Classic bladder exstrophy in a nonhuman primate: a comparative analysis.
To describe the pelvic floor musculature and bony pelvic anatomy in a case of naturally occurring classic bladder exstrophy in a rhesus monkey, the first reported case in the animal population since 1832, and compare the results to exstrophy seen in human newborns. A 7-day-old male rhesus monkey with classic bladder exstrophy was examined by a pediatric urologist and primate veterinarian before being killed. A multidetector row computed tomography study with three-dimensional reconstruction was obtained, and a comparison computed tomography study of a 17-day-old male human with exstrophy was also reconstructed three dimensionally. The bony pelvis and pelvic floor muscular anatomy of both subjects were then examined and compared. On gross examination, a similar appearance of classic bladder exstrophy in the rhesus monkey and human newborn were noted, including an open exposed bladder, associated penile epispadias, and widely separated pubic bones. The evaluation of the three-dimensional models showed a similar orientation of the bony pelvis in both the rhesus and the human newborn. The iliac wings were significantly rotated outward, and the sacroiliac joint was 10 degrees wider than that seen in normal children. The exstrophy pelvic floor in both the rhesus and the newborn was markedly flattened, with approximately 33% of the muscle located anterior to the rectum to support the pelvic structures (normal children have 50% of their levator ani anterior to the rectum). By using advancements in imaging modalities, this study illustrated that naturally occurring classic bladder exstrophy in the human newborn and rhesus monkey were identical in both external appearance and internal anatomy.


Trends in Small Animal Reproduction: A Bibliometric Analysis of the Literature.
Small animal reproduction (SAR) is a main research field in veterinary medicine and bibliometric analyses are useful to investigate trends in specific research areas. The objective of the present study was to conduct a bibliometric analysis of the literature of the last decade on SAR. A search equation was created, and documents were retrieved from the Web of Science database. Documents were manually revised, categorized and R software version 4.1.2 with Bibliometrix R package version 3.1 and MS Excel were used to perform the analyses. The included documents (n = 1470) were mainly research articles (78%). The top countries for the number of documents and citations were Brazil, United States, Italy, Poland, and Korea. These also account for the most prolific authors and institutions. Analyses by author keywords, categories, and recent reviews of the literature suggest that research on the canine species is more abundant than research on the feline one and that reproductive biotechnologies are a main research focus. Some clinical topics are still considered niche or neglected themes (e.g., semen collection in tomcats, neonatology). However, heterogeneity and ambiguity in keywords and categories are undeniable. This study offers interesting insights, providing definitions for main keywords in the field of SAR.


Use of an absorbable plate in the management of a clavicle fracture in an adolescent.
Management of clavicle fractures continues to evolve. Indications for operative management seem to be expanding, particularly in athletic youth. Surgical intervention has potential complications, many associated with use of metal implants. To my knowledge, this case report is the first to describe use of a biodegradable implant. The subcutaneous position of the clavicle makes it ideal for fixation with a biodegradable implant in which no second surgery is required for implant removal.


The determination of the DNA sequence specificity of bleomycin-induced abasic sites.
The DNA sequence specificity of the cancer chemotherapeutic agent, bleomycin, was determined with high precision in purified plasmid DNA using an improved technique. This improved technique involved the labelling of the 5'- and 3'-ends of DNA with different fluorescent tags, followed by simultaneous cleavage by bleomycin and capillary electrophoresis with laser-induced fluorescence. This permitted the determination of bleomycin cleavage specificity with high accuracy since end-label bias was greatly reduced. Bleomycin produces single- and double-strand breaks, abasic sites and other base damage in DNA. This high-precision method was utilised to elucidate, for the first time, the DNA sequence specificity of bleomycin-induced DNA damage at abasic sites. This was accomplished using endonuclease IV that cleaves DNA at abasic sites after bleomycin damage. It was found that bleomycin-induced abasic sites formed at 5'-GC and 5'-GT sites while bleomycin-induced phosphodiester strand breaks formed mainly at 5'-GT dinucleotides. Since bleomycin-induced abasic sites are produced in the absence of molecular oxygen, this difference in DNA sequence specificity could be important in hypoxic tumour cells.


[Clinical features, care pathways and behaviors of patients with high level of cardiovascular risk: transversal study in south-west region of France].
To screen and to follow-up the patients with high cardiovascular risk in general practice may amplify the decrease of the cardiovascular morbi-mortality observed since a few years. The objective of this study is to identify the patients with high cardiovascular risk and to describe the management of these patients by general practitioners in Aquitaine. Transversal study of a sample of patients from 18 to 70 years old with high cardiovascular risk (combining at least 3 factors), included by voluntary general practitioners (GP). Forty-seven GP included 102 patients, presenting on average 3.7 risk factors among which 2.6 modifiable. The target values were reached for 59 % of patients with high blood pressure, 56 % of patients with diabetes and 53 % of patients with high cholesterol level. The analysis of care pathways identified the cardiologist as the privileged interlocutor. The doctors thought that seven patients out of 10 could change their risk behaviors. For the patients, the scale of declared importance to change was 6.6 on 10 for tobacco, 6.0 for food habits and 6.2 for physical activity. The confidence in their capacity to change was 3.8 on 10 for the tobacco, 5.2 for the food habits and 4.7 for the physical activity. Although doctors' sample is not representative, these results give an original overview of the management of patients with high cardiovascular risk and their care pathways. Medical treatments were globally in accordance with guidelines. The difficulty to change risk behaviors illustrates the necessity of patient therapeutic education.


Enhancement of cell adhesion, retention, and survival of HUVEC/cbMSC aggregates that are transplanted in ischemic tissues by concurrent delivery of an antioxidant for therapeutic angiogenesis.
A recurring obstacle in cell-base strategies for treating ischemic diseases is the significant loss of viable cells that is caused by the elevated levels of regional reactive oxygen species (ROS), which ultimately limits therapeutic capacity. In this study, aggregates of human umbilical vein endothelial cells (HUVECs) and cord-blood mesenchymal stem cells (cbMSCs), which are capable of inducing therapeutic angiogenesis, are prepared. We hypothesize that the concurrent delivery of an antioxidant N-acetylcysteine (NAC) may significantly increase cell retention following the transplantation of HUVEC/cbMSC aggregates in a mouse model with hindlimb ischemia. Our in vitro results demonstrate that the antioxidant NAC can restore ROS-impaired cell adhesion and recover the reduced angiogenic potential of HUVEC/cbMSC aggregates under oxidative stress. In the animal study, we found that by scavenging the ROS generated in ischemic tissues, NAC is likely to be able to establish a receptive cell environment in the early stage of cell transplantation, promoting the adhesion, retention, and survival of cells of engrafted aggregates. Therapeutic angiogenesis is therefore enhanced and blood flow recovery and limb salvage are ultimately achieved. The combinatory strategy that uses an antioxidant and HUVEC/cbMSC aggregates may provide a new means of boosting the therapeutic efficacy of cell aggregates for the treatment of ischemic diseases.


Remineralizing potential of the biomimetic P11-4 self-assembling peptide on noncavitated caries lesions: A retrospective cohort study evaluating semistandardized before-and-after radiographs.
Self-assembling peptide (SAP) P11-4 was introduced to treat initial caries lesions by means of guiding hydroxyapatite regeneration within the lesion. The objective of this study was to assess its effectiveness in a practical clinical setting. Caries lesions in permanent teeth treated with monomeric and polymeric SAP P11-4 from May 2015 through October 2020 were retrospectively analyzed at lesion and child levels by means of bite-wing radiography for changes in stage and cavitation and restoration. Two hundred and nineteen children aged 10 through 19 years with a total of 405 proximal lesions in posterior teeth were followed from 0.4 through 5.5 years (median, 7 months; interquartile range, 6-19 months). Regression occurred in 37% of stage RA1 (radiolucency in the outer one-half of enamel) (95% CI, 31% to 44%), 38% of stage RA2 (radiolucency in the inner one-half of enamel plus or minus the enamel-dentin junction) (95% CI, 30% to 45%), and 40% of stage RA3 (radiolucency limited to the outer one-third of dentin) (95% CI, 16% to 68%) lesions. The proportion of lesions with no cavitation was 0.96 (95% CI, 0.94 to 0.98) after 1 year and 0.91 (95% CI, 0.88 to 0.95) after 2 years. Real-world clinical data indicate that SAP P11-4 can lead to recovery and a healthier tooth stage. SAP P11-4 is a safe treatment for initial caries lesions in permanent teeth that remineralizes in the deepest zone of the lesion and can be introduced easily into routine dental practice.


Do Sports-related Concussions Induce Subsequent Injuries in Elite Male Football Players?
To assess the players' risk of a subsequent injury after sustaining concussive injuries and their return-to-competition in German professional men's football. A prospective injury database in the 1st Bundesliga was created encompassing 7 seasons (2014/15-2020/21). Cox proportional hazard model analyzed whether a concussive injury increased the risk of a subsequent injury in the first year after the index injury. 6,651 injuries were reported (n=182 concussive injuries). The incidence rate was 0.15 (95% CI 0.13-0.17) per 1000 football hours. A concussive injury was associated with only a slightly numerical higher risk of 7% (HR=1.07, 95% CI 0.78-1.47) in the subsequent year after the injury compared to a randomly selected non-concussive injury, but the effect was not significant. The risk was higher after 6-12 months post-SRC reaching 70% (HR=1.70, 95% CI 1.15-2.52). For 0-3 months (HR=0.76, 95% CI 0.48-1.20) and 3-6 months (HR=0.97, 95% CI 0.62-1.50) the injury risk was lower. The present data do not confirm previously published investigations about an increased injury risk after SRC. Contrasting effects of lower hazard ratios were found early after SRC, followed by an increase after 6-12 months. Further research should look into compliance rates with regards to return-to-competition protocols.


The combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is feasible and can be an option for relapsed/refractory multiple myeloma.
Thalidomide has recently proven to be a useful drug for treatment of refractory and relapsed multiple myeloma patients, up to 35% of whom achieve remission. However, little is known about the potential additive or synergistic effect upon its association with other drugs with proven efficacy in MM. The present pilot study was designed to evaluate the toxicity and response rate of the association of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) in 22 refractory or relapsed MM patients. The protocol scheduled the administration of thalidomide at escalating doses (200 to 800 mg/day), daily oral cyclophosphamide (CTX) (50 mg/day) and pulsed dexamethasone (40 mg/day, four days every three weeks). Adverse effects were moderate (grade <or=2) with only two patients in whom treatment was withdrawn due to neuropathy and severe somnolence. Infections were recorded in six patients, four requiring hospitalization for intravenous antibiotic therapy. No cases of thrombocytopenia grade >or=2 were noted. Other side effects included grade <or=2 constipation (29%), somnolence (35%) or dizziness (12%). In addition, one case of meralgia paresthetica and one with a deep venous thrombosis were noted. Two cases displayed hyperglycemia and myopathy attributed to dexamethasone, which was solved upon changing to prednisone. With a median follow-up of 12 months, 17 patients were evaluable for response; 13 (77%) responded to the therapy, including nine cases (53%) with a >50% M-component reduction (two of them with a complete remission). Only two responders have already progressed, with a projected event free survival of 51% at 12 months. Seven patients have died due to disease progression (n=5), sudden death (n=1) and infection (n=1). This study shows that ThaCyDex is a feasible and promising therapeutic approach for patients with relapsed/refractory MM.


Intracellular localization of natural and modified oligonucleotides in primary human endothelial cells.
Intracellular localization of natural and fluorescent-labeled oligonucleotides in primary human endothelial cells was studied by means of fluorescence microscopy and radioisotope analysis. Transport and distribution of oligonucleotides in endotheliocytes depended on their structure and resistance to hydrolysis under the effect of cell nucleases. Modification of 5'-terminal phosphate and 3'-terminal oligonucleotide increased the stability and ensures nuclear localization of oligonucleotides in cells.


Meta-analysis of the risk of dementia in elderly patients with late-onset epilepsy.
Although available literature indicates a high risk of dementia in elderly patients with late-onset epilepsy (LOE), the findings are yet inconsistent and relevant risk factors are unclear, rendering rational clinical interpretation rather challenging. This article systematically evaluates the risk of dementia in elderly LOE patients. The potential risk factors were analyzed to provide a specific basis for clinical prediction of dementia. PubMed and web of science databases were searched for the published cohort studies of dementia in elderly LOE patients. The search results were subject to a meta-analysis with Stata16.0 statistical software. Seven articles were included for a comparison of dementia risk between epilepsy cases and controls, yielding a hazard ration (HR) of 2.1 (95 %CI:1.6~2.75,p = 0.00); dementia was more prevalent in female patients than in male counterparts, though without a statistical difference [1.2 % (95 %CI, 0.9 %-1.6 %) vs. 0.8 % (95 %CI, 0.5 %-1.1 %)]; compared with the non-LOE group, the LOE population reported a significantly higher incidence of diabetes mellitus [14.1 % (95 %CI, 12.8 %-15.4 %) vs. 10.9 % (95 %CI, 10.1 %-11 %), p < 0.01]. The findings suggest that elderly patients with late-onset epilepsy run a higher risk of dementia than non-epileptic patients and diabetes mellitus may serve as a potential risk factor for dementia in this elderly populace.


Angiokeratoma circumscriptum arranged in a systematized band-like pattern suggesting mosaicism.
A 10-year-old girl with vascular lesions that had been present since birth is reported. Initially, small red macules were limited to the legs, but later the lesions became more extensive. A hyperkeratotic aspect of the lesional skin surface had developed at the age of 2 years. On clinical examination, hyperkeratotic vascular lesions in a band-like distribution on the trunk, legs and face were observed. The type of lesion varied from discrete macules with no or slight hyperkeratosis to confluent, protruding verrucous plaques. The clinical and histopathological findings were consistent with a diagnosis of angiokeratoma circumscriptum. The systematized band-like arrangement observed in the present case strongly supports the concept that angiokeratoma circumscriptum reflects a mosaic state of a mutation that is so far unknown.


The kidney and strategies for the treatment of hypertension.
Renal compensatory mechanisms are a chief consideration when selecting an antihypertensive agent. The relationships, therefore, between renal blood flow and glomerular filtration rate, sodium handling by the kidney, and release of renin require particular attention. We shall examine therapeutic measures such as beta adrenergic blockers, vasodilators, calcium entry blockers, and converting enzyme inhibitors in light of their effects on renal blood flow.


Oral complications of head and neck radiotherapy: prevalence and management.
The aim of the study was to evaluate the short-term and long-term toxicity caused by radiation treatment in the head and neck with the technique of intensity-modulated radiotherapy (IMRT). We selected 20 patients, 18 men and 2 women aged between 21 and 71 years, undergoing radiation therapy (IMRT) in head and neck. Patients were visited during radiotherapy and followed for six months after the end of the therapy. We assessed the presence of: mucositis, xerostomia, dysgeusia, dysphagia, pain, trismus and, in the case of late-onset complications, radiation cavities. Acute toxicity: in 20 patients, 18 reported mucositis, 19 xerostomia, 17, dysgeusia, 15 dysphagia, 18 had pain and 3 patients had trismus. Tardive toxicity: in 14 patients, 5 reported mucositis, 11 xerostomia, 6 dysgeusia, 2 dysphagia, 3 had pain, 4 trismus and in 4 patients were found radiation cavities. Acute complications with higher prevalence were xerostomia (19 of 20 patients), dysgeusia of 2nd grade (11 patients of 20), mucositis of 1st grade and pain of 1st grade (10 patients of 20). Among the late complications it was noted a maintenance of the high prevalence of xerostomia (11 patients of 14) and an increase in prevalence of trismus (4 patients of 14) against a reduction of all other complications. The presence of radiation cavities in 4 patients of 14 was also recorded.


Proteolytic activity of the house dust mite allergen Der p 1 enhances allergenicity in a mouse inhalation model.
We have recently demonstrated that intraperitoneal immunization of mice with proteolytically active Der p 1, the major house dust mite allergen, results in a significant and selective enhancement of total and Der p 1-specific IgE synthesis compared to mice immunized with proteolytically inactive Der p 1. To investigate whether the proteolytic activity of Der p 1 would lead to enhanced inflammatory cellular infiltration of the lungs and systemic IgE production when administered through the respiratory system, which is the natural route of entry for this allergen. Groups of mice were initially sensitized with proteolytically active Der p 1 through the intraperitoneal and the subcutaneous routes and subsequently exposed intranasally to either proteolytically active Der p 1, inactive Der p 1 or PBS. The extent of cellular infiltration of the lungs and systemic IgE production in the three animal groups were then compared. Here, we show for the first time that the administration of proteolytically active Der p 1 to mice through the intranasal route leads to significant inflammatory cellular infiltration of the lungs and systemic production of IgE. These data underline the important role of the proteolytic activity of Der p 1 in driving the allergic response in the lungs.


Variations in hydrogen isotopic fractionation in higher plants and sediments across different latitudes: Implications for paleohydrological reconstruction.
Sedimentary δDn-alkane value is widely utilized as a reliable proxy for paleo-hydrological reconstruction. Applications of this proxy must be based upon a globally clear understanding of the relationship between leaf wax δDn-alkane values and precipitation δD (δDp), defined as apparent fractionation (εapp). However, there is a critical concern about whether relatively constant εapp values exist across different latitudes. In this study, we systematically analyzed the variations of available εapp with latitudes based upon two compiled-new databases of higher plants and sediments over the world. We found that the total average εapp was relatively constant, i.e., -116 ± 5‰ (n = 941), in higher plants across different latitudes without consideration of plant types (e.g., dicots, monocots, gymnosperms), and was still constant but slightly lower average εapp, i.e., -125 ± 6‰ (n = 460), in sediments across the latitudes. The slightly lower average εapp in sediments relative to higher plants probably derived from the contribution of aquatic plants with isotopically D-depleted εapp in lake sediments. Interestingly, with consideration of plant types, average εapp increased in dicots but decreased in monocots slightly from low to high latitudes. The counteraction of these competing trends generates relatively constant average εapp values in higher plants, and resultantly constant average εapp values occur in sediments at the global scale. It is important to elaborate relatively constant εapp values from higher plants and sediments across different latitudes when sedimentary δDn-alkane is utilized as a proxy for paleohydrological reconstruction.


Livestock Gene Editing by One-step Embryo Manipulation.
The breakthrough and rapid advance of clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) technology has enabled the efficient generation of gene-edited animals by one-step embryo manipulation. Clustered regularly interspaced short palindromic repeat/CRISPR-associated protein 9 delivery to the livestock embryos has been typically achieved by intracytoplasmic microinjection; however, recent studies show that electroporation may be a reliable, efficient, and practical method for CRISPR/Cas9 delivery. The source of embryos used to generate gene-edited animals varies from in vivo to in vitro produced, depending mostly on the species of interest. In addition, different Cas9 and gRNA reagents can be used for embryo editing, ranging from Cas9-coding plasmid or messenger RNA to Cas9 recombinant protein, which can be combined with in vitro transcribed or synthetic guide RNAs. Mosaicism is reported as one of the main problems with generation of animals by embryo editing. On the other hand, off-target mutations are rarely found in livestock derived from one-step editing. In this review, we discussed these and other aspects of generating gene-edited animals by single-step embryo manipulation.


Studies on the major fucosylated glycoprotein released into the medium by cultured human skin fibroblasts.
Electrophoretic analysis of the proteins synthesized by cultured human skin fibroblasts demonstrated that the major component released into the medium is a high molecular weight fucosylated glycoprotein (MFGP). Gel filtration chromatography under denaturing and reducing conditions indicated that MFGP has a molecular weight of approx. 250,000; but appears to behave as a disulphide-linked dimer when unreduced. MFGP is further distinguished as the major labelled macromolecule in the medium after incubation of fibroblasts with [35S]cysteine. The role of this glycoprotein is unknown but it bears a striking resemblance to a presumptive structural glycoprotein recently shown to be secreted by arterial smooth muscle cells in culture, and may also be related to a group of much studied cell surface glycoproteins.


Giant asymptomatic left atrial myxoma.
The classic triad of myxoma clinical presentation is characterized by intracardiac obstruction, embolisms, and constitutional symptoms with fever, weight loss, or symptoms resembling connective tissue disease. Giant myxoma without symptoms are very rare. We present a case of a 30-year-old female with a giant asymptomatic myxoma in the left atrium, discovered by echocardiography. The patient was asymptomatic.


