Long-term results of a pilot study of low dose cranial-spinal irradiation for cerebellar medulloblastoma.
Between May 1974 and March 1983, 44 children with histologically verified cerebellar medulloblastoma were seen for post-operative cranial-spinal irradiation following attempted total tumor removal. Six patients were excluded from review because they received all or part of their treatment at another institution (3 patients) or did not complete the planned course of irradiation (3 patients). All of the 38 remaining patients were treated by a previously described technique on a 4 MeV Linear Accelerator with 55 Gy delivered to the primary tumor site. Prior to December 1978, 19 consecutive children (Group A) had spinal prophylactic doses of 30-40 Gy and brain prophylactic doses of 40-50 Gy. After the date, 25 Gy was given to the cranial-spinal axis of 19 consecutive children (Group B). This lower dose was arbitrarily selected with the hope of reducing morbidity in treated survivors and achieving the same tumor control. Risk factors that define good and poor prognosis were evaluated for each group, and there were no differences noted. Myelography and CSF cytology were not routinely performed. Follow-up for the 38 patients ranges from 20 months to 124 months. For the low risk patients, survival (12/15 or 80%) was independent of cranial-spinal radiation dose (Group A 6/8, Group B 6/7). For the high risk patients survival was poor (9/23 or 39%), not dependent on cranial-spinal radiation dose (Group A 5/11, Group B 4/12), and associated with failure at the primary site (10/14), often with CSF seeding (8/10). The other 4 failures include 2 who had moved outside the United States (details of failure are unknown), 1 with supratentorial, CSF seeding and distant metastases, and 1 with distant metastasis only. There were no isolated spinal failures. This pilot study shows that the prophylactic radiation dose to the cranial-spinal axis can be decreased to 25 Gy without jeopardizing control rate and survival in patients with medulloblastoma.


Mbaka lakes isotopic ((18)O and (2)H) and water balances: discussion on the used atmospheric moisture compositions.
The water balances of small crater lakes Masoko, Katubwi, Kyambangunguru, Ilamba, Kingiri, located north of lake Malawi (Tanzania), are established with the Craig-Gordon model of evaporation. In this approach, it is difficult to evaluate the isotopic composition of evaporated vapour (deltaE), which is indirectly estimated from the atmospheric moisture signature (deltaA). Given that 'precipitation equilibrium' approach does not lead to realistic solutions in this tropical region, the lake balances are established and discussed from both the sampled deltaA and those derived from the terminal lake Rukwa. The mean local sampled signature (deltaAm : delta(18)O =-13.7per thousand and delta(2)H =-76per thousand) is inferior to that derived from lake Rukwa (deltaAtl : delta(18)O =-10.4per thousand and delta(2)H =-64per thousand), which may be due to altitudinal and latitudinal effects but both are influenced by recycling continental vapour. Water balances enable us to confirm and quantify high inflows and groundwater outflows that account for typologies of Mbaka lakes. The proposed sampling and measurement method allows us then to access reasonable moisture compositions in far-away regions.


Transglutaminase-catalyzed protein cross-linking in the molecular program of apoptosis and its relationship to neuronal processes.
1. One type of transglutaminase is usually accumulated in various forms of naturally occurring cell death and apoptosis. The accumulated enzyme is activated during the death process, leading to the formation of cross-linked protein structures. Degradation of the cross-linked apoptotic bodies results in the elevation of the epsilon (gamma-glutamyl)lysine isodipeptide concentration in body fluids, which may provide a diagnostic tool to monitor the apoptosis rate in various tissues under normal and pathologic conditions. 2. Extensive protein cross-linking may be directly related to the act of killing in some cells. In others, the effect of protein cross-linking is palliative, preventing leakage of macromolecules and enhancing phagocytosis of the dead cells. 3. Tissue transglutaminase has been implicated in some physiologic functions of the nervous system. 4. The molecular machinery of apoptosis is present and easily evoked in neuronal cells. 5. Effector elements of the apoptosis process have been associated with the pathogenesis of neurologic disorders. Tissue transglutaminase, representing one of the effector elements of apoptosis, may be induced and activated in cells following ischemia. It may also participate in the formation of abnormal cell inclusions and A beta deposits in amyloid plaques.


Evaluation of in vivo acute immunotoxicity of a major organic arsenic compound arsenobetaine in seafood.
In this study, we observed the in vivo acute immunotoxicity of a trimethyl arsenic compound, arsenobetaine (AsBe), which is present in large quantities in various marine animals that are daily ingested as seafood in many countries. The synthetic pure AsBe was orally administered to CDF(1) mice at a dose of 1.625 g/kg mouse weight once a day on days -6, -4, -2 and 0 (four times, total 6.5 g/kg mouse weight), and its effect on the immune organs and immune effector cells were assessed until day 8. Orally administered AsBe was temporally distributed to the immune organs, such as the spleen and thymus, but was not very toxic both quantitatively and qualitatively on these immune organs and immune effector cells, splenocytes, thymocytes, Peyer's patch lymphocytes and peritoneal macrophages. This finding suggests that the ingestion of AsBe contained in marine animals is relatively safe to the health of people who often consume marine animals in their daily diet.


Hip resurfacing: not your average hip replacement.
Hip resurfacing (HR) has become a widely used surgical intervention for younger patients requiring hip joint arthroplasty. While case reports have been published describing rehabilitation programs following HR, there has yet to be established rehabilitation guidelines. Through experience and clinical reasoning, the following guidelines have been developed based on the patients at the Hospital for Special Surgery. The demographics of the typical HR patient, along with the surgical process are described. Current published literature reporting rehabilitation for patients with arthritic hip pathologies has been incorporated into the guidelines and is presented. The guidelines are divided into three phases, with goals for each phase explained. A progression through phases by way of reaching certain milestones and goals is advocated.


Effects of low-level radioactive soil contamination and sterilization on the degradation of radiolabeled wheat straw.
After the explosion of reactor 4 in the nuclear power plant near Chernobyl, huge agricultural areas became contaminated with radionuclides. In this study, we want to elucidate whether (137)Cs and (90)Sr affect microorganisms and their community structure and functions in agricultural soil. For this purpose, the mineralization of radiolabeled wheat straw was examined in lab-scale microcosms. Native soils and autoclaved and reinoculated soils were incubated for 70 days at 20 °C. After incubation, the microbial community structure was compared via 16S and 18S rDNA denaturing gradient gel electrophoresis (DGGE). The radioactive contamination with (137)Cs and (90)Sr was found to have little effect on community structure and no effect on the straw mineralization. The autoclaving and reinoculation of soil had a strong influence on the mineralization and the community structure. Additionally we analyzed the effect of soil treatment on mineralization and community composition. It can be concluded that other environmental factors (such as changing content of dissolved organic carbon) are much stronger regulating factors in the mineralization of wheat straw and that low-level radiation only plays a minor role.


Radiologic assessment preoperative to endoscopic sinus surgery.
At our institution, the screening coronal section CT scan has largely replaced the use of the sinus series for the initial evaluation of patients suspected to have sinus pathology. However, in those patients with obvious mucosal disease on endoscopic examination, the screening coronal section CT scan is bypassed and a complete coronal section CT scan obtained. Axial section CT scans are not routinely obtained and bone windows are consistently selected for viewing.


Bis(μ2-N-methyl-N-phenyl-dithio-carbamato)-κ3S,S':S;κ3S:S,S'-bis-[(N-methyl-N-phenyl-dithio-carbamato-κ2S,S')cadmium]: crystal structure and Hirshfeld surface analysis.
The title compound, [Cd2(C8H8NS2)4], is a centrosymmetric dimer with both chelating and μ2-tridentate di-thio-carbamate ligands. The resulting S5 donor set defines a CdII coordination geometry inter-mediate between square-pyramidal and trigonal-bipyramidal, but tending towards the former. The packing features C-H⋯S and C-H⋯π inter-actions, which generate a three-dimensional network. The influence of these inter-actions, along with intra-dimer π-π inter-actions between chelate rings, has been investigated by an analysis of the Hirshfeld surface.


Fragment Reattachment: A 4-Year Case Report of Uncomplicated Dental Fractures.
Two fractured maxillary central incisors were restored via the crown fragment reattachment technique with adhesive systems and composite resin material. A long-term successful outcome was achieved after 4 years of follow-up. The patient presented with fractured maxillary central incisors, and a comprehensive intraoral and radiographic examination revealed that both teeth had extended crown fractures with no pulpal exposure (Class II, Ellis and Davey). The tooth fragments were thoroughly cleaned and inspected before being repositioned. Both fragments were in excellent condition with almost no pieces missing. Therefore, the proposed treatment was fragment reattachment. After verifying the repositioning and adaptation of the fractured fragments, a flowable composite was used to perform the reattachment procedure under rubber dam isolation. With modern dental adhesives, the reattachment of tooth fragments in good condition is considered a more conservative option for restoring tooth morphology, esthetics, and function. Although one tooth showed signs of irreversible pulpitis and required root canal treatment 2 weeks after the restoration, the clinical and radiographic evaluations at the 4-year follow-up visits confirmed the success of the restorative treatment. The restorations showed good functional and esthetic outcomes after 4 years of follow-up.


Simulation and dynamic optimisation of animal cell culture.
In animal cell culture, there are some 25 substrates that both have a significant effect on the culture performance and which can be measured with relative ease. A detailed dynamic simulation for such a culture has been produced and an optimisation policy that use this model to identify ideal media conditions has been developed. This paper describes an extension of that work to include the dynamic optimisation of cultures under fed-batch operation. Two different types of feeding policy were considered - in the first, discrete shots of feed were supplied, while in the second, feed was added continuously. Both policies offered significant improvements in the predicted productivity of the culture - up to 30% that of an experimentally "optimised"batch culture.


Machine learning and statistic analysis to predict drug treatment outcome in pediatric epilepsy patients with tuberous sclerosis complex.
We aimed to investigate the association between multi-modality features and epilepsy drug treatment outcomes and propose a machine learning model to predict epilepsy drug treatment outcomes with multi-modality features. This retrospective study consecutively enrolled 103 epilepsy children with rare TSC. Multi-modality data were used to characterize risk factors for epilepsy drug treatment outcome of TSC, including clinical data, TSC1, and TSC2 genes test results, magnetic resonance imaging (MRI), computerized tomography (CT), and electroencephalogram (EEG). Three common feature selection methods and six common machine learning models were used to find the best combination of feature selection and machine learning model for epilepsy drug treatment outcomes prediction with multi-modality features for TSC clinical application. The analysis of variance based on selected 35 features combined with multilayer perceptron (MLP) model achieved the best area-under-curve score (AUC) of 0.812 (±0.005). Infantile spasms, EEG discharge type, epileptiform discharge in the right frontal area of EEG, drug-resistant epilepsy, gene mutation type, and type II lesions were positively correlated with drug treatment outcome. Age of onset and age of visiting doctors were negatively correlated with drug treatment outcome (p < 0.05). Our machine learning results found that among MRI features, lesion type is the most important in the outcome prediction, followed by location and quantity. We developed and validated an effective prediction model for epilepsy drug treatment outcomes of TSC. Our results suggested that multi-modality features analysis and MLP-based machine learning can predict epilepsy drug treatment outcomes of TSC.


Multiple sclerosis potpourri. Paroxysmal symptoms, seizures, fatigue, pregnancy, and more.
Several symptom complexes in multiple sclerosis (MS) are found in unusual circumstances but are characteristic of the disease. Most of these are amenable to treatment and will be confronted by the physiatrist treating patients who have MS. This article begins by addressing paroxysmal symptoms such as trigeminal neuralgia, paroxysmal dysarthria and ataxia, parathesia and pain, paroxysmal itching, and akinesia. Seizures, adventitious movements, fatigue, and complications related to pregnancy also are addressed.


A systematic review of the efficacy and safety of topical cyclosporine in dermatology.
Cyclosporine-A (Cyc-A) was initially prescribed as systemic therapy for patients receiving solid organ transplants or in patients with graft versus host disease (GVHD). Topical Cyc-A is an ideal form of cyclosporine in the treatment of mucocutaneous disorders as it causes fewer systemic side effects and has more stable results than steroids; however, poor absorption through the skin makes the development of new formulations necessary to improve skin permeability. The aim of this study was to evaluate the efficacy and safety of topical Cyc-A in different dermatological conditions. A thorough systematic review was performed on PubMed/Medline, Embase, Scopus, and Web of Science databases as well as Google Scholar, and relevant studies from 2000 until January 3, 2022, were selected. The study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA). Topical Cyc-A was observed to be an effective medication in the treatment of oral lichen planus, psoriasis, burning mouth syndrome, Pyoderma Gangrenosum, and Zoon's balanitis. Adverse side effects such as dysphagia, burning sensation, lips swelling, and gastrointestinal upset were reported following Cyc-A mouthwash use, whereas mild erythema, dryness, and fissuring of the skin were observed following the Cyc-A lipogel application. Topical Cyc-A was found to be a good alternative to traditional treatment regimens for immune-mediated mucocutaneous conditions. Cyc-A can be considered as a safe and efficient option in cases of long-term treatment as it does not have the same adverse effects of long-term steroids.


Prevalence of asthma and allergies among children in the United Arab Emirates: A cross-sectional study.
Asthma, allergic rhinitis, and atopic dermatitis are the most common chronic inflammatory disorders in children worldwide. These conditions place a significant burden on the healthcare system due to their multiple related complications and the necessity of hospital visits. This study aimed to evaluate the prevalence and severity of asthma and allergic diseases among school children aged 6-7 years and 13-14 years in Dubai and the Northern Emirates, United Arab Emirates (UAE). This was a multicenter, cross-sectional study that recruited children from March to June 2019 via school class registers in Dubai and the Northern Emirates, UAE. The Arabic and English versions of the International Study of Asthma and Allergies in Childhood (ISAAC) core questionnaires on asthma, allergic rhinitis, and atopic dermatitis were completed by parents or legal guardians of children aged 6-7 years, and by the children themselves in those aged 13-14 years. In this study, we included 3436 children (1944 children aged 6-7 years and 1793 children aged 13-14 years). We estimated the prevalence of asthma (11.9%), wheezing (44.2%), allergic rhinitis (46.5%), hay fever (22.1%), and atopic dermatitis (12.9%) in the 6- to 7-year-old group. In the 13- to 14-year-old group, the prevalence was 9.8%, 33.1%, 51.3%, 19.9%, and 14.6%, respectively. The prevalence of any history of asthma was higher in boys than girls in the 6- to 7-year-old group (13.9% vs. 10%) and in the 13- to 14-year-old group (11.2% vs. 8.7%). In the 6- to 7-year-old group, the highest prevalence of asthma, sneezing, and atopic dermatitis was observed in Dubai, Ajman, and Umm Al Quwain, respectively. In the 13- to 14-year-old group, the highest prevalence of asthma was observed in Ras Al Khaimah, and the highest prevalence of sneezing and atopic dermatitis was observed in Sharjah. We found that the prevalence of asthma, allergic rhinitis, and atopic dermatitis in the UAE is comparable to that in neighboring countries; the prevalence of asthma, wheezing, and hay fever was higher in the 6- to 7-year-old group, while in the 13- to 14-year-old group, the prevalence of allergic rhinitis and atopic dermatitis was higher. Overall, the prevalence of any history of asthma was highest in Ras Al Khaimah, followed by Dubai, and lowest in Ajman. Our findings suggest that allergic disorders represent a healthcare burden in the UAE and more efforts are needed to organize nationwide campaigns to detect undiagnosed children to overcome the burden caused by these conditions.


Modeling of dynamical systems through deep learning.
This review presents a modern perspective on dynamical systems in the context of current goals and open challenges. In particular, our review focuses on the key challenges of discovering dynamics from data and finding data-driven representations that make nonlinear systems amenable to linear analysis. We explore various challenges in modern dynamical systems, along with emerging techniques in data science and machine learning to tackle them. The two chief challenges are (1) nonlinear dynamics and (2) unknown or partially known dynamics. Machine learning is providing new and powerful techniques for both challenges. Dimensionality reduction methods are used for projecting dynamical methods in reduced form, and these methods perform computational efficiency on real-world data. Data-driven models drive to discover the governing equations and give laws of physics. The identification of dynamical systems through deep learning techniques succeeds in inferring physical systems. Machine learning provides advanced new and powerful algorithms for nonlinear dynamics. Advanced deep learning methods like autoencoders, recurrent neural networks, convolutional neural networks, and reinforcement learning are used in modeling of dynamical systems.


Present and future directions in diabetic kidney disease.
Diabetic kidney disease (DKD) is the leading cause of kidney failure and is associated with substantial risk of cardiovascular disease, morbidity, and mortality. Traditionally, DKD prevention and management have focused on addressing hyperglycemia, hypertension, obesity, and renin-angiotensin system activation as important risk factors for disease. Over the last decade, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists have been shown to meaningfully reduce risk of diabetes-related kidney and cardiovascular complications. Additional agents demonstrating benefit in DKD such as non-steroidal mineralocorticoid receptor antagonists and endothelin A receptor antagonists are further contributing to the growing arsenal of DKD therapies. With the availability of greater therapeutic options comes the opportunity to individually optimize DKD prevention and management. Novel applications of transcriptomic, proteomic, and metabolomic/lipidomic technologies, as well as use of artificial intelligence and reinforced learning methods through consortia such as the Kidney Precision Medicine Project and focused studies in established cohorts hold tremendous promise for advancing our understanding and treatment of DKD. Specifically, enhanced understanding of the molecular mechanisms underlying DKD pathophysiology may allow for the identification of new mechanism-based DKD subtypes and the development and implementation of targeted therapies. Implementation of personalized care approaches has the potential to revolutionize DKD care.


Clinical results of definitive chemoradiotherapy for cervical esophageal cancer: Comparison of failure pattern and toxicities between intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy.
The efficacy of intensity-modulated radiotherapy (IMRT) for cervical esophageal cancer has not been determined. Eighty patients with cervical esophageal cancer treated with definitive chemoradiotherapy from 2002 to 2014 were analyzed. Overall survival (OS), failure patterns, and toxicity incidence were compared between the IMRT (N = 32) and 3D conformal radiotherapy (RT; N = 48) groups. The median follow-up was 35.9 months. The 3-year OS of the IMRT, 3D conformal RT, and total groups was 81.6%, 57.2%, and 66.6%, respectively. Pulmonary toxicity was not observed with IMRT. Six of 62 cases (9.6%) with nodal involvement developed upper cervical node recurrence outside the prophylactic region. Ten patients in the IMRT group were salvaged, and 60% survived without recurrence; 20% of the 3D conformal RT group was salvaged. The IMRT group was comparable with 3D conformal RT group, with a better salvage rate. We recommend extended cervical irradiation for nodal involvement.


A nanoscale combing technique for the large-scale assembly of highly aligned nanowires.
The controlled assembly of nanowires is a key challenge in the development of a range of bottom-up devices. Recent advances in the post-growth assembly of nanowires and carbon nanotubes have led to alignment ratios of 80-95% for a misalignment angle of ±5° (refs 5, 12, , 14) and allowed various multiwire devices to be fabricated. However, these methods still create a significant number of crossing defects, which restricts the development of device arrays and circuits based on single nanowires/nanotubes. Here, we show that a nanocombing assembly technique, in which nanowires are anchored to defined areas of a surface and then drawn out over chemically distinct regions of the surface, can yield arrays with greater than 98.5% of the nanowires aligned to within ±1° of the combing direction. The arrays have a crossing defect density of ∼0.04 nanowires per µm and efficient end registration at the anchoring/combing interface. With this technique, arrays of single-nanowire devices are tiled over chips and shown to have reproducible electronic properties. We also show that nanocombing can be used for laterally deterministic assembly, to align ultralong (millimetre-scale) nanowires to within ±1° and to assemble suspended and crossed nanowire arrays.


Influence of mobilization and weight bearing on in-hospital outcome in geriatric patients with hip fractures.
Early recovery of mobilization after a fracture of the hip is associated with improved long-term ability to walk, lower complication rates, and mortality. In this context, early mobilization and full weight bearing are favorable. The aim of this study was (1) to analyze the influence of time between operation and first mobilization on in-hospital outcome and (2) the influence of early mobilization, full weight bearing, and ASA on pain, mobility of the hip, and ability to walk during the in-hospital phase of recovery. This is a retrospective in-hospital study of 219 patients aged 70 years or older who were treated with surgery after a hip fracture. Data were collected by a review of medical records. The outcomes were mortality, complications, length of stay, and the Merle d'Aubigné score which evaluates pain, mobility of the hip, and ability to walk. Factors were sought in bivariate and multivariate analyses. A shorter time between operation and first mobilization was significantly associated with lower in-hospital mortality and complications. Early mobilization (within 24 h after the operation) and full weight bearing had no influence on pain, mobility of the hip, and ability to walk as well as length of stay in our cohort. Fracture type and treatment influenced mobility of the hip, while age as well as physical health status affected the ability to walk. Patients with femoral neck fractures, respectively after total hip arthroplasty, had less pain and showed better mobility of the hip and ability to walk during hospitalization than patients with trochanteric fractures; these results were irrespective of early vs. late mobilization and full vs. partial weight bearing. Foremost, a shorter time between operation and first mobilization is associated with lower complication and mortality rates.


Roles of Vegetable Surface Properties and Sanitizer Type on Annual Disease Burden of Rotavirus Illness by Consumption of Rotavirus-Contaminated Fresh Vegetables: A Quantitative Microbial Risk Assessment.
Enteric viruses are often detected in water used for crop irrigation. One concern is foodborne viral disease via the consumption of fresh produce irrigated with virus-contaminated water. Although the food industry routinely uses chemical sanitizers to disinfect post-harvest fresh produce, it remains unknown how sanitizer and fresh produce properties affect the risk of viral illness through fresh produce consumption. A quantitative microbial risk assessment model was conducted to estimate (i) the health risks associated with consumption of rotavirus (RV)-contaminated fresh produce with different surface properties (endive and kale) and (ii) how risks changed when using peracetic acid (PAA) or a surfactant-based sanitizer. The modeling results showed that the annual disease burden depended on the combination of sanitizer and vegetable type when vegetables were irrigated with RV-contaminated water. Global sensitivity analyses revealed that the most influential factors in the disease burden were RV concentration in irrigation water and postharvest disinfection efficacy. A postharvest disinfection efficacy of higher than 99% (2-log10 ) was needed to decrease the disease burden below the World Health Organization (WHO) threshold, even in scenarios with low RV concentrations in irrigation water (i.e., river water). All scenarios tested here with at least 99.9% (3-log10 ) disinfection efficacy had a disease burden lower than the WHO threshold, except for the endive treated with PAA. The disinfection efficacy for the endive treated with PAA was only about 80%, leading to a disease burden 100 times higher than the WHO threshold. These findings should be considered and incorporated into future models for estimating foodborne viral illness risks.


Radiological features of IgG4-related disease in the head, neck, and brain.
Immunoglobulin (Ig) G4-related disease is a recently designated benign clinical entity histopathologically characterized by sclerosing inflammation and infiltration of numerous IgG4+ plasma cells that affects multiple organs. The purpose of this study is to characterize the imaging findings of patients with histopathologically proven IgG4-related disease in the head, neck, and brain. A total of 17 patients (15 males, 2 females; mean age, 66.1 ± 7.4 years) with histopathologically proven IgG4-related disease in the head, neck, and brain were identified in two hospitals between January 2004 and December 2010. Imaging findings were retrospectively reviewed, with particular attention to the location and number of lesions, internal architecture, enhancement patterns, presence of vascular occlusion or compression, and changes in adjacent bones. The lesions, presented as either enlarged gland(s), or focal, localized nodules/masses, were distributed in the lacrimal gland (n = 7), the parotid gland (n = 14), the submandibular gland (n = 10), the pituitary gland (n = 2), skull base dura mater (n = 2), and the pterygopalatine fossa (n = 3). All lesions were well-defined and iso- to hypointense on T2-weighted magnetic resonance images and showed homogeneous enhancement. No lesion showed vascular occlusion or compression. Bones adjacent to the lesions showed remodeling (erosion or sclerosis) without signs of destruction (n = 6). Four patients had lesions involving multiple areas which extended along the trigeminal nerve, accompanied by expansion of neural foramina along their courses, with no signs of bone destruction. Sites of predilection for IgG4-related disease in the head, neck, and brain include the lacrimal, salivary, and pituitary glands. Recognition of the typical radiological features of IgG4-related disease, such as well-defined lesion borders, T2 hypointensity, homogeneous and gradual enhancement pattern, absence of vascular occlusion or compression, and presence of bone remodeling without destruction, may be of help in the diagnosis of this benign clinical entity.


A fluorescence turn-on H2O2 probe exhibits lysosome-localized fluorescence signals.
A new fluorescence turn-on probe that responds exclusively to H(2)O(2) exhibits subcellular localized fluorescence staining of lysosomes.


Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action.
The existence of an endogenous cannabinoid system was demonstrated conclusively with the discovery of endogenous brain constituents capable of activating the cannabinoid receptors functionally. These compounds are synthesized by neuronal cells and inactivated through re-uptake and enzymatic hydrolysis by both neurons and astrocytes. In analogy with the endorphins they can be referred to as endocannabinoids. Apart from the identification of their metabolic pathways, research carried out in the past six years has focused on the possible cellular and molecular targets for the actions of endocannabinoids. These studies have confirmed a similarity between the endocannabinoids and the psychoactive substance in marijuana, delta9(-)-tetrahydrocannabinol, and have suggested a role for endocannabinoids in the modulation of neurotransmitter action and release.


Delivery siRNA with a novel gene vector for glioma therapy by targeting Gli1.
Gene therapy has recently shown considerable clinical benefit in cancer therapy during the past few years, and the application of this choice in cancer treatments is increasing continually. Gli1 is an ideal candidate target for cancer gene therapy and is important for tumorigenesis. In this study, we developed a novel gene delivery system with a self-assembly method by using a 1,2-dioleoyl-3-trimethylammonium-propane and methoxy poly (ethylene glycol)-poly(lactide) copolymer (DMP), with zeta potential of 32.7 mV and measuring 35.6 nm. The effect of this delivery system was tested in vitro and in vivo. DMP showed good performance in delivering siRNA to glioma cells in vitro with high transfection performance (98%). Moreover, DMP-Gli1si shows a satisfactory anti-glioma effect via induction of cell apoptosis and cell growth inhibition in vitro. Furthermore, for subcutaneous tumor-bearing mice, treatment with the DMP-Gli1si complex significantly inhibited tumor growth by inhibiting Gli1 protein expression, promoting apoptosis, and reducing proliferation. The complex of Gli1 siRNA and DMP may potentially play an important role as a new drug in the clinical treatment of gliomas.


Recent Endovascular Stroke Trials and Their Impact on Stroke Systems of Care.
Five recently published randomized trials of endovascular therapy versus medical management, including intravenous thrombolysis, demonstrated strong positive data in support of intra-arterial thrombectomy procedures. The American Heart Association/American Stroke Association released a focused update of the 2013 guidelines on the early management of acute ischemic strokes to specifically incorporate the findings of the 5 "positive" trials. In this review, we examine the key results of those trials and the principal changes in the updated guidelines. We discuss the ongoing and future changes in stroke systems of care, with an emphasis on the role of pre-hospital stroke triage, interhospital transfer, and the 2 main levels of stroke center certification (primary and comprehensive).


[Effect of a single ethanol administration on the behavior and the RNA-synthesizing activity of the cell nuclei of the cerebral cortex of the rat].
A single intraperitoneal injection of ethanol (2 g/kg) disturbed the learning and performance of one trial passive avoidance task and decreased (by 14 %) the level of RNA-synthesizing activity of brain cortical synaptosomes in rats. The data obtained are discussed in accordance with the hypothesis that ethanol affects synaptic transmission in the central nervous system.


Composition, variation and contribution of chromophoric dissolved organic matter in Laizhou Bay estuaries, North China.
To address the complex biogeochemical processes and potential function of dissolved organic matter (DOM) in estuaries before it enters the sea, water samples were collected seasonally in a dozen Laizhou Bay estuaries and in the Yellow River estuary, North China. The results showed that chromophoric dissolved organic matter (CDOM) varied in abundance but had consistent spectral slopes at the same sampling time. Gradually, CDOM decreased while spectral slopes increased from freshwater to seawater. The spectral slope of CDOM varied temporally (higher in October and lower in August) more than it varied spatially. The fluorescent components and biological indices of CDOM indicated that in situ biological activities were the dominant sources in the waters examined in this study. The CDOM was generally more variable than the dissolved organic carbon (DOC) in most of the estuaries. However, marine CDOM may obviously increase in estuaries when indirectly stimulated by rapidly decomposing terrestrial DOM.


Characteristics of traditional Chinese medicine users and prescription analysis for pediatric atopic dermatitis: a population-based study.
Atopic dermatitis among children is an important issue due to relapses and skin manifestations. Traditional Chinese medicine (TCM) is commonly used to treat children with atopic dermatitis. The aim of this study was to investigate the characteristics and TCM prescriptions of patients with atopic dermatitis using a nationwide database. Children younger than 12 years of age diagnosed with atopic dermatitis, defined as ICD-9-CM codes 691.8 and 692.x, were identified from the database. Data on age, diagnosis codes, area of residence and use of corticosteroids of the TCM users were recorded. Association rule mining was used to analyze the prescriptions used for atopic dermatitis. We identified 13,646 children with atopic dermatitis using TCM in 2007. Female gender (OR: 0.83 for male gender), adolescence (OR: 10.0, 95 % CI: 8.88-11.15) and allergic rhinitis (OR: 2.44, 95 % CI: 2.10-2.85) were associated with the use of TCM. Fewer of the TCM users were prescribed with corticosteroids (35.8 % of all TCM users), but the TCM users had a higher rate of long-term topical corticosteroid therapy (10.6 % for TCM users versus 2.0 % for those who did not use TCM). Chinese herbal medicine (CHM) was used by 93.7 % of all TCM users in 36,398 prescriptions. On average, 5.6 kinds of CHM were used in combination. The relationship between the CHMs constituted a network, in which Xiao-Feng-San was the core treatment for atopic dermatitis. In this study, we described the characteristics of children with atopic dermatitis who use TCM in Taiwan. and identified the core CHM treatment. Further research on the safety and efficacy of this treatment are still needed.


Different spectrophotometric methods applied for the analysis of binary mixture of flucloxacillin and amoxicillin: A comparative study.
Three different spectrophotometric methods were applied for the quantitative analysis of flucloxacillin and amoxicillin in their binary mixture, namely, ratio subtraction, absorbance subtraction and amplitude modulation. A comparative study was done listing the advantages and the disadvantages of each method. All the methods were validated according to the ICH guidelines and the obtained accuracy, precision and repeatability were found to be within the acceptable limits. The selectivity of the proposed methods was tested using laboratory prepared mixtures and assessed by applying the standard addition technique. So, they can be used for the routine analysis of flucloxacillin and amoxicillin in their binary mixtures.


Exopolysaccharide-peptide complex from oyster mushroom (Pleurotus ostreatus) protects against hepatotoxicity in rats.
Liver damage involves oxidative stress and a progression from chronic hepatitis to hepatocellular carcinoma (HCC). The increased incidence of liver disease in Egypt and other countries in the last decade, coupled with poor prognosis, justify the critical need to introduce alternative chemopreventive agents that may protect against liver damage. The aim of this study was to evaluate the efficacy of exopolysaccharide-peptide (PSP) complex extracted from Pleurotus ostreatus as a hepatoprotective agent against diethylnitrosamine (DEN)/carbon tetrachloride (CCL4)-induced hepatocellular damage in rats. The levels of liver injury markers (ALT, AST and ALP) were substantially increased following DEN/CCl4 treatment. DEN/CCl4 - induced oxidative stress was confirmed by elevated levels of lipid peroxidation and decreased levels of superoxide dismutase, glutathione-S-transferase, and reduced glutathione. PSP reversed these alterations in the liver and serum, and provided protection evidenced by reversal of histopathological changes in the liver. The present study demonstrated that PSP extract from P. ostreatus exhibited hepatoprotective and antioxidant effects against DEN/CCl4-induced hepatocellular damage in rats. Given the high prevalence of HCV-related liver damage in Egypt, our results suggest further clinical evaluation of P. ostreatus extracts and their potential hepatoprotective effects in patients with liver disease.


BRCA1 gene therapy reduces systemic inflammatory response and multiple organ failure and improves survival in experimental sepsis.
Sepsis-related complications and mortality remain a major clinical problem. Increased cell death and unresolved cellular repair have been implicated as key upstream mediators of sepsis-induced organ dysfunction and death. We hypothesised that gene therapy with BRCA1, a critical regulator of DNA damage repair and cell survival, would attenuate the sequelae of sepsis and peritonitis in mice subjected to caecal ligation and perforation (CLP) and thioglycollate stimulation. C57Bl/6J mice underwent sham or CLP surgery 3 days following treatment with either human BRCA1 adenovirus (AdBRCA1) or the adeno-CMV-null vector (Adnull). The 24-h post-CLP mortality was 2.8% vs 17.9% (P<0.001) and the median post-CLP survival was 50.5 vs 33 h (P<0.05) for AdBRCA1- vs Adnull-treated mice, respectively. AdBRCA1 therapy blunted CLP-associated cardiac, pulmonary, hepatic and renal dysfunction and also reduced CLP-elicited double strand breaks and apoptosis in the liver. BRCA1 gene therapy was associated with lower CLP-evoked cardiac and hepatic superoxide generation that in the liver was in part due to improved reactive oxygen species removal. CLP also elevated mesenteric arteriolar and serum intercellular adhesion molecule-1, both of which were partially abrogated with AdBRCA1 administration. Thioglycollate-challenged AdBRCA1-treated mice displayed reduced peritoneal neutrophil recruitment and dampened cytokine elaboration relative to their Adnull-treated counterparts. Taken together, we report a novel role of BRCA1 gene therapy in limiting systemic inflammation, multiple-organ failure and mortality in experimental sepsis.


Synthesis of carboxymethylated β-glucan from naked barley bran and its antibacterial activity and mechanism against Staphylococcus aureus.
This study aimed to elucidate the antimicrobial efficacy of carboxymethylated β-glucan (CMG) against Staphylococcus aureus and the possible underlying mechanisms. β-Glucan (BG) was extracted from naked barley bran, then ultrafiltrated to obtain four fractions (BG-1, BG-2, BG-3, BG-4). Five types of CMG were prepared using an amidation reaction and characterized by FTIR spectroscopy. The underlying mechanisms were studied using changes in the transmembrane electrical potential, pH gradient, and intracellular ATP, confocal laser scanning microscopy, and electron microscopy. The data showed that CMG-2 had the highest antibacterial activity. CMG-2 induced membrane permeabilization, morphological changes, and structural disruption in S. aureus cells, with the formation of blebs and microspheres, the disruption of cell walls and membranes, and cell lysis. Our findings provide insight into the antimicrobial mechanism of CMG against S. aureus, which will provide a foundation for developing CMG as a novel antibacterial agent in the food and biomedical fields.


Effect of melatonin on secreted and induced matrix metalloproteinase-9 and -2 activity during prevention of indomethacin-induced gastric ulcer.
Matrix metalloproteinases (MMPs) maintain the crucial role in physiological turnover of extracellular matrix (ECM) proteins in gastric tissues. However, a little is known about the relationship of MMPs with ECM degradation during gastric ulceration and ECM remodeling during healing. Our objective was to investigate the effect of melatonin (N-acetyl-5 methoxytryptamine) on the regulation of MMP-9 and MMP-2 activity during prevention of gastric ulcer. In the present study, biochemical and zymographic methods were used to analyze the mechanism of melatonin in indomethacin-induced gastric ulcer in a rat model. Our studies reveal that melatonin dose-dependently downregulates the expression and secretion of pro-MMP-9 which is induced (approximately 10-fold) during indomethacin-induced gastric ulceration. Furthermore, melatonin prevents gastric ulceration in a dose-dependent manner through upregulation (approximately two- to threefold) of both pro-MMP-2 and active MMP-2 at the level of induction as well as secretion. It also prevents gastric ulcers by blocking glutathione depletion and lipid peroxidation in cytosolic and microsomal fractions. The novel findings of this study are attributed to the attenuation of the pro-MMP-9 and increase of MMP-2 activity by pretreatment with melatonin. The finding defines one of the MMP-mediated pathways for melatonin's action in gastric ulcer.


Early programming of CD8+ T cell response by the orphan nuclear receptor NR4A3.
Enhancing long-term persistence while simultaneously potentiating the effector response of CD8+ T cells has been a long-standing goal in immunology to produce better vaccines and adoptive cell therapy products. NR4A3 is a transcription factor of the orphan nuclear receptor family. While it is rapidly and transiently expressed following T cell activation, its role in the early stages of T cell response is unknown. We show that NR4A3-deficient murine CD8+ T cells differentiate preferentially into memory precursor and central memory cells, but also produce more cytokines. This is explained by an early influence of NR4A3 deficiency on the memory transcriptional program and on accessibility of chromatin regions with motifs for bZIP transcription factors, which impacts the transcription of Fos/Jun target genes. Our results reveal a unique and early role for NR4A3 in programming CD8+ T cell differentiation and function. Manipulating NR4A3 activity may represent a promising strategy to improve vaccination and T cell therapy.


The occurrence of malolactic fermentation in brandy base wine and its influence on brandy quality.
In this study we determined the extent to which lactic acid bacteria (LAB) occurred in brandy base wines, their ability to catalyse the malolactic fermentation (MLF) and the effect of MLF on the quality of the base wine and the brandy distillate. Lactic acid bacteria were isolated and enumerated from grape juice, experimental and commercially produced brandy base wines. Spontaneous MLF occurred in approximately 50% of the commercial base wines. The occurrence of MLF had an influence on the quality of the base wines and the resulting distillates. In samples where MLF occurred there was a loss of fruitiness and in the intensity of aroma. Volatile compounds like iso-amyl acetate, ethyl acetate, ethyl caproate, 2-phenethyl acetate and hexyl acetate decreased in samples having undergone MLF, while ethyl lactate, acetic acid and diethyl succinate increased in the same samples. Spontaneous malolactic fermentation does occur in commercial brandy base wines and it has an influence on base wine and brandy quality. This study showed that MLF influences the quality of the base wine and the resulting distillate and with this in mind commercial base wine producers should be able to produce brandy of higher quality.


Formation of the Indian ocean.
Palaeomagnetic results suggest a possible sequence for the fragmentation of the land masses around the Indian Ocean.


Plasma Serotonin in Laying Hens (Gallus gallus domesticus) With and Without Foot pad Dermatitis.
The aim of this study was to investigate whether plasma serotonin (5-hydroxytryptamine [5-HT]) was associated with the presence of foot pad dermatitis (FPD) in laying hens. FPD birds (n = 20) and healthy individuals (n = 22) were included. Plasma 5-HT was investigated. FPD laying hens showed significantly higher 5-HT levels (median = 6 µmol/L) compared with healthy individuals (median = 4.28 µmol/L, P < .001). When present, FPD were scored as either 1 (n = 12) indicating mildly to moderately abnormal or 2 indicating severely abnormal (n = 8). The subjects whose lesions scored 2 had higher plasma 5-HT levels than those whose lesions scored 1. Inflammatory mechanisms seem to be related to plasma 5-HT levels in laying hens. Assessing plasma 5-HT could be useful to evaluate chicken welfare.


BlpC-mediated selfish program leads to rapid loss of Streptococcus pneumoniae clonal diversity during infection.
Successful colonization of a host requires bacterial adaptation through genetic and population changes that are incompletely defined. Using chromosomal barcoding and high-throughput sequencing, we investigate the population dynamics of Streptococcus pneumoniae during infant mouse colonization. Within 1 day post inoculation, diversity was reduced >35-fold with expansion of a single clonal lineage. This loss of diversity was not due to immune factors, microbiota, or exclusive genetic drift. Rather, bacteriocins induced by the BlpC-quorum sensing pheromone resulted in predation of kin cells. In this intra-strain competition, the subpopulation reaching a quorum likely eliminates others that have yet to activate the blp locus. Additionally, this reduced diversity restricts the number of unique clones that establish colonization during transmission between hosts. Genetic variation in the blp locus was also associated with altered transmissibility in a human population, further underscoring the importance of BlpC in clonal selection and its role as a selfish element.


Revascularization of corpus cavernosum for erectile failure.
Revascularization of the penis for erectile disability was performed in 10 patients in whom arterial obstruction had been documented. Inferior epigastric artery anastomosis to the corpus cavernosum was not successful, although bypass grafts from the femoral artery to the corpus cavernosum have helped restore potency in 4 of 6 patients. Complications included embolus to the leg, postoperative hemorrhage, and three small hematomas. This procedure can be considered a clinical experiment and would call for more study to assess its ultimate value.


Modulation of lymphatic smooth muscle contractile responses by the endothelium.
The endothelium regulates smooth muscle tone in blood vessels through the release of endothelium-deprived relaxing factor (EDRF). We hypothesized that the lymphatics possess endothelium-dependent relaxant properties analogous to those in blood vessels. Fresh porcine tracheobronchial lymphatic vessel rings were mounted in organ baths and connected to force-displacement transducers. Rings were submaximally precontracted with 10(-5) M histamine and exposed to cumulative addition of acetylcholine (ACH; 10(-7)-3 x 10(-4) M) or bradykinin (BRD; 10(-8)-3 x 10(-6) M), both of which are known to promote release of EDRF. ACH caused concentration-dependent relaxation (maximum effect = -2.3 +/- 2.6% of initial histamine-induced active tension), while a similar but less pronounced effect was seen with BRD (39.6 +/- 5.4%). The relaxant effects of ACH and BRD were inhibited by collagenase pretreatment and mechanical endothelial denudation. The results confirm our hypothesis that lymphatic vessels possess endothelium-dependent relaxant properties and suggest that lymph vessels can regulate lymph flow through processes similar to those found in blood vessels.


The Moberg deltoid-triceps replacement and key-pinch operations in quadriplegia: preliminary experiences.
The use of the tendons of the lateral four extensors of the toes in order to transfer the pull of the posterior deltoid to extend the elbow is successful in the OCu:2 quadriplegic patient. The Moberg operation for key pinch in its various modifications also improves the function of these patients and is well received by them. The necessity for prolonged protecton (three months) and for simplicity in surgical procedures in these patients is illustrated in seven patients.


Reciprocal changes in vasoactive hormones in the rat myocardial infarction model of heart failure.
The purpose of this study was to determine (1) if there is a relationship between the changes in the plasma levels of atrial natriuretic peptide (ANP) and plasma renin activity (PRA) as rats compensated from 3 days to 6 weeks after coronary ligation and (2) if these changes are related to myocardial infarction (MI) size. Arterial blood was drawn twice from 34 conscious rats (control, n = 10; small MI, n = 10; large MI, n = 14). Histologic MI size correlated better with ANP 3 days (r = .72, P < .001) than with ANP 6 weeks after MI (r = .39, P = .021). The reverse was true for an electrocardiographic index of MI size that used the sum of the Q waves minus the sum of the R waves in leads I, aVL, and V5. Atrial natriuretic peptide at 3 days was increased in both MI groups and was highest in the large MI group (control, 25.6; small MI, 41.0; large MI, 58.6 pM). Atrial natriuretic peptide decreased significantly from 3 days to 6 weeks in the large MI group and normalized in the small MI group (control, 25.0; small MI, 26.4; large MI, 44.4 pM). Plasma renin activity was not elevated at either time. However, the change in ANP from 3 days to 6 weeks in the MI rats was negatively related to the change in PRA (r = .48, P = .016). Atrial natriuretic peptide levels early after MI may be a good predictor of infarct size. The pattern of ANP and PRA changing in opposite directions over time suggest a counterregulatory link between these two systems.


Gravitational Constraints on a Lightlike Boundary.
We analyse the boundary structure of general relativity in the coframe formalism in the case of a lightlike boundary, i.e. when the restriction of the induced Lorentzian metric to the boundary is degenerate. We describe the associated reduced phase space in terms of constraints on the symplectic space of boundary fields. We explicitly compute the Poisson brackets of the constraints and identify the first- and second-class ones. In particular, in the 3+1-dimensional case, we show that the reduced phase space has two local degrees of freedom, instead of the usual four in the non-degenerate case.


The effects of methionine- and leucine-enkephalin on spinal neurones of the cat.
Extra- and intracellular recordings were obtained from physiologically identified, spinal neurones in the 6th and 7th lumbar segments of the pentobarbitone-anaesthetized cat. Microiontophoretically applied methionine- and leucine-enkephalin reversibly inhibited the spontaneous, synaptically induced, and L-glutamate-induced activity in the majority of dorsal horn neurones studied in laminae 4, 5 and 6 of Rexed. Most of these depressant effects were antagonized by the prior microiontophoretic application of the opiate antagonist naloxone. Intracellular studies performed on dorsal horn neurones and motoneurones revealed that microiontophoretically applied methionine- and leucine-enkephalin caused no change in the resting membrane potential or the membrane resistance. Neither spike initiation nor spike overshoot were detectably altered by either enkephalin. The membrane depolarization and associated decrease in membrane resistance following microiontophoretic L-glutamate application were effectively blocked by the prior application of enkephalin. Naloxone, which by itself had no detectable effect on the membrane resistance, antagonized this effect. We propose that [enkephalinergic] cells in lamina II and III may modulate cells subserving somatosensory perception, including pain.


Synthesis of prostaglandins by pig blastocysts cultured in medium containing estradiol or catechol estrogen.
Two experiments were conducted to determine the effects of 2-hydroxy-estradiol-17 beta (2-OH-E2; 0, 50 and 100 microM) and estradiol-17 beta (E2; 0, 25 and 50 microM) on prostaglandin (PG) E and PGF2 alpha synthesis by day-10 pig blastocysts (day 0 is first day of estrus). Blastocysts were incubated in a modified Krebs-Ringer bicarbonate medium, supplemented with bovine serum albumin (4 mg/ml) and the vitamins and amino acids (essential and nonessential) in Minimum Essential Medium (without phenol red or antibiotics). The incubations were conducted at 39 degrees C for three 2-h periods; the second and third periods included an E2 or catechol estrogen treatment. Release of PGF2 alpha into the culture medium decreased (p less than 0.001) linearly with increasing concentrations of 2-OH-E2 in both periods. Release of PGE was not affected by 2-OH-E2, therefore 2-OH-E2 increased (p less than 0.06) the PGE:PGF2 alpha. When E2 was added to the medium, release of PGE was decreased (p less than 0.01) during the second and third periods. Release of PGF2 alpha also was decreased (p less than 0.05) by E2 during period 2, but E2 did not alter the PGE:PGF2 alpha. Content of PGs in blastocysts at recovery was less than 10% of the PGs released in vitro. Therefore, these studies demonstrate effects of both the primary and catechol forms of E2 on the synthesis of PGE and PGF2 alpha. Catechol estrogens and E2 may inhibit PG synthesis and modify the PGE:PGF2 alpha during the establishment of pregnancy in pigs.


Chronic arthritis in systemic lupus erythematosus: distinct features in 336 paediatric and 1830 adult patients.
The objectives of this study are to assess the frequency of chronic arthritis and compare the clinical and laboratory features in a large population of childhood-onset systemic lupus erythematosus (cSLE) and adult-onset (aSLE) patients. This historical study evaluated 336 cSLE and 1830 aSLE patients. Chronic arthritis was defined as synovitis of at least 6 weeks of duration. Rhupus was characterised as the association of SLE and chronic inflammatory arthritis with erosion and positive rheumatoid factor. Jaccoud's arthropathy is a non-erosive subluxation leading to severe deformity of the hands and feet. Data were compared using Student's t test or the Mann-Whitney test for continuous variables. For categorical variables, differences were assessed by Fisher's exact test and Pearson chi-square. Frequencies of chronic arthritis were similar in cSLE and aSLE (2.4 vs. 3.8%, p = 0.261). The median time from disease onset to appearance of chronic arthritis was shorter in cSLE (0 vs. 10 years, p < 0.001), and the median of age at chronic arthritis diagnosis was [10.8 (4.2-14.6) vs. 40 (21-67), p < 0.001]. The children presented with more chronic polyarthritis than the adults (75 vs. 32%, p = 0.024), a higher median number of joints with arthritis [8.5 (1-18) vs. 3 (1-9), p = 0.017] and a higher number of joints with limitation [1.5(0-24) vs. 0(0-4), p = 0.004]. The chronic arthritis diagnosis frequencies of hepatomegaly (25 vs. 0%, p = 0.009), splenomegaly (25 vs. 0%, p = 0.009), pericarditis (25 vs. 0%, p = 0.009), nephritis (37 vs. 3% , p = 0.006), haematuria (37 vs. 1.4%, p = 0.002), lupus anticoagulant (40 vs. 1.6%, p = 0.012), anticardiolipin IgM (40 vs. 1.5%, p = 0.012) and median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) [10.5(1-20) vs. 6(4-16), p = 0.029] were higher in cSLE. Frequency of rhupus, (12 vs. 17%, p = 1.0), Jaccoud's arthropathy (0 vs. 17%, p = 0.343) and treatments were similar in cSLE and aSLE. We determined that chronic arthritis in SLE has distinct features in children, with very early onset, polyarticular involvement and association with active disease. We further demonstrated in this series that a proportion of chronic arthritis involvement in SLE is manifested as rhupus and Jaccoud's arthropathy.


The temporal localization of frame-shift ubiquitin-B and amyloid precursor protein, and complement proteins in the brain of non-demented control patients with increasing Alzheimer's disease pathology.
Transcriptional misreading of dinucleotide repeats that generates deletions in RNA and produces frame-shift proteins with loss of function has been reported in Alzheimer's disease (AD). Here frame-shift ubiquitin-B and amyloid precursor protein were immunochemically shown to exist in the brain of high pathology control (HPC) patients with AD pathology but without prior dementia. These proteins were absent in low pathology control patients with limited AD pathology and no dementia. Since the HPC patients can be regarded as preclinical AD patients, our results suggest the accumulation of these proteins involved in the initial steps of AD pathogenesis. By contrast, complement proteins were detected in the AD patients, whereas only trace amounts were found in the HPC patients, indicating the involvement of complement proteins in the later stage of AD dementia.


Stress and skin leukocyte trafficking as a dual-stage process.
Stress responses are known to modulate leukocyte trafficking. In the skin, stress was reported both to enhance and reduce skin immunity, and the chronicity of stress exposure was suggested as a key determining factor. We here propose a dual-stage hypothesis, suggesting that stress, of any duration, reduces skin immunity during its course, while its cessation is potentially followed by a period of enhanced skin immunity. To start testing this hypothesis, rats were subcutaneously implanted with sterile surgical sponges for four-hours, during or after exposure to one of several acute stress paradigms, or to a chronic stress paradigm. Our findings, in both males and females, indicate that numbers of sponge-infiltrating leukocytes, and their specific subsets, were reduced during acute or chronic stress, and increased after stress cessation. Studying potential mediating mechanisms of the reduction in leukocyte numbers during acute stress, we found that neither adrenalectomy nor the administration of beta-adrenergic or glucocorticoid antagonists prevented this reduction. Additionally, administration of corticosterone or epinephrine to adrenalectomized rats did not impact skin leukocyte numbers, whereas, in the blood, these treatments did affect numbers of leukocytes and their specific subsets, as was also reported previously. Overall, our findings support the proposed dual-stage hypothesis, which can be evolutionally rationalized and accounts for most of the apparent inconsistencies in the literature regarding stress and skin immunity. Other aspects of the hypothesis should be tested, also using additional methodologies, and its predictions may bear clinical significance in treatment of skin disorders related to hyper- or hypo-immune function.


The relationship between the MMP system, adrenoceptors and phosphoprotein phosphatases.
The MMPs and their inhibitors [tissue inhibitor of MMPs (TIMPs)] form the mainstay of extracellular matrix homeostasis. They are expressed in response to numerous stimuli including cytokines and GPCR activation. This review highlights the importance of adrenoceptors and phosphoprotein phosphatases (PPP) in regulating MMPs in the cardiovascular system, which may help explain some of the beneficial effects of targeting the adrenoceptor system in tissue remodelling and will establish emerging crosstalk between these three systems. Although α- and β-adrenoceptor activation increases MMP but decreases TIMP expression, MMPs are implicated in the growth stimulatory effects of adrenoceptor activation through transactivation of epidermal growth factor receptor. Furthermore, they have recently been found to catalyse the proteolysis of β-adrenoceptors and modulate vascular tone. While the mechanisms underpinning these effects are not well defined, reversible protein phosphorylation by kinases and phosphatases may be key. In particular, PPP (Ser/Thr phosphatases) are not only critical in resensitization and internalization of adrenoceptors but also modulate MMP expression. The interrelationship is complex as isoprenaline (ISO) inhibits okadaic acid [phosphoprotein phosphatase type 1/phosphoprotein phosphatase type 2A (PP2A) inhibitor]-mediated MMP expression. While this may be simply due to its ability to transiently increase PP2A activity, there is evidence for MMP-9 that ISO prevents okadaic acid-mediated expression of MMP-9 through a β-arrestin, NF-κB-dependent pathway, which is abolished by knock-down of PP2A. It is essential that crosstalk between MMPs, adrenoceptors and PPP are investigated further as it will provide important insight into how adrenoceptors modulate cardiovascular remodelling, and may identify new targets for pharmacological manipulation of the MMP system.


Functions of the corpus callosum: observations from callosotomy performed for intractable epilepsy.
The effects of complete and partial corpus callosotomy in 6 patients are reported. Only the 2 cases undergoing total callosotomy showed evidence of impaired interhemispheric sensory transfer, related to sectioning of the splenium. Only mild long-lasting neuropsychological deficits were detected. Post-commissurotomy mutism and akinesia appeared in 4 cases, 2 with total, and 2 with partial anterior callosotomy. The short-and long-term effects of corpus callosotomy appear to be related to the extent of the section the creation of lesions during the surgical procedure, and a peculiar organization of cognitive functions in chronic epileptic patients.


Alternative Reading Frames are an Underappreciated Source of Protein Sequence Novelty.
Protein-coding DNA sequences can be translated into completely different amino acid sequences if the nucleotide triplets used are shifted by a non-triplet amount on the same DNA strand or by translating codons from the opposite strand. Such "alternative reading frames" of protein-coding genes are a major contributor to the evolution of novel protein products. Recent studies demonstrating this include examples across the three domains of cellular life and in viruses. These sequences increase the number of trials potentially available for the evolutionary invention of new genes and also have unusual properties which may facilitate gene origin. There is evidence that the structure of the standard genetic code contributes to the features and gene-likeness of some alternative frame sequences. These findings have important implications across diverse areas of molecular biology, including for genome annotation, structural biology, and evolutionary genomics.


"Corination" of the proANP converting enzyme.
The membrane protease, corin, has been shown to be the proatrial natriuretic peptide (ANP)-converting enzyme. Like mice lacking ANP, corin-deficient animals are hypertensive and have cardiac hypertrophy.


A spotter's guide to SNPtic exons: The common splice variants underlying some SNP-phenotype correlations.
Cryptic exons are typically characterised as deleterious splicing aberrations caused by deep intronic mutations. However, low-level splicing of cryptic exons is sometimes observed in the absence of any pathogenic mutation. Five recent reports have described how low-level splicing of cryptic exons can be modulated by common single-nucleotide polymorphisms (SNPs), resulting in phenotypic differences amongst different genotypes. We sought to investigate whether additional 'SNPtic' exons may exist, and whether these could provide an explanatory mechanism for some of the genotype-phenotype correlations revealed by genome-wide association studies. We thoroughly searched the literature for reported cryptic exons, cross-referenced their genomic coordinates against the dbSNP database of common SNPs, then screened out SNPs with no reported phenotype associations. This method discovered five probable SNPtic exons in the genes APC, FGB, GHRL, MYPBC3 and OTC. For four of these five exons, we observed that the phenotype associated with the SNP was compatible with the predicted splicing effect of the nucleotide change, whilst the fifth (in GHRL) likely had a more complex splice-switching effect. Application of our search methods could augment the knowledge value of future cryptic exon reports and aid in generating better hypotheses for genome-wide association studies.


Allosteric inhibition and kinetic characterization of Klebsiella pneumoniae CysE: An emerging drug target.
The emergence and spread of multidrug-resistant strains of Klebsiella pneumoniae is a major concern that necessitates the development of unique therapeutics. The essential requirement of serine acetyltransferase (SAT/CysE) for survival of several human pathogens makes it a very promising target for inhibitor designing and drug discovery. In this study, as an initial step to structure-based drug discovery, CysE from K. pneumonia was structurally and biochemically characterized. Subsequently, blind docking of selected natural products into the X-ray crystallography determined 3D structure of the target was carried out. Experimental validation of the inhibitory potential of the top-scorers established quercetin as an uncompetitive inhibitor of Kpn CysE. Molecular dynamics simulations carried out to elucidate the binding mode of quercetin reveal that this small molecule binds at the trimer-trimer interface of hexameric CysE, a site physically distinct from the active site of the enzyme. Detailed analysis of conformational differences incurred in Kpn CysE structure on binding to quercetin provides mechanistic understanding of allosteric modulation. Binding of quercetin to CysE leads to conformation changes in the active site loops and proximal loops that affect its internal dynamics and consequently its affinity for substrate/co-factor binding, justifying the reduced enzyme activity.


2,2'-[Imidazolidine-1,3-diylbis(methyl-ene)]diphenol.
In the title mol-ecule, C(17)H(20)N(2)O(2), the imidazolidine ring adopts a twist conformation. The mean plane through the five atoms of the imidazolidine ring makes dihedral angles of 70.18 (4) and 74.14 (4)° with the planes of the two aromatic rings. The dihedral angle between the benzene rings is 53.11 (5)°. Both phenol -OH groups form intra-molecular hydrogen bonds to the N atoms, with graph-set motif S(6). In the crystal, pairs of O-H⋯O hydrogen bonds link the mol-ecules into dimers with R(4) (4)(18) ring motifs. The crystal packing is further stabilized by C-H⋯O and weak C-H⋯π inter-actions.


Long-term monitoring of drug consumption patterns during the COVID-19 pandemic in a small-sized community in Brazil through wastewater-based epidemiology.
The abuse of legal and illegal drugs is a global public health problem, also affecting the social and economic well-being of the population. Thus, there is a significant interest in monitoring drug consumption. Relevant epidemiological information on lifestyle habits can be obtained from the chemical analysis of urban wastewater. In this work, passive sampling using polar organic chemical integrative samplers (POCIS) was used to quantify licit and illicit drugs biomarkers in wastewater for the application of wastewater-based epidemiology (WBE). In this WBE study, a small urban community of approximately 1179 inhabitants was monitored from 18 March 2020 to 3 March 2021, covering the mobility restriction and flexibilization periods of the COVID-19 pandemic in Brazil. Consumption was estimated for amphetamine, caffeine, cocaine, MDMA, methamphetamine, nicotine, and THC. The highest estimated consumption among illicit drugs was for THC (2369 ± 1037 mg day-1 1000 inh-1) followed by cocaine (353 ± 192 mg day-1 1000 inh-1). There was a negative correlation between consumption of caffeine, cocaine, MDMA, nicotine, and THC with human mobility, expressed by cellular phone mobility reports (P-value = 0.0094, 0.0019, 0.0080, 0.0009, and 0.0133, respectively). Our study is the first long-term drug consumption evaluation during the COVID-19 pandemic, with continuous sampling for almost a whole year. The observed reduction in consumption of both licit and illicit drugs is probably associated with stay-at-home orders and reduced access, which can be due to the closure of commercial facilities during some time of the evaluated period, smaller drug supply, and reduced income of the population due to the shutdown of companies and unemployment. The assay described in this study can be used as a complementary and cost-effective tool to the long-term monitoring of drug use biomarkers in wastewater, a relevant epidemiological strategy currently limited to short collection times.


Detection of human papillomavirus type 18 E6 and E7-specific CD4+ T-helper 1 immunity in relation to health versus disease.
The most common high-risk human papillomavirus types, HPV16 and 18, differ markedly with respect to their interaction with the host. Clearance of HPV18 infections generally takes longer and HPV18-positive cancers have a poorer prognosis. We therefore evaluated Th1-type immunity against the E6 and E7 oncoproteins of HPV18 in healthy subjects and in patients with HPV18-positive genital cancer, and compared the results to our previously obtained data for HPV16. Approximately 20% of the healthy individuals displayed immunity against HPV18 E6. In contrast, none of the patients showed such responses, despite the presence of HPV18-positive lesions. Several of the patients did respond to HPV18 E7, whereas this immunity is rarely found in healthy subjects. This pattern of immune reactivity is essentially similar to that previously found for HPV16. It is unlikely that this similarity is the result of immunological cross-reactivity between the E6 and E7 antigens of HPV types 16 and 18. Our data confirm the relation between failure of E6-specific Th1 immunity and high-risk HPV-induced cervical neoplasia and argue that parameters other than these determine the differences in pathological impact between HPV types 16 and 18.


The associations between social support change and physical activity trajectory from late adolescence to young adulthood.
Previous research examined the associations between social support and physical activity. However, little is known about the associations between social support change and trajectories of physical activity during the transition from late adolescence to young adulthood. The current study sought to examine these issues among 434 Chinese college students (Mage = 19.15, SDage = 0.61; 46.1% male), who completed questionnaