-day intervention; no significant changes were seen in urinary concentrations of mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP). Methyl and propyl paraben concentrations decreased by 43.9% (95% CI: -61.3, -18.8) and 45.4% (95% CI: -63.7, -17.9), respectively. Unexpectedly, concentrations of ethyl and butyl paraben concentrations increased, although concentrations were low overall and not detected in almost half the samples. Triclosan concentrations decreased by 35.7% (95% CI: -53.3, -11.6), and BP-3 concentrations decreased by 36.0% (95% CI: -51.0, -16.4). This study demonstrates that techniques available to consumers, such as choosing personal care products that are labeled to be free of phthalates, parabens, triclosan, and BP-3, can reduce personal exposure to possible endocrine-disrupting chemicals. Involving youth in the design and implementation of the study was key to recruitment, retention, compliance, and acceptability of the intervention. Harley KG, Kogut K, Madrigal DS, Cardenas M, Vera IA, Meza-Alfaro G, She J, Gavin Q, Zahedi R, Bradman A, Eskenazi B, Parra KL. 2016. Reducing phthalate, paraben, and phenol exposure from personal care products in adolescent girls: findings from the HERMOSA Intervention Study. Environ Health Perspect 124:1600-1607; http://dx.doi.org/10.1289/ehp.1510514.


[Preclinical imaging in animal models of radiation therapy].
Modern radiotherapy benefits from precise and targeted diagnostic and pretherapeutic imaging. Standard imaging modalities, such as computed tomography (CT) offer high morphological detail but only limited functional information on tumors. Novel functional and molecular imaging modalities provide biological information about tumors in addition to detailed morphological information. Perfusion magnetic resonance imaging (MRI) CT or ultrasound-based perfusion imaging as well as hybrid modalities, such as positron emission tomography (PET) CT or MRI-PET have the potential to identify and precisely delineate viable and/or perfused tumor areas, enabling optimization of targeted radiotherapy. Functional information on tissue microcirculation and/or glucose metabolism allow a more precise definition and treatment of tumors while reducing the radiation dose and sparing the surrounding healthy tissue. In the development of new imaging methods for planning individualized radiotherapy, preclinical imaging and research plays a pivotal role, as the value of multimodality imaging can only be assessed, tested and adequately developed in a preclinical setting, i.e. in animal tumor models. New functional imaging modalities will play an increasing role for the surveillance of early treatment response during radiation therapy and in the assessment of the potential value of new combination therapies (e.g. combining anti-angiogenic drugs with radiotherapy).


A theory of measurement error and its implications for spatial and temporal gradient sensing during chemotaxis. II. The effects of non-equilibrated ligand binding.
Cells generally chemotax along a direction in which their receptor occupancy gradient--whether spatial or temporal--is maximum. Occupancy differentials are, however, often so small as to be masked by thermal noise; i.e., by fluctuations inherent in the stochastic nature of ligand binding. Such fluctuations therefore impose a fundamental limit on the sensitivity of a cell's ability to detect a chemoattractant gradient. In order to pursue the implications of this limit, fluctuation theories have been developed. The theories assume that the signal is some function of the receptor occupancy gradient, allow an estimate of the standard deviation about the mean signal, and permit an evaluation of, among other things, the extent to which a receptor defect can impair an effective response. Previous theories have assumed an equilibrated ligand-receptor interaction. In this paper we introduce a generalized definition of a signal caused by a receptor occupancy gradient that allows us to develop a non-equilibrium theory of thermal noise. We show that previous formulations are a special case of the current development. More specifically, we find the following. Swimming cells subject to Brownian tumbling must generally average their signals over a very long time period to achieve a signal-to-noise ratio less than or equal to 1. Spatial gradient detection is possible with ligand-receptor equilibrium constants less than 10(3)M-1, but since such ligands are rare, theory predicts that tumbling cells will generally not detect gradients by measuring spatial occupancy differentials. These conclusions hold irrespective of whether chemical equilibrium is achieved. For crawling cells not subject to Brownian tumbling, a range of affinities exists in which spatial or temporal gradient detection is possible. In general a spatial mechanism is more efficient for low affinity ligands (dissociation times less than 0.3 s), whereas a temporal mechanism is more efficient for higher K. In this case the detection of gradients in slowly dissociating ligand will be facilitated if signal processing begins prior to chemical equilibration. An important new parameter is indicated by the theory. The definitions of a temporal gradient signal is based on estimating and comparing average occupancy over two time intervals displaced by a time t1. The theory predicts an optimal t1, of order milliseconds, that leads to the shortest minimum averaging time. For t1 values at and longer than the optimum, and for all averaging times exceeding some minimum, the cell will detect a temporal signal.(ABSTRACT TRUNCATED AT 400 WORDS)


Birth preparedness and complication readiness among husbands and its association with skilled birth attendance in southern Ethiopia.
Birth preparedness and Complication Readiness (BPCR) promotes prompt use of skilled delivery and readiness for any complications to reduce delays in the provision of emergency care. Husband's involvement in preparation for childbirth is one way to mitigate life-threatening delays in providing care during childbirth. The current study assessed the association of the husband's involvement in birth preparedness and complication readiness with the use of skilled birth attendants. A community-based cross-sectional study was conducted among 1,432 husbands. Study participants were selected from Arbaminch university health and demographic surveillance sites. Data were collected electronically using the Open Data Kit. The data were exported to STATA version 16 for analysis. Descriptive statistics were computed to describe the sociodemographic and reproductive variables of the study. The associations between birth preparedness and complication readiness practice and birth in the presence of a skilled birth attendant were assessed using multiple logistic regressions after adjusting for known confounders. Explanatory variables on bivariate logistic regression analysis were entered into multivariable logistic regression analysis, and a p-value of less than 0.05 was used to ascertain statistical significance. Mean age of respondents was 33.7 (SD ± 6.2) years. Of all the respondents, 140 (10.3%) had made at least three preparations according to birth preparedness and complication readiness. After controlling for confounders through multivariable logistic regression, giving birth in the presence of a skilled birth attendant consistently increased with husbands involved in birth preparedness and complication readiness (AOR = 4.1, 95% CI: 2.5-6.9). Husbands whose wives had complications during previous pregnancy were 33% less likely to have skilled birth attendants (AOR = 0.67, 95% CI: 0.49-0.917). Moreover, husbands whose houses were near the health facilities were more likely to have skilled birth attendants for their wives (AOR = 3.93, 95% CI: 2.57-6.02). Husband's involvement in birth preparedness and complication readiness is strongly associated with using skilled birth attendants in Ethiopia. It is imperative that when designing husband's involvement programs targeting birth preparedness and complication readiness, programs and strategies should focus on enhancing activities that are inclusive of husbands in birth preparedness and complication education.


Is wearing a face mask associated with symptomatic dry eye disease among medical students during the COVID-19 era? An online survey.
Coronavirus disease 2019 has necessitate the routine use of masks worldwide. This study assessed the relationship between wearing a facemask and dry eye disease (DED) among a sample of medical students in Jordan. This cross-sectional online survey enrolled medical students from all medical schools in Jordan. The questionnaire, which was shared via social media platforms, assessed sociodemographic information, ocular and medical history, facemask-wearing habits, the use of ocular devices, and the relationship with ocular discomfort. The ocular surface disease index (OSDI) questionnaire was also administered to quantify DED symptoms. A total of 1,219 students participated in this study. In total, 58.3% participants were females, and 52% were in the clinical science years. Symptomatic DED was found in 71.7% of participants. Female sex, basic science years, allergy reporting, and spending more than 6 h looking at screens were significantly associated with symptomatic DED. Wearing a facemask was not significantly associated with symptomatic DED. Further studies are needed to investigate the effect of wearing a facemask on the ocular surface.


Prevalence of malnutrition & anemia in preschool children; a single center study.
Malnutrition including undernutrition, overnutrition, and micronutrient deficiencies are considerable problems worldwide, with variable burdens among different communities. Its complications include physical and cognitive impairment, with the probability of irreversible lifelong consequences. We aimed to assess the prevalence of undernutrition, overweight, obesity, and anemia in preschoolers, being a risk group for developmental adverse events. We recruited 505 healthy preschool children, with a male: female ratio of 1.05:1. Children with chronic diseases were excluded. We used anthropometry and complete blood count to screen for malnutrition and anemia. The mean age of the study group was 3.8 ± 1.4 years (1.02-7). The screening results were average in 228 (45.1%) children, while 277 (54.9%) children had either abnormal anthropometry, anemia, or both. We observed undernutrition in 48 (9.5%) children; among them, 33 (6.6%) were underweight, 33 (6.6%) wasted, and 15 (3%) were stunted, with no significant difference between children aged below or above five. We identified overnutrition in 125 (24.8%); 43 (8.5%) were overweight, 12 (2.4%) were obese, and 70 (13.9%) had a high body mass index Z score, not qualifying the definition of overweight. Anemia was diagnosed in 141 (27.9%) children and was significantly more frequent among older children without gender discrimination. About 10% (50 children) had both anemia and abnormal anthropometry. The frequency of abnormal anthropometry was comparable between children with anemia and those with normal hemoglobin. Malnutrition and anemia in preschoolers are still a heavy burden affecting about half of our study group, with an upward trend towards the overnutrition side. Anemia is still a moderate public health problem in preschoolers.


The monkey safety test for neurovirulence of yellow fever vaccines: the utility of quantitative clinical evaluation and histological examination.
Two different derivatives of the 17D strain of yellow fever (YF) vaccine virus, i.e. ALV-free seed virus 6676 and three consecutive vaccine lots, A, B and C, obtained from another seed, were compared in monkey neurovirulence tests using rhesus and cynomolgus monkeys. In addition the ALV-contaminated seed lot AB 237 was safety tested in rhesus monkeys. According to WHO clinical criteria for acceptability, lots A, B, C and lot AB 237 consistently passed, while lot 6676 passed some tests and failed others. In the same tests, quantitative clinical evaluation and histological examination of CNS gave more definitive and consistent data on the higher degree of neurovirulence of lot 6676. Especially differentiating histological findings were obtained from some anatomical structures of the CNS ('discriminator areas') and almost no difference was found between the products in the structures apparently most susceptible to YF virus ('target areas'). Although some of the target and discriminator areas were different, cynomolgus monkeys were not less susceptible than rhesus monkeys to YF vaccine virus. The use of a quantitative method of scoring specific lesions in CNS of monkeys and the comparison of the average scores of a YF vaccine lot under study with a 'reference' vaccine, which has proven to be safe and effective in humans, should provide for a more reproducible method of assessing vaccine neurovirulence.


Understanding type 2 diabetes.
Practice profiles are reflective pieces written by nurses in practice and based on continuing professional development articles. This week Susan Ackroyd discusses type 2 diabetes.


Effects of high-pass filter frequency and slope on BAEP amplitude, latency and wave form.
The effects of increases in analogue high-pass filter frequency and slope on the BAEP were investigated in a group of 20 subjects. Frequency effects were additionally compared to the wide-band recorded signal and slope effects to a zero-phase shift filter, all filters being digitally simulated. Absolute amplitude, latency and interpeak latency were significantly reduced by both progressive filter frequency and steepness. Additionally, different effects on the ascending and descending limbs of waves I, III and V were observed which explain wave form distortions. The results suggest that filtering should be limited to, at most, 6 dB/oct and 100 Hz frequency.


Pharmacokinetics of metoprolol during pregnancy and lactation.
The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25-750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight-adjusted dose (n = 3). Because of the large, pregnancy-induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker.


Effect of androgen on the transcription of rat prostatic binding protein genes.
The mechanisms whereby androgens modulate mRNA levels for the C1, C2 and C3 prostatic binding protein genes in the rat ventral prostate have been investigated. Transcription rates for the 3 genes were lowered 2-3-fold upon castration but found to increase again upon re-administration of testosterone. Although this demonstrated a direct effect of androgens at the transcriptional level for these genes, the rates of mRNA synthesis were insufficient to account for previously observed steady-state measurements. This was confirmed by analysis of the nuclear steady-state levels for each mRNA following hormonal manipulation of the rats in vivo. It is concluded that besides direct transcriptional regulation, androgens must also exert a major effect of the half-life of these mRNAs in the rat ventral prostate.


MBD2-mediated transcriptional repression of the p14ARF tumor suppressor gene in human colon cancer cells.
The p14(ARF) and p16(INK4A) tumor suppressor genes are commonly inactivated by aberrant methylation of their promoter regions in human colon cancer. The methyl-CpG-binding domain protein MBD2 is physically associated with the methylated promoters of the p14(ARF) and p16(INK4A) genes in specific tumor cell lines. Moreover, deficiency of MBD2 strongly inhibits intestinal tumorigenesis in the Min mouse, raising the possibility that the protein might be involved in transcriptional repression of methylated tumor suppressor genes. The aim of this study was to evaluate the role of MBD2 in the silencing of p14(ARF) and p16(INK4A) in cancer. The MBD2 protein was stably knocked down by RNA interference in RKO, a colon cancer cell line in which both p14(ARF) and p16(INK4A) are silenced by methylation. We demonstrate here that MBD2 associates with the methylated promoter of the p14(ARF) gene in the RKO colon cancer cell line. Depletion of MBD2 by RNAi leads to selective upregulation of the p14(ARF) but not the p16(INK4A) gene transcript. In addition, p14(ARF) repression can be restored by expressing mouse MBD2 protein in MBD2-deficient RKO cells. These findings implicate MBD2 in transcriptional repression of the methylated p14(ARF) tumor suppressor gene and suggest that repression by MBD2 selectively affects a subset of methylated promoters.


RNA as a transcriptional activator.
Two recent reports demonstrate that in vivo selection can isolate novel RNAs that activate transcription when tethered to a gene promoter. This highlights the structural plasticity that allows RNA to fulfill many functions normally carried out by proteins.


Catheter ablation of idiopathic ventricular tachycardia without the use of fluoroscopy.
Catheter ablation is the treatment of choice for many patients with idiopathic ventricular tachycardia (VT). Unfortunately, conventional catheter ablation is guided by fluoroscopy, which is associated with a small but definite radiation risk for patients and laboratory personnel. The aim of our study is to assess feasibility, success rate and safety of idiopathic VT ablation procedure performed without the use of fluoroscopy. Nineteen consecutive patients undergoing idiopathic VT ablation at our institution have been included. The ablation procedures were performed under the guidance of electroanatomical mapping (EAM) system and intracardiac echocardiography (ICE). Nineteen patients (mean age 38.7 years) underwent ablation procedure for idiopathic VT. Twelve (63%) had outflow tract VT, 3 (18%) fascicular tachycardia, 2 (11%) peri-tricuspidal VT, 1 (5%) peri-mitral VT, and 1 (5%) lateral left free-wall VT. The mean procedural time was 170.2 ± 45.7 min. No fluoroscopy was used in any procedural phase. Acute success rate was 100%. No complication was documented in any patients. After a mean follow up of 18 ± 4 months, recurrences occurred in 2 patients. In our preliminary experience idiopathic VT ablation without the use of fluoroscopy was feasible and safe, using a combination of EAM and ICE. Success rate was excellent with no complication.