Detection of Specific RNA Targets by Multimerization.
Detection of specific RNA targets via amplification-mediated techniques is widely used in fundamental studies and medicine due to essential role of RNA in transfer of genetic information and development of diseases. Here, we report on an approach for detection of RNA targets based on the particular type of isothermal amplification, namely, reaction of nucleic acid multimerization. The proposed technique requires only a single DNA polymerase possessing reverse transcriptase, DNA-dependent DNA polymerase, and strand-displacement activities. Reaction conditions that lead to efficient detection of the target RNAs through multimerization mechanism were determined. The approach was verified by using genetic material of the SARS-CoV-2 coronavirus as a model viral RNA. Reaction of multimerization allowed to differentiate the SARS-CoV-2 RNA-positive samples from the SARS-CoV-2 negative samples with high reliability. The proposed technique allows detection of RNA even in the samples, which were subjected to multiple freezing-thawing cycles.


First glimpse of the functional benefits of clitoral hood piercings.
In this exploratory study, we identify a positive relationship between vertical clitoral hood piercing and desire, frequency of intercourse and arousal. There were no dramatic differences in orgasmic functioning. Clinicians can play key roles in educating patients about potential outcomes and risks of genital piercing.


Effect of anatomic region on immunofluorescence diagnosis of bullous pemphigoid.
Forty-six patients with clinical and histologic criteria of bullous pemphigoid, and on whom direct immunofluorescence testing had been done, were analyzed by anatomic region of the lesions and by the region from which the immunofluorescence biopsy specimens were taken. One third of immunofluorescence tests from the lower extremities were negative, compared with only 3% from all other areas. The possible reasons for this result are discussed. The lower extremity should probably be avoided as a biopsy site for immunofluorescence in bullous pemphigoid.


LEADER 7: cardiovascular risk profiles of US and European participants in the LEADER diabetes trial differ.
To determine whether US and European participants in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial differ regarding risk factors for cardiovascular mortality and morbidity. Baseline data, stratified for prior cardiovascular disease (CVD), were compared using multivariable logistic regression analysis to establish whether region is an independent determinant of achieved targets for glycated hemoglobin (HbA1c), blood pressure (BP), and low-density lipoprotein (LDL)-cholesterol. Independent of CVD history, US participants were more often of non-White origin and had a longer history of type 2 diabetes, higher body weight, and higher baseline HbA1c. They had substantially lower systolic and diastolic BP, and a marginally lower LDL-cholesterol level. Fewer US participants were diagnosed with left ventricular dysfunction. In the largest group of patients, those with prior CVD and the highest cardiovascular risk, US participants were more often female, had a higher waist circumference, and had a decreased estimated glomerular filtration rate, but less frequently prior myocardial infarction or angina pectoris. There were baseline differences between US and European participants. These differences may result from variation in regional targets for cardiovascular risk factor management, and should be considered in the analysis and reporting of the trial results. Clinical trial identifier: ClinicalTrials.gov, NCT01179048.


The integrated impact of GDP growth, industrialization, energy use, and urbanization on CO2 emissions in developing countries: Evidence from the panel ARDL approach.
Developing economies are an important engine of world economic growth. However, ensuring the quality of environmental assets is maintained amid rapid economic change remains a major challenge for most developing countries. Using the Panel Autoregressive Distributed Lag (ARDL) approach and the heterogeneous causality test, this study analyzes the combined effects of energy usage, industrialization, gross domestic product (GDP) growth, and urbanization on CO2 emissions for 23 developing countries across the 1995 to 2018 period. From our analysis, the long-run results reveal that a 1% increase in energy use, economic growth, industrialization, and urbanization increases CO2 emissions by 0.23%, 0.17%, 0.54%, and 2.32%, respectively. Moreover, our model's short- to long-term equilibriums are adjusted at a yearly rate of 0.19%. Finally, to verify the panel ARDL long-run results, robustness tests were carried out using the Fully Modified Ordinary Least Squares (FMOLS) and Dynamic Ordinary Least Squares (DOLS) approaches. Our results confirm that in the case of developing countries, CO2 emissions are primarily influenced by GDP growth, energy use, industrialization, and urbanization. Furthermore, the panel causality analysis identified a bidirectional causal relationship between energy use, GDP growth, urbanization, industrialization, and CO2 emissions. While these results can play an instrumental role in formulating CO2 emission policies among our selected countries, our research can also assist policy makers and stakeholders in other developing economies implement important policy initiatives. These include, tax incentives and infrastructural developments that nurture environmentally friendly industrialization, deploy low-carbon technologies, promote sustainable forms of urbanization and urban planning, while also facilitating increases in both the investment in and adoption of renewable energy platforms. The establishment of such a comprehensive policy agenda can help emerging economies achieve strong and environmentally sustainable GDP growth over the long-term.


Plasmacytoid myoepithelioma of the soft palate. Report of a case with cytologic, immunohistochemical and electron microscopic studies.
The plasmacytoid variant is a rare and controversial subtype of myoepithelioma that lacks myogenic differentation and the cytologic findings of which have not been reported previously. A 46-year-old man presented with a painless tumor located in the soft palate. Fine needle aspiration cytology (FNAC) showed odd-shaped cellular aggregates and single cells with round nuclei and finely granular cytoplasm resembling plasma cells together with strands of metachromatic stroma. The light, immunohistochemical and ultrastructural studies performed on the surgical specimen confirmed the initial cytologic diagnosis. Recognition of the cytologic findings of plasmacytoid myoepithelioma on needle aspirates allows a reliable and quick diagnosis that prompts correct management.


[Lipid lowering therapy in geriatric patients].
Cardiovascular disease is also the most frequent cause of mortality in the elderly population. Invasive diagnostic and therapeutic interventions are performed at an increasing rate in older patients in order to maintain functional capacities and, thus, an adequate quality of life. Thus, strategies to prevent cardiovascular events (e.g., lipid lowering therapy) are also of great importance in elderly. With respect to the side effects of statin therapy, the risk of drug interaction has to be considered, as well as myopathy. Discrepant study results exist about the influence of statins on cognitive function. Retrospective analyses indicate that statin therapy might be related to an increased risk for type.2 diabetes in certain risk groups. The indication for statin therapy should, therefore, consider the risk profile and especially the individual situation of the older patient.


Treatment of Osteochondral Fractures After Acute Patellofemoral Instability: A Critical Analysis Review.
An osteochondral fracture (OCF) of the patella or the femur is a frequent sequela after an episode of acute patellofemoral instability. Patients commonly present with anterior knee pain after direct trauma to the patella or a noncontact twisting injury. Radiographs and magnetic resonance imaging (MRI) are the most common imaging modalities that are used to diagnose OCFs. Arthroscopy may be indicated in cases of displaced OCFs, and the decision regarding osteochondral fragment fixation or loose body removal depends on fragment size, location, and extent of injury. Most of the current literature suggests worse outcomes for patients with OCFs who undergo nonoperative treatment, no significant differences in outcomes for patients sustaining an acute patellar dislocation with or without an OCF, and inconclusive results concerning outcomes for patients treated with loose body removal compared with fixation. Current outcome data are limited by studies with low levels of evidence; therefore, well-designed randomized controlled trials are needed.


The visual word form area and the frequency with which words are encountered: evidence from a parametric fMRI study.
Cohen and Dehaene et al. proposed that the Visual Word Form Area (VWFA) in the left midfusiform gyrus, contrary to its name, is limited to the extraction of an abstract letter string and not involved in proper visual word recognition. We examined this prelexical function of the VWFA by a parametric block design with five levels of written word frequency. The lowest level was represented by pseudowords and the highest level by words of very high frequency. Contrary to the assumed prelexical function of the VWFA, increasing frequency was associated with decreasing brain activation in a large posterior cluster of the left hemisphere including middle and posterior fusiform regions. The same negative relation between frequency and activation was found in several left frontal clusters. The relation of increasing frequency and decreasing activation in occipitotemporal regions corresponds to a similar relation in the same brain regions found by studies which experimentally manipulated object or face familiarity. This convergence suggests that fusiform regions are specialized for extracting and storing abstract patterns when processing visual objects and these patterns serve as recognition units in subsequent encounters with the same objects.


Outpatient Robotic surgery: Considerations for the Anesthesiologist.
A shortage of inpatient beds and nurses during the coronavirus disease 2019 pandemic has lent priority to safe same-day discharge after surgery. The minimally invasive nature of robotic surgery has allowed an increasing number of procedures to be done on an outpatient basis. Anesthetic management should be designed to complement the technical advantages of robotic surgery in facilitating early discharge.


Radiochemical synthesis and tissue distribution of p-[18F]DMPPF, a new 5-HT1A ligand for PET, in rats.
Several studies have demonstrated the potential of p-[(18)F]MPPF as a radiopharmaceutical to study the 5-HT(1A) receptor family in animals and humans. A structural modification leading to a higher radioactive signal at an equipotent dose would greatly enhance this potential. With this goal, the desmethylated 4-(2'-methoxyphenyl)-1-[2'-[N-(2''-pyridinyl)-p-fluorobenzamido]ethyl]-piperazine (p-MPPF), identified as p-DMPPF, was synthesized, labeled with fluorine-18 and evaluated through ex vivo tissue distribution in rats. The new compounds p-DMPPF, p-DMPPNO(2), MEM-p-MPPF and MEM-p-MPPNO(2) were isolated and fully identified ((1)H and (13)C NMR, LC-MS). The final compound, p-[(18)F]DMPPF, was obtained ready for injection, with an overall radiochemical yield of 10% (EOB corrected) within 90 min and a specific activity of 62 GBq/mumol. Tissue distributions showed that the carbon-fluorine bond was stable in vivo and that this compound could cross the blood-brain barrier. For kidney, lung, heart, spleen, bone, testicle, liver and muscle, the percentage of injected dose per gram of tissue obtained with p-[(18)F]DMPPF was of the same order of magnitude as that of p-[(18)F]MPPF. The amount of radioactivity reaching the brain was much higher (approximately fivefold at 60 min) for p-[(18)F]DMPPF compared with p-[(18)F]MPPF, which was taken as reference. The distribution and specificity were in total agreement with the known localization of 5-HT(1A) receptors in rats. The radioactivity increase was more important for specific tissues (hippocampus and frontal cortex) than for cerebellum or striatum, leading to better contrast (hippocampus/cerebellum=5.8 at 60 min). The levels of metabolites found in plasma showed that p-[(18)F]DMPPF appears to be less metabolized than p-[(18)F]MPPF. p-[(18)F]DMPPF deserves further evaluation as a radiopharmaceutical candidate.


The effect of griseofulvin on the heme pathway. Studies on tissue explant cultures.
The effect of griseofulvin on porphyrin biosynthesis was studied in vitro and in vivo using liver and skin explants from mice. Neither porphyrin nor precursors accumulation was detected after in vitro treatment of explants with griseofulvin. Culture medium porphyrins formed from added delta-amino-laevulinic acid (ALA) were increased after oral chronic intoxication. Similar results were obtained by cutaneous and oral intoxication. Consequently griseofulvin topical application is proposed as an alternative method to produce experimental erythropoietic protoporphyria. Probable intoxication mechanisms are proposed to explain the porphyrinogenic action of griseofulvin.


Engineering the isoelectric point of a renal cell carcinoma targeting antibody greatly enhances scFv solubility.
The murine A6H monoclonal antibody targets a cell surface antigen associated with renal cell carcinoma with high specificity and excellent biodistribution properties. Tumor to blood ratios of > 40:1 have been achieved in clinical studies. In order to generate an antibody engineering system that would allow the construction of improved derivatives for diagnostics and therapeutics, a single-chain Fv antibody (scFv) derived from A6H was constructed. The initial single-chain Fv, constructed with a cysteine residue and hexa-histidine sequence at the C-terminus, displayed a limited solubility of 100 microg/ml at pH 7.4. The low solubility and refolding yield of the original single-chain Fv required that a more soluble variant be designed and constructed. We hypothesized that lowering the pI of the scFv antibody away from the physiological range would yield a more soluble antibody. A derivative was thus subsequently engineered with five glutamic acid residues followed by the cysteine and hexa-histidine residues. The cysteine was included to provide a conjugation site for future radiolabeling studies. The redesigned A6H single-chain Fv has a predicted pI of 6.1, relative to 7.5 for the native scFv. The redesigned A6H scFv displayed a greatly enhanced solubility of > 15 mg/ml at pH 7.4. Both the original scFv and the redesigned single-chain Fv exhibited a strong tendency to form dimers and soluble high molecular weight aggregates. The monomer and disulfide bonded dimer were separated from the aggregates and complete cell binding isotherms were obtained, demonstrating that the purified A6H scFv retains much of the activity of the parent monoclonal. The addition of glutamic acid to the C-terminus of poorly soluble scFv antibodies could provide a straightforward avenue for improving their solubility properties. The increased solubility of the A6H scFv allowed the purification of the monomeric and dimeric species from the soluble aggregated species.


Obstacles for T-lymphocytes in the tumour microenvironment: Therapeutic challenges, advances and opportunities beyond immune checkpoint.
The tumour microenvironment (TME) imposes a major obstacle to infiltrating T-lymphocytes and suppresses their function. Several immune checkpoint proteins that interfere with ligand/receptor interactions and impede T-cell anti-tumour responses have been identified. Immunotherapies that block immune checkpoints have revolutionized the treatment paradigm for many patients with advanced-stage tumours. However, metabolic constraints and soluble factors that exist within the TME exacerbate the functional exhaustion of tumour-infiltrating T-cells. Here we review these multifactorial constraints and mechanisms - elevated immunosuppressive metabolites and enzymes, nutrient insufficiency, hypoxia, increased acidity, immense amounts of extracellular ATP and adenosine, dysregulated bioenergetic and purinergic signalling, and ionic imbalance - that operate in the TME and collectively suppress T-cell function. We discuss how scientific advances could help overcome the complex TME obstacles for tumour-infiltrating T-lymphocytes, aiming to stimulate further research for developing new therapeutic strategies by harnessing the full potential of the immune system in combating cancer.


Maintenance of column performance at scale.
Pack-in-place column packing methods were developed for Q Sepharose Big Beads at 40 cm I.D. and scaled up to 200 cm I.D. in Chromaflow columns. The efficiency and asymmetry of the packed bed were evaluated as a function of test velocity and sample volume. The performance of the packed beds at both scales approached the theoretical limits of column performance (Hred =2 and Af=1) expected in small analytical columns. The packing strategy was effective for scale up and the stability of the packed beds, the effectiveness of the column design with respect to the mobile phase distribution system and the stability of the media to the pack-in-place technology, are presented.


Argon laser intraocular photocoagulation.
Argon laser intraocular photocoagulation is now available during vitreous surgery, to treat retinal breaks and to give panretinal photocoagulation. Twenty patients, including phakic patients with gas-filled eyes, were treated using a new operative contact lens without complication. This intraoperative technique allows controlled rapid application of laser lesions at a safe distance from the retina, and eliminated the need for attempting treatment through the often hazy media of an irritated postoperative eye. A group of five rhesus monkeys were treated with various power settings to assess the histopathologic features of these laser lesions.


Emergency medicine pharmacist interventions reducing exposure to costs (EMPIRE-C).
Emergency Medicine (EM) pharmacists are considered essential healthcare providers in the Emergency Department (ED). Limited data are available representing the types of interventions performed by ED pharmacists, especially in community-based health systems. Retrospective, multi-centered, observational review of documented EM clinical pharmacist interventions into the electronic medical record (EMR) across five separate EDs between July 1, 2020 and June 30, 2021. Interventions were separated into three categories: ED Intervention, ED Outpatient Culture Review, and ED Discharge Antimicrobial Review. Interventions with supporting literature related to cost avoidance were also analyzed. A total of 23,794 interventions were logged by the EM pharmacy team between the three categories. Of those, 9181 were cost avoidance interventions resulting in $5,350,755.63 in total cost avoidance, or $582.81 per intervention. EM pharmacists practicing in community settings have a substantial impact on patients as evidenced by the large quantity and variety of interventions logged which also results in significant cost avoidance to the healthcare system.


Kaposi's sarcoma in cyclosporine-induced gingival hyperplasia.
In the cases presented in this report, Kaposi's sarcoma developed in the gingiva of two patients with cyclosporine-induced gingival hyperplasia. The tumor was clinically inapparent, and was diagnosed unexpectedly following biopsy of the hypertrophied gingiva. This unusual presentation has not been reported previously.


Phantom study quantifying the depth performance of a handheld magnetometer for sentinel lymph node biopsy.
The use of a magnetic nanoparticle tracer and handheld magnetometer for sentinel lymph node biopsy (SLNB) was recently introduced to overcome drawbacks associated with the use of radioisotope tracers. Unlike the gamma probe, the used magnetometers are not only sensitive to the tracer, but also the diamagnetic human body. This potentially limits the performance of the magnetometer when used clinically. A phantom, mimicking the magnetic and mechanical properties of the human axilla, was constructed. The depth performance of two current generation magnetometers was evaluated in this phantom. LN-phantoms with tracer uptake ranging from 5 to 500μg iron were placed at clinically relevant depths of 2.5, 4 and 5.5cm. Distance-response curves were obtained to quantify the depth performance of the probes. The depth performance of both probes was limited. In the absence of diamagnetic material and forces on the probe (ideal conditions) a LN-phantom with high uptake (500μg iron) could first be detected at 3.75cm distance. In the phantom, only superficially placed LNs (2.5cm) with high uptake (500μg iron) could be detected from the surface. The penetration depth was insufficient to detect LNs with lower uptake, or which were located deeper. The detection distance of the current generation magnetometers is limited, and does not meet the demands formulated by the European Association for Nuclear Medicine for successful transcutaneous SLN localization. Future clinical trials should evaluate whether the limited depth sensitivity is of influence to the clinical outcome of the SLNB procedure.


Biology and clinical impact of human natural killer cells.
Natural killer (NK) cells, through elaboration of cytokines and cytolytic activity, are critical to host defense against invading organisms and malignant transformation. Two subsets of human NK cells are identified according to surface CD56 expression. CD56dim cells compose the majority of NK cells and function as effectors of natural cytotoxicity and antibody-dependent cellular cytotoxicity, whereas CD56bright cells have immunomodulatory function through secretion of cytokines. For a long time, NK cells have held promise for cancer immunotherapy because, unlike T-lymphocytes, NK cells can lyse tumor cells without tumor-specific antigen recognition. To date, NK cell therapy, largely focused on in vivo expansion and activation with cytokines, has met with only modest success. However, recent understanding of the importance of NK receptors (NKR) for recognition and lysis of tumor cells while normal cells are spared suggests novel therapeutic strategies. The balance of inhibitory and activating signals through surface receptors that recognize major histocompatibility complex class I and class I-like molecules on target cells determines whether NK cells activate killing. Identification of NKR ligands and their level of expression on normal and neoplastic cells has important implications for the rational design of immunotherapy strategies for cancer. We review recent development in the biology and clinical relevance of NK cells in cancer immunotherapy.


Partial characterization of immunoreactive substance P in the rat pituitary gland.
Two distinct carboxy-terminus-directed anti-substance P (SP) sera (R-1C and R-6G) were used to characterize immunoreactive SP (I-SP) in acetic acid extracts of anterior pituitary (AP) and posterior pituitary (PP) glands of adult male rats. The tissue concentrations of I-SP measured by R-1C and R-6G were comparable. The contents of I-SP were 600-1150 pg/AP and 25-52 pg/PP. I-luteinizing hormone releasing hormone and I-somatostatin (I-SOM) were undetectable in AP extracts, but PP extracts contained the equivalents of 325-785 pg I-SOM/gland. Serial dilutions of AP and PP extracts produced displacement curves with both SP antisera that were parallel to the respective synthetic SP standard and hypothalamic extract displacement curves. Gel filtrations of AP and PP extracts on a Sephadex G-25 column produced I-SP peaks eluting in the same fractions as synthetic SP and hypothalamic I-SP. However, the AP I-SP profile also revealed a side peak migrating between the void volume and the major I-SP peak. Neither immunoreactive species in the AP extract were eliminated when eluted with 6.0 M guanidine HCl, a strong denaturing agent. In vitro incubation of paired anterior hemipituitaries for 30 min in the presence of a 56 mM K+ concentration resulted in a significant (p less than .0001), 25-fold increase in the release of I-SP into the incubation medium above the mean control value. Radiofrequency lesions placed in the median eminence-arcuate region of male rats caused a significant (p less than .001) reduction of I-SP in both the AP and PP. These reductions were inversely related to the plasma prolactin values. The elevation in plasma prolactin was taken as an index of completeness of lesions. We conclude that: 1) the rat pituitary contains I-SP as assessed by its immunologic and chromatographic behavior, 2) K+ depolarization is a potent stimulator of the release of AP I-SP in vitro, 3) the ME-arcuate region is important for the maintenance of pituitary I-SP levels in the rat.


Acetoacetate is a trigger of NLRP3 inflammasome activation in bovine peripheral blood mononuclear cells.
Repeat breeding, which is non-pregnancy following three or more breeding attempts, is a serious reproductive disorder in cattle. In the present study, metabolomic profiling was used to identify metabolites in the blood plasma of repeat breeder cows (RBCs) and non-RBCs. Metabolomic analysis showed that acetoacetate (AcAc), a ketone body, was detected in RBCs, but not in non-RBCs. In contrast, β-hydroxybutyrate (BHB) was at similar levels in both RBCs and non-RBCs. We hypothesized that an imbalance of AcAc and BHB induces abnormal inflammatory conditions, especially the NLRP3 inflammasome, which regulates sterile inflammation to control interleukin (IL)-1β secretion, and may be associated with repeat breeding in cattle. To investigate this hypothesis, blood samples were collected from both non-RBCs and RBCs on day 7 of the estrous cycle. The mRNA expression of IL1B in peripheral blood mononuclear cells (PBMCs) was observed to be higher in RBCs than in non-RBCs. To test the effects of AcAc and BHB on inflammatory responses, blood samples were collected from healthy cows and PBMCs were isolated. PBMCs were treated with AcAc and BHB to investigate the activation of the NLRP3 inflammasome (complex of NLRP3, ASC, and caspase-1) and IL-1β secretion. AcAc treatment resulted in higher protein and/or mRNA expression of NLRP3 and IL-1β in PBMCs. Moreover, AcAc increased the co-localization of NLRP3 and ASC and stimulated caspase-1 activation, indicating the formation of the platform of the NLRP3 inflammasome. Addition of specific NLRP3 inhibitor, MCC950, suppressed AcAc stimulation-induced IL-1β secretion. Contrary to the effects of AcAc, BHB treatment suppressed the activation of NLRP3 inflammasome and IL-1β secretion in response to AcAc and typical NLRP3 inflammasome triggers. These findings demonstrate that AcAc can potentially trigger NLRP3 inflammasome activation, resulting in IL-1β secretion, and that these inflammatory responses are suppressed by BHB in bovine PBMCs. In addition, the imbalance between AcAc and BHB with higher levels of IL-1β may be associated with repeat breeding in cattle.


Fading and tachyphylaxis to the contractile effects of substance P in the guinea-pig ileum.
Substance P (SP) caused an immediate and vigorous contraction of the longitudinal smooth muscle layer of the guinea-pig ileum. The contractile response to SP, unlike that to acetylcholine or histamine was not maintained but faded to baseline levels in about 6 min. When 0.3-1.0 nM SP was added the fading time was shorter than 6 min and tachyphylaxis did not develop. Higher concentrations of SP produced fading times of about 6 min that could not be increased even by adding extremely high concentrations of the peptide, up to 1800 nM. Short fading times and the lack of development of tachyphylaxis are the result of the rapid adsorption and/or metabolism of SP. The addition of exogenous peptidases such as pronase, chymotrypsin and an extract of black widow spider venom gland dramatically increased the rate of degradation of SP, shortened the fading response and blocked the development of tachyphylaxis. Tetrodotoxin and atropine reduced the fading time by 25%, while eserine increased its duration several-fold; these findings are consistent with the existence of a cholinergic nerve component in the mediation of some of the effects of SP receptor and, in part, to adsorption and metabolism of the peptide. The magnitude of the tachyphylaxis to SP was proportional to the concentration of the desensitizing dose of the peptide and was specific to SP and to the related peptide physalaemin; no cross-tachyphylaxis towards other agents was found.


Recognition, treatment and complications of meningococcal disease.
Meningococcal disease remains a major cause of death in young children. A decrease in mortality requires recognition and treatment of the disease at a number of stages in the illness. Life-threatening meningococcal disease usually presents as septicaemia rather than meningitis. The cardinal feature of meningococcal septicaemia is the purpuric rash. Many parents recognise the rash and seek medical advice because of it. When primary care physicians recognise the rash, the administration of parenteral penicillin may decrease mortality. However, antibacterials are not given promptly if there is no rash or if the disease presents in an atypical form. In hospital, antibacterial therapy with a third-generation cephalosporin should be given. Disease severity needs to be assessed by a valid method, such as the Glasgow Meningococcal Septicaemia Prognostic Score (GMSPS). This can identify those patients who need intensive care and/or might benefit from new therapies. The 2 life-threatening complications are septic shock and meningoencephalitis with raised intracranial pressure. Despite numerous case reports of success with potential new treatments, none has been proven safe and/or effective by controlled trials. Although it is tempting to focus on new treatments, the early recognition of severe meningococcal disease by parents, primary care physicians and junior hospital doctors is equally, if not more, important as a potential means of decreasing mortality.


The role of oxidative stress in rhinovirus induced elaboration of IL-8 by respiratory epithelial cells.
A direct correlation has been reported between the severity of symptoms associated with rhinovirus infection and the concentration of interleukin-8 in nasal secretions. The purpose of these studies was to examine the mechanism of rhinovirus-induced IL-8 elaboration. Rhinovirus infection induced oxidative stress in Beas-2b cells and the concentration of H2O2 in supernatant media from rhinovirus challenged cells was 12.5 +/- 6.1 microM 1 h after challenge compared to 0.7 +/- 0.3 microM in supernatant from control cells. N-acetyl cysteine inhibited RV-induced NF-kappaB activation and IL-8 elaboration. IL-8 concentrations were 36 +/- 2 pg/ml and 10 +/- 1 pg/ml 6 h after virus challenge in untreated and NAC-treated (30 mM NAC) cells, respectively. Despite the effects of NAC on IL-8 elaboration and NF-kappaB activation, RV stimulated increases in supernatant H2O2 were not altered by NAC. These data suggest that RV stimulation of IL-8 in respiratory epithelium is mediated through production of oxidative species and the subsequent activation of NF-kappaB.


Isoforms of an N-acetyl-beta-D-glucosaminidase from the Antarctic krill, Euphausia superba: purification and antibody production.
Two forms of the chitinolytic enzyme N-acetyl-beta-D-glucosaminidase (NAGase, EC 188.8.131.52) have been isolated from the Antarctic krill, Euphausia superba, in order to study their potential role in temperature adaptation processes. A chromatographic protocol was developed that allowed complete separation of the two enzyme forms, named NAGase B and NAGase C. The latter was purified to homogeneity with 600-fold enrichment and a yield of 17%. The molecular mass was 150 kDa. NAGase B showed characteristics of a glycoprotein due to affinity towards concanavalin A sepharose, while NAGase C did not. Highly specific polyclonal antibodies to NAGase C [anti-(E. superba-NAGase C)-IgG] showed only negligible cross-reactivity with NAGase B isoforms. A comparison with the Northern krill, Meganyctiphanes norvegica, revealed a corresponding chromatographic pattern with two main activity peaks, for differentiation named NAGase II and NAGase III. Application of the antibody on M. norvegica revealed a high specificity toward NAGase III and a low cross-reactivity with NAGase II. First indication is given that the two forms are no isoenzymes in a strict sense but instead may have different functions in the metabolism of krill.


Stability of dexamethasone sodium phosphate in rat plasma.
The use of corticosteroid prodrugs in pharmacokinetic studies poses the risk of overestimation of corticosteroid concentrations due to in vitro hydrolysis of prodrugs after sample collection. This study tests the effectiveness of the anticoagulant EDTA as a stabilizer for dexamethasone sodium phosphate (DSP) in rat plasma and provides simultaneous HPLC analysis of DSP and dexamethasone. An already developed ion-paired reversed-phase HPLC assay for simultaneous measurement of corticosteroid phosphate ester prodrugs and their active steroids was applied in this study. This assay was used for analyzing samples from an in vitro DSP hydrolysis study in rat plasma. In agreement with allometric principles, the prodrug hydrolysis occurred at a much faster rate (in vitro half-life of 1.75 h) in rat plasma as compared with previously reported prodrug hydrolysis half-life of 10-12 h in sheep and human plasma. The in vitro degradation of the prodrug in rat plasma was greatly minimized in plasma containing EDTA at the concentration commonly used an anticoagulant. This study demonstrates that artifacts in pharmacokinetic profiles of corticosteroids due to in vitro prodrug hydrolysis can be greatly minimized by collecting blood samples with EDTA as the anticoagulant.


Freudenfreude and Schadenfreude Test (FAST) scores of depressed and non-depressed undergraduates.
The Freudenfreude and Schadenfreude Test (FAST) had moderate test-retest reliability in an undergraduate sample. Freudenfreude scores were lower and Schadenfreude scores were higher among mildly depressed than nondepressed students. Distinctive reactions to personal success and failure were associated with depression. Responses to others' success and failure may also be related to depression.


Clinical activity of leukotriene inhibitors.
Data from the emerging clinical trials with compounds such as zileuton, ICI 204,219, Bay X1005, MK571, MK679, and MK591 are demonstrating the importance of the leukotrienes as mediators of asthma and possibly other diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. One of the major questions facing the asthma community is how much improvement in the FEV1 is needed to improve the quality of life of the asthmatic patient. Comparing the various approaches to asthma treatment, there is typically 15-20% improvement in the lung function with inhaled steroids. Leukotriene interventions apparently will improve lung function to similar levels as with inhaled steroids, and thus may offer an alternative to steroids. Like the steroids, zileuton appears to also reduce the inflammatory cell influx into the antigen-challenged site, which may have the long-term effect of reversing some of the tissue alterations that occur as a result of the inflammation seen with asthma. Importantly, the reported experience to date has shown that the leukotriene modulators do not have the same side-effects as the current therapies, and thus offer the hope that both safe and effective treatment may be derived from this approach. The clinical data reported do not yet define a preferred approach to the modulation of leukotriene pathology. As more studies are published in other diseases the broad spectrum use of these inhibitors will become known.


Hypotension induced by inhibition of angiotensin-converting enzyme in pentobarbital-anesthetized dogs.
The mechanism of the hypotensive response produced by inhibition of the angiotensin converting enzyme was studied in pentobarbital anesthetized dogs. A recently developed potent inhibitor of the converting enzyme, SQ 14,225 (D-3-mercapto-2-methyl propanoyl-L-proline), administered i.v. to intact dogs resulted in a rapid marked decrease in blood pressure. In nephrectomized dogs, SQ 14,225 retained significant hypotensive activity, although the absolute magnitude of the decreases in blood pressure were less than had been observed in dogs with intact kidneys. SQ 14,225 also lowered blood pressure when administered to intact dogs in which angiotensin II receptors had been blocked with the receptor antagonist Sar1,Ala8-angiotensin II. This apparent ability of SQ 14,225 to decrease blood pressure in the absence of a functional renin angiotensin system was shared by a structurally dissimilar, nonapeptide, angiotensin converting enzyme inhibitor, SQ 20,881 (Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro). SQ 20,881 also produced significant decreases in blood pressure in nephrectomized dogs. These findings indicate that the angiotensin converting enzyme inhibitors, SQ 14,225 and SQ 20,881 may lower blood pressure in anesthetized normotensive dogs via a mechanism unrelated to either the renin angiotensin system or the renal kinin system.


Prevention of Atrial Fibrillation After Atrial Flutter Ablation With Ramipril (from the PREFACE Study).
The clinical efficacy of the inhibitors of the renin-angiotensin-aldosterone system (RAAS) as an upstream therapy for atrial fibrillation (AF) prevention is controversial. No study has itemized so far the role of RAAS inhibitors in AF prevention after atrial flutter (AFL) ablation. This trial aims to investigate the effect of ramipril compared with placebo on AF occurrence in patients hospitalized for AFL ablation without structural heart disease. The Prevention of Atrial Fibrillation by Inhibition Conversion Enzyme (ICE) After Radiofrequency Ablation of Atrial Flutter (PREFACE) trial was a prospective, multicenter, randomized, double-blind, double-dummy trial depicting the AF occurrence during a 12-month follow-up as the primary end point. A total of 198 patients hospitalized for AFL ablation were enrolled in the trial and randomized to placebo or ramipril 5 mg/day. Patients were followed up during 1 year after AFL ablation using 1-week Holter electrocardiogram at 3, 6, 9, and 12 months. The intention-to-treat population encompassed 97 patients in the ramipril group and 101 patients in the placebo group. The primary end point, such as AF occurrence during the 1-year follow-up, was not different between the 2 groups (p = 0.96). Secondary end points, including the occurrence of supraventricular arrhythmia (p = 0.50), heart failure, stroke, and death, were not different between the 2 groups. Safety outcome parameters, including serious adverse events leading to treatment disruption (p = 0.10), hypotension, impairment of renal function, and elevated serum potassium level, also were not different between the 2 groups. In conclusion, RAAS inhibition using ramipril does not reduce AF occurrence in patients facing AFL ablation during the 1-year follow-up.


Effects of Ginkgo biloba Extract EGb 761, Donepezil and their Combination on Central Cholinergic Function in Aged Rats.
Ginkgo extract EGb 761 and cholinesterase inhibitors have been shown to be effective in the treatment of dementia patients. In addition to neuroprotective effects, Ginkgo extract EGb 761 has been reported to elevate brain levels of certain neurotransmitters such as dopamine, noradrenaline, and acetylcholine. In the present study, we investigated the impact of EGb 761, donepezil and the combination of both drugs on the central cholinergic system in aged rats. 24 month old rats received EGb 761 (100 mg/kg/day), donepezil (1.5 mg/kg/day), the combination of both drugs or vehicle control by oral gavage for 14 days. We used microdialysis in rat hippocampus to monitor extracellular concentrations of acetylcholine (ACh), choline, glucose and lactate. Brain homogenates were prepared to measure activities of acetylcholinesterase (AChE), choline acetyltransferase (ChAT) and high affinity choline uptake (HACU). While EGb 761 alone had no effect, donepezil and the combination of donepezil and EGb 761 increased basal ACh levels by 2- to 3-fold. Concomitantly, significant reductions of AChE and HACU were measured in both groups. No differences were seen between donepezil and the combination in these parameters. Treatment with EGb 761 decreased extracellular choline release and showed a tendency to moderately elevate ChAT activity. We found that donepezil and EGb 761 do not display a pharmacological interaction when given together. Adding EGb 761 did not modify the effects of donepezil on the hippocampal cholinergic system. Reduced choline levels indicate neuroprotective properties of EGb 761. Therefore, the combination of EGb 761 and donepezil may be beneficial in the treatment of Alzheimer's disease (AD). This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Behavioral classes related to physical activity and sedentary behavior on the evaluation of health and mental outcomes among Brazilian adolescents.
Latent Class Analysis can assist researchers interested in a better understanding of behavioral patterns and their association with health outcomes. This study aimed to identify lifestyle latent classes related to distinct domains of physical activity (PA) and sedentary behavior (SB) among adolescents and their association with health outcomes. This cross-sectional study included 217 Brazilian adolescents (15 to 18 years old, 49.3% female). The classes were based on moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), number of steps, sedentary behavior (SB), and screen time (ST). To assess these behaviors, participants wore an accelerometer for one week. ST, demographic characteristics, socioeconomic status, and signs of common mental disorders (CMD) were evaluated through questionnaires. Latent Class Analysis was used to identify lifestyle classes. Three classes were recognized: "Active-Non-sedentary" (class 1) with 28.1% of adolescents; "Inactive-Non-sedentary" (class 2), 48.85%; and "Inactive-Sedentary" (class 3), 23.04%. Sex and signs of CMD were associated with the prevalence of the classes. Female adolescents presented 4.48 (95% CI 2.04-9.77) times more chance of belonging to the "Inactive-Sedentary" (class 3). Adolescents who presented CMD had 11.35 (95% CI 3.45-101.1) times more chance of belonging to the "Inactive-Non-sedentary" (class 2). The interaction between sex and signs of CMD showed that girls with signs of CMD were 9.20 (95% CI 1.17-71.52) more likely to belong to the Inactive-Sedentary class than the "Active-Non-sedentary". Results indicate that sex and signs of CMD can affect the prevalence of the classes. Our findings highlight that physical inactivity and SB can be associated with signs of CMD, especially in female adolescents.


Abdominal contour procedures: evaluating the options.
Surgical science continues to increase the options available to an individual seeking an improved abdominal contour. Appropriately applied, abdominal-contouring procedures offer significant aesthetic improvements and result in a high level of patient satisfaction. Liposuction is one procedure in a continuum of techniques available for addressing abdominal contour, and it is the one with which patients are most familiar and most likely to request. Advising patients of the many available methods involves an understanding of the scope of each technique and an accurate assessment of individuals' anatomy and their expectations and perceptions of what a successful result represents. This article outlines the various surgical methods of abdominal contouring and fosters an understanding of how to select the appropriate procedure.


Functional anatomy of the human temporal muscle.
The authors carried out an anatomical and magnetic resonance imaging study on the architecture of the mandibular elevator muscles of 169 cadavers. The aim of the study was to define the organisational architecture of the human masseter, temporal and pterygoid muscles. Layer by layer dissection and anatomical cuts in different spatial planes showed that the temporal muscle has a different architecture to the other mandibular elevator muscles. Indeed this muscle does not have the pennate structure of the masseter and pterygoid muscles. Through electromyographic study the behavior of this muscle allowed the establishment of its functional segmentation during the masticatory cycle. Our study showed three distinct anatomical portions in the middle of the temporal muscle which correspond to this functional classification. The MRI study confirmed the results of our anatomical study.


A rapid and sensitive assay for protein disulphide isomerase activity.
An assay procedure for the determination of protein disulphide isomerase activity is presented. The method is based on the reactivation of randomly cross-linked RNAase, the extent of RNAase reactivation being determined from the degradation of radioactively labelled RNA. The method is rapid and sensitive and allows one to test a large number of samples simultaneously.


Cross-fostering of DBA and C57Bl mice. Increase in voluntary consumption of alcohol by DBA weanlings.
Weanling mice of the alcohol-avoiding DBA strain cross-fostered to mothers of the alcohol-selecting C57Bl strain drank twice as much alcohol as did nonfostered DBA mice. In contrast, C57Bl mice cross-fostered to DBA mothers drank the same amount of alcohol as did nonfostered C57Bl mice. Differences in maternal behavior seem to be responsible for differences in alcohol selection by weanlings.


A stapled POL κ peptide targets REV1 to inhibit mutagenic translesion synthesis.
Stapled α-helical RIR (Rev1-interacting region) peptides of DNA POL κ bind more effectively to the RIR-interface of the C-terminal recruitment domain of the translesion synthesis DNA polymerase Rev1 than unstapled peptide. The tightest-binding stapled peptide translocates into cells and enhances the cytotoxicity of DNA damaging agents while reducing mutagenesis. Drugs with these characteristics could potentially serve as adjuvants to improve chemotherapy and reduce acquired resistance by inhibiting Rev1-dependent mutagenic translesion synthesis.


Characterization of clinicopathologic and abdominal ultrasound findings in dogs with glucocorticoid deficient hypoadrenocorticism.
Clinical findings of glucocorticoid-deficient hypoadrenocorticism (GDH) can overlap with other diseases, presenting a diagnostic challenge. Describe clinicopathologic and ultrasonographic features of dogs with GDH and those suspected of having GDH that had the disease ruled out. Six hundred twenty-three dogs. Records from dogs with suspected GDH between 2003 and 2018 were reviewed. Dogs with hyperkalemia or hyponatremia were excluded. Dogs were categorized as controls when the resting serum cortisol or post-ACTH cortisol concentration were > 2 μg/dL. Clinicopathologic and ultrasonographic features were compared between groups. The optimal cut-point, area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were calculated for individual features used to detect GDH. Dogs were categorized as GDH (n = 29) or controls (n = 594). Lymphocyte count (>1750 cells/L; sensitivity, 96.6%; 95% confidence interval [CI], 82.8%-99.8%; specificity, 60.3%; 95% CI, 56.3%-64.1%; AUC, 0.828; 95% CI, 0.762-0.894) and albumin/globulin ratio (<1.081; sensitivity, 86.2%; 95% CI, 69.4%-94.5%; specificity, 78.8%; 95% CI, 75.3%-81.9%; AUC, 0.886; 95% CI, 0.827-0.944) had the highest discriminatory power between groups. Left adrenal gland width <0.39 cm was 80% (95% CI, 58.4%-91.9%) sensitive and 82.4% (95% CI, 74.2-88.4) specific for GDH. Serum cobalamin concentrations and ultrasonographic abnormalities of the GI tract were not different between groups. No single variable could be used to confidently rule out GDH and obviate the need for cortisol testing in dogs with a clinical presentation consistent with GDH.


The effect of ultralow-dose antibiotics exposure on soil nitrate and N2O flux.
Exposure to sub-inhibitory concentrations of antibiotics has been shown to alter the metabolic activity of micro-organisms, but the impact on soil denitrification and N2O production has rarely been reported. In this study, incubation and column transport experiments were conducted on soils exposed to as many as four antibiotics in the ng · kg(-1) range (several orders of magnitude below typical exposure rates) to evaluate the impact of ultralow dose exposure on net nitrate losses and soil N2O flux over time. Under anaerobic incubation conditions, three antibiotics produced statistically significant dose response curves in which denitrification was stimulated at some doses and inhibited at others. Sulfamethoxazole in particular had a stimulatory effect at ultralow doses, an effect also evidenced by a near 17% increase in nitrate removal during column transport. Narasin also showed evidence of stimulating denitrification in anaerobic soils within 3 days of exposure, which is concurrent to a statistically significant increase in N2O flux measured over moist soils exposed to similar doses. The observation that even ultralow levels of residual antibiotics may significantly alter the biogeochemical cycle of nitrogen in soil raises a number of concerns pertaining to agriculture, management of nitrogen pollution, and climate change, and warrants additional investigations.


Milk osteopontin promotes brain development by up-regulating osteopontin in the brain in early life.
Osteopontin (OPN) is a pleiotropic protein and is abundantly present in milk. Its functions include immune modulation and cellular proliferation and differentiation. OPN is highly expressed in the brain. We investigated the effects of milk-derived OPN on brain development of mouse pups. Wild-type (WT) dams producing OPN+ milk and OPN knockout (KO) dams producing OPN- milk nursed WT pups (OPN+/+), yielding 2 pup treatment groups, OPN+ OPN+/+ and OPN- OPN+/+, for comparison. Preliminary studies supported use of this model by showing high concentrations of OPN in milk of WT dams and no OPN in milk of OPN KO dams, and production of similar amounts of milk by WT and KO dams. The ability of ingested milk OPN to enter the brain was revealed by appearance of orally gavaged [125I]-labeled and antibody-probed milk OPN in brains of pups. Brain OPN mRNA levels were similar in both nursed groups, but the brain OPN protein level was significantly lower in the OPN- OPN+/+ group at postnatal days 6 and 8. Behavior tests showed impaired memory and learning ability in OPN- OPN+/+ pups. In addition, our study revealed increased expression of myelination-related proteins and elevated proliferation and differentiation of NG-2 glia into oligodendrocytes in the brain of OPN+ OPN+/+ pups, accompanied by increased activation of ERK-1/2 and PI3K/Akt signaling. We concluded that milk OPN can play an important role in brain development and behavior in infancy by promoting myelination.-Jiang, R., Prell, C., Lönnerdal, B. Milk osteopontin promotes brain development by up-regulating osteopontin in the brain in early life.


Prosthetic Mitral Surgical Valve in Transcatheter Aortic Valve Replacement Recipients: A Multicenter Analysis.
The aim of this study was to determine the prognosis and specific complications of patients with prosthetic mitral valves (PMVs) undergoing transcatheter aortic valve replacement (TAVR). TAVR is performed relatively often in patients with PMVs, but specific risks are not well described. A multicenter analysis was conducted, including patients with severe symptomatic aortic stenosis who underwent TAVR at 10 centers. Patients' clinical characteristics and outcomes were evaluated according to the presence of a PMV. The mean age of the study population (n = 2,414) was 81 ± 8 years, and 48.8% were men. A total of 91 patients (3.77%) had PMVs. They were more commonly women, younger, and had higher surgical risk. PMVs were implanted a median of 14 years before TAVR, and most patients had mechanical prostheses (73.6%). Eighty-six patients (94.5%) were on long-term vitamin K inhibitor therapy, and bridging antithrombotic therapy was administered in 59 (64.8%). TAVR device embolization occurred in 6.7% (vs. 3.3% in the non-PMV group; p = 0.127), in all instances when distance between the PMV and the aortic annulus was <7 mm. Mortality rates did not show a difference, but the rate of bleeding was higher in patients with PMV (24.2% vs. 16.1%; p = 0.041), even in those treated via the transfemoral approach (22.2% vs. 13.9%; p = 0.048). Indeed, bleeding complications, prior atrial fibrillation, chronic obstructive pulmonary disease, surgical risk, and New York Heart Association functional class were independent predictors of mortality. TAVR presents similar mortality irrespective of the presence of a PMV. However, patients with PMVs had higher bleeding risk that was independently associated with higher mortality. Risk for valve embolization was relatively high, but it occurred only in patients with PMV-to-aortic annulus distances <7 mm.


Electronic control of ventricular tachyarrhythmias: overview and future directions.
Although pacing techniques for the termination of ventricular tachycardia are successful in some patients, the widespread use of these devices has not been possible until the recent availability of high energy (25 J) automatic defibrillators. The implantable defibrillator will serve both as a primary means of arrhythmia termination and as backup device to treat pacer mediated acceleration of ventricular tachycardia. The subsequent mortality of patients with ventricular tachycardia and/or fibrillation should diminish considerably.


Short-term group therapy with depressed adolescent outpatients.
A selected review of the literature about short-term therapy and social skills as they may apply to depressed adolescents is presented. Two forms of group therapy are described. These are social skills and a traditional discussion group format. Some of the difficulties in establishing and evaluating a group therapy program are outlined.


Increasing arterial oxygen partial pressure during cardiopulmonary resuscitation is associated with improved rates of hospital admission.
As recent clinical data suggest a harmful effect of arterial hyperoxia on patients after resuscitation from cardiac arrest (CA), we aimed to investigate this association during cardiopulmonary resuscitation (CPR), the earliest and one of the most crucial phases of recirculation. We analysed 1015 patients who from 2003 to 2010 underwent out-of-hospital CPR administered by emergency medical services serving 300,000 inhabitants. Inclusion criteria for further analysis were nontraumatic background of CA and patients >18 years of age. One hundred and forty-five arterial blood gas analyses including oxygen partial pressure (paO2) measurement were obtained during CPR. We observed a highly significant increase in hospital admission rates associated with increases in paO2 in steps of 100 mmHg (13.3 kPa). Subsequently, data were clustered according to previously described cutoffs (≤ 60 mmHg [8 kPa]], 61-300 mmHg [8.1-40 kPa], >300 mmHg [>40 kPa]). Baseline variables (age, sex, initial rhythm, rate of bystander CPR and collapse-to-CPR time) of the three compared groups did not differ significantly. Rates of hospital admission after CA were 18.8%, 50.6% and 83.3%, respectively. In a multivariate analysis, logistic regression revealed significant prognostic value for paO2 and the duration of CPR. This study presents novel human data on the arterial paO2 during CPR in conjunction with the rate of hospital admission. We describe a significantly increased rate of hospital admission associated with increasing paO2. We found that the previously described potentially harmful effects of hyperoxia after return of spontaneous circulation were not reproduced for paO2 measured during CPR. n/a.


Railway track-like dermatitis: an atypical Mondor's disease?
The cases of two patients with linear, cordlike lesions on the anterolateral chest wall are reported. Both cases suggested a clinical diagnosis of Mondor's disease (i.e., sclerosing periphlebitis of the chest wall) with atypical aspects. The histologic picture showed a diffuse dermal infiltrate, predominantly of eosinophils mixed with lymphocytes and histiocytes, with some evidence of collagen degeneration. No flame figures were seen. Problems of differential diagnosis are discussed.


Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons.
To report preliminary clinical outcomes for pediatric patients treated with proton beam radiation for intracranial ependymoma and compare the dose distributions of intensity-modulated radiation therapy with photons (IMRT), three-dimensional conformal proton radiation, and intensity-modulated proton radiation therapy (IMPT) for representative patients. All children with intracranial ependymoma confined to the supratentorial or infratentorial brain treated at the Francis H. Burr Proton Facility and Harvard Cyclotron between November 2000 and March 2006 were included in this study. Seventeen patients were treated with protons. Proton, IMRT, and IMPT plans were generated with similar clinical constraints for representative infratentorial and supratentorial ependymoma cases. Tumor and normal tissue dose-volume histograms were calculated and compared. At a median follow-up of 26 months from the start date of radiation therapy, local control, progression-free survival, and overall survival rates were 86%, 80%, and 89%, respectively. Subtotal resection was significantly associated with decreased local control (p = 0.016). Similar tumor volume coverage was achieved with IMPT, proton therapy, and IMRT. Substantial normal tissue sparing was seen with proton therapy compared with IMRT. Use of IMPT will allow for additional sparing of some critical structures. Preliminary disease control with proton therapy compares favorably with the literature. Dosimetric comparisons show the advantage of proton radiation compared with IMRT in the treatment of ependymoma. Further sparing of normal structures appears possible with IMPT. Superior dose distributions were accomplished with fewer beam angles with the use of protons and IMPT.


Interspecies Phylogenetic Analysis of Clonorchis sinensis in High-incidence Areas of Hunan Province, China.
This study aims to investigate the infection of Clonorchis sinensis ( C. sinensis) in high-incidence areas of Hunan Province, China. The phylogenetic analysis of the C. sinensis species in the highly infected areas was carried out. Infection of the definitive human host and intermediate fish host by C. sinensis was investigated, and the mitochondrial genes cox1 and Nad1were used as genetic markers for phylogenetic analysis. In 2016-2020, the average population infection rate of Hunan was 1.38%, while in Tongdao County the rate was up to 26.90%, and the highest fish infection rate was detected in Qiyang County (99.44% in the dorsal fin of crucian carp). High genetic sequence similarity was observed in the samples from Qiyang and Lengshuitan which exhibited high homology with those from Guangdong and Gansu, whereas the parasitic species from Tongdao was highly homologous with those located in high-latitude areas. Moreover, no significant difference was found in the gene sequence of the parasitic species in definitive hosts dogs and cats. The systematically study of C. sinensis infection in the high-incidence areas will contribute greatly to the prevention and effectively controlling the spread of Clonorchis sinensis in Hunan Province The endemic of C. sinensis infection in Hunan Province is the result of co-action of local and foreign parasite species.


Evaluating Real-World Characteristics of Patients With Advanced Urothelial Carcinoma Eligible for Avelumab Maintenance Therapy: A Multicountry Retrospective Medical Chart Review.
Urothelial carcinoma (UC) is a malignancy of the urothelium that encompasses the renal pelvis, bladder, and urethra. Current treatment guidelines for advanced (ie, locally advanced or metastatic) UC recommend using avelumab maintenance therapy in patients with nonprogressive disease following first-line platinum-based chemotherapy. This study aimed to assess the representativeness of the patient population in the JAVELIN Bladder 100 (JB-100) trial, which examined the efficacy and safety of avelumab first-line maintenance, vs. real-world patients with advanced UC that had not progressed with first-line platinum-based chemotherapy treated between 2015 and 2018 by reviewing demographic and clinical characteristics. A medical chart review (MCR) study collected demographics and treatment characteristics for patients with advanced UC in the United States, the United Kingdom, and France. Data were analyzed descriptively for review with data collected from patients enrolled in JB-100. Clinical characteristics were consistent between JB-100 and the MCR. Most patients were male, received 4 to 6 cycles of platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All patients in the MCR had either stable disease or a response with platinum-based chemotherapy (∼75% achieved a complete or partial response). Fewer than half (42.5%) of all patients in the MCR received subsequent therapy. Patient demographics, clinical characteristics, and treatment patterns from a MCR of patients with advanced UC that had not progressed following first-line platinum-based chemotherapy appeared similar to data from patients enrolled in JB-100. Future studies should examine whether real-world outcomes are consistent with findings from JB-100. NCT02603432.


The Effect of Butin on the Vitiligo Mouse Model Induced by Hydroquinone.
Vernonia anthelmintica (L.) Willd has been traditionally used in the treatment of vitiligo in Uyghur medicine. This study used butin, the main component of V. anthelmintica, to study the influence on hydroquinone-induced vitiligo in mice. The animals were randomly divided into six groups: control, model, 8-methoxypsoralen (8-MOP, 4.25 mg/kg), and butin (0.425, 4.25, and 42.5 mg/kg) groups. The number of melanin-containing hair follicles, basal layer melanocytes, melanin-containing epidermal cells, the expression of tyrosinase (TYR) and tyrosinase-related protein-1 (TRP-1), the malondialdehyde (MDA), and cholinesterase (CHE) activity in serum were measured. Our results indicated that compared with the model group, the melanin-containing hair follicles, the expression of TYR and TRP-1 increased, the activity of CHE decreased after treatment with 8-MOP and all doses of butin (p < 0.05, p < 0.01), the basal layer melanocytes and melanin-containing epidermal cells increased significantly after treatment with butin 4.25 and 42.5 mg/kg (p < 0.05, p < 0.01), and the MDA activity decreased after using butin 4.25 and 42.5 mg/kg and 8-MOP (p < 0.05, p < 0.01). Our results support the use of butin on vitiligo, and its possible mechanisms may be related to increase the TYR and TRP-1 protein expression and decrease the activity of MDA and CHE in hydroquinone-induced vitiligo model in mice. Copyright © 2017 John Wiley & Sons, Ltd.


A vitamin E analogue suppresses malignant mesothelioma in a preclinical model: a future drug against a fatal neoplastic disease?
Malignant mesothelioma is a fatal type of neoplasia of the pleura and the peritoneum with currently no known cure. Therefore, discovery of an efficient antimesothelioma drug with low deleterious side effects is desirable. Here, we studied in vivo the effect of alpha-tocopheryl succinate, a semisynthetic vitamin E analogue with proapoptotic and anticancer activity and selectivity for malignant cells, on experimental peritoneal mesothelioma using immunocompromised mice. Compared to untreated animals, the agent increased their survival >3-fold. Our finding warrants further testing of vitamin E analogues as potential antimesothelioma drugs.


Clinical application of single-layer annular vaginal flap in transvaginal repair for vesicovaginal fistula.
To compare the first-time success rate and prognosis of repairing vesicovaginal fistula (VVF) by transvaginal and transvesical approaches, and to highlight a modified transvaginal repair technique which only require single layer closure of an annular vaginal flap. Retrospective analysis of 57 consecutive patients who underwent VVF repair between 2007 and 2021. Fistula characteristics, operative factors, post-surgical complications and outcomes were analyzed. A total of 57 women with a median age of 50.4 (27-75) years were included. The history ranged from 7 days to 8 years, with an average of 20 months. 56 cases (98.2%) of VVFs were caused by pelvic surgery, and only one resulted from difficult labour. 11 cases (19.3%) had a history of surgical repair failure. All 57 cases of surgery were smoothly completed. Among them, 17 patients underwent transvaginal repair, whereas 40 (70.2%) women had transvesical repair. Transvaginal approach had a significantly shorter operative time, less intraoperative blood loss, reduced postoperative hospital stay, less hospitalization cost and lower minor complication rates than transvesical group (p < 0.05). No serious complications occurred in the two groups. No cystostomy was performed in the transvaginal group, but 12 cases (30%) in the transvesical group. The average follow-up time was 18.5 (3-48) months. The first-time success rates of transvaginal and transvesical techniques were 82.3 and 75%, respectively. VVF repair with single layer closure of an annular vaginal flap is a technically feasible, simple and successful approach with significantly better operative parameters and lower complications rates.


Macromolecular crowding in equine bone marrow mesenchymal stromal cell cultures using single and double hyaluronic acid macromolecules.
Macromolecular crowding (MMC) enhances and accelerates extracellular matrix (ECM) deposition in eukaryotic cell culture. Single hyaluronic acid (HA) molecules have not induced a notable increase in the amount and rate of deposited ECM. Thus, herein we assessed the physicochemical properties and biological consequences in equine bone marrow mesenchymal stromal cell cultures of single and mixed HA molecules and correlated them to the most widely used MMC agents, the FicollⓇ cocktail (FC) and carrageenan (CR). Dynamic light scattering analysis revealed that all HA cocktails had significantly higher hydrodynamic radius than the FC and CR; the FC and the 0.5 mg/ml 100 kDa and 500 kDa single HA molecules had the highest charge; and, in general, all molecules had high polydispersity index. Biological analyses revealed that none of the MMC agents affected cell morphology and basic cell functions; in general, CR outperformed all other macromolecules in collagen type I and V deposition; FC, the individual HA molecules and the HA cocktails outperformed CR in collagen type III deposition; FC outperformed CR and the individual HA molecules and the HA cocktails outperformed their constituent HA molecules in collagen type IV deposition; FC and certain HA cocktails outperformed CR and constituent HA molecules in collagen type VI deposition; and all individual HA molecules outperformed FC and CR and the HA cocktails outperformed their constituent HA molecules in laminin deposition. With respect to tri-lineage analysis, CR and HA enhanced chondrogenesis and osteogenesis, whilst FC enhanced adipogenesis. This work opens new avenues in mixed MMC in eukaryotic cell culture. STATEMENT OF SIGNIFICANCE: Mixed macromolecular crowding (MMC) in eukaryotic cell culture is still under-investigated. Herein, single and double hyaluronic acid (HA) macromolecules, along with the traditional MMC agents FicollⓇ cocktail (FC) and carrageenan (CR), were used as MMC agents in equine mesenchymal stromal cell cultures. Biological analysis showed that none of the MMC agents affected cell morphology and basic cell functions. Protein deposition analysis made apparent that CR outperformed all other macromolecules in collagen type I and collagen type V deposition, whilst FC, the individual HA macromolecules and the HA cocktails outperformed CR in collagen type III deposition. Tri-lineage analysis revealed that CR and HA enhanced chondrogenesis and osteogenesis, whilst FC enhanced adipogenesis. These data illustrate that MMC agents are not inert macromolecules.


[Study on isoniazid-resistant Mycobacterium tuberculosis isolates by multiple-polymerase chain reaction-single strand conformation polymorphism].
To develop a new multiple-polymerase chain reaction-single strand conformation polymorphism (multi-PCR-SSCP) system for detecting the aphC promoter, inhA, and katG gene mutations in isoniazid-resistant Mycobacterium tuberculosis isolates in the single reaction, and for the quick diagnosis of isoniazid-resistant Mycobacterium tuberculosis isolates. Three pairs of oligonucleotide primers were designed according to the aphC promoter, inhA, and katG genes of Mycobacterium tuberculosis to examine isoniazid-resistance by multi-PCR-SSCP. Isoniazid-sensitivity and resistance were analyzed with general PCR and multi-PCR at the same time, and H(37) Rv was used as a control. These two protocols amplified the anticipated fragments, the rate of consistency being 100%. By single gene PCR-SSCP, the mutation rates of aphC promoter, inhA, and katG gene were 17%, 20%, and 66%, respectively. The mutation rate detected by multi-PCR-SSCP was 83%. Multi-PCR-SSCP is a sensitive and specific method for rapid detection of aphC promoter, inhA, and katG gene mutations in isoniazid-resistant Mycobacterium tuberculosis isolates. Drug-resistant gene detection may be clinically useful in the therapy of tuberculosis.


Human protein C induces anticoagulation and increased fibrinolytic activity in the cat.
The effect of activated human Protein C (PCa) infusion on the coagulation and fibrinolytic systems of the cat was examined. Cats received bolus i.v. injections of PCa of 3 micrograms/mL (n = 7), 10 micrograms/mL (n = 2) or 16 micrograms/mL (n = 1) of calculated total blood volume. Control cats (n = 7) received either unactivated Protein C (10 micrograms/mL) or the activation vehicle containing heparin and antithrombin in tris-saline buffer. Citrated blood samples were drawn prior to infusion and 5, 10, 20, 40, 60, 120 and 180 minutes post infusion. PCa caused an immediate, dose dependent increase in anticoagulation as measured by APTT which began to normalize within 20 minutes. PCa also increased fibrinolytic activity measured by euglobulin clot lysis time and an 125I whole blood clot lysis assay. However, the profibrinolytic effect of PCa did not parallel the anticoagulant effect. In all treated cats, maximum fibrinolytic activity did not occur until 40-120 minutes after infusion. Control cats demonstrated no significant change in coagulation or fibrinolytic activity. Our results demonstrate that infusion of activated human Protein C can induce anticoagulation and fibrinolytic activity in the cat.


The relationship of oxidative stress markers and parameters of myocardial function in a rat model of cardiotoxicity.
Although a majority of studies related oxidative stress to cardiovascular diseases, the pathophysiological relevance has been remaining unknown. The aim of this study was to establish the relationship among different commonly used biomarkers of oxidative stress and cardiovascular dys/function in rats. A pathological state in many aspects similar to that of acute myocardial infarction was induced by administration of isoprenaline (100mg.kg(-1), s.c.) in Wistar:Han rats. Haemodynamic, biochemical and ECG parameters were measured in two sets of experiments: after 24hours and continuously during the first 2hours following the administration of isoprenaline. Serum cardiac troponin T (cTnT) correlated strongly with cardiac function, myocardial calcium levels, wet ventricles weight and relevant ECG parameters (T wave, R wave and J - junction - point amplitudes). However, only weak negative correlations were found for cTnT and total blood glutathione or serum vitamin C concentrations, while no significant associations were found with serum vitamin E and plasma TBARS. Although the oxidized form of glutathione correlated positively with heart rate, no correlation with the above-mentioned ECG parameters was found. However, correlations of in 8-isoprostane with both R wave and J-junction-point amplitudes were observed. Conclusively, more selective markers of oxidative stress may predict the functional status of the heart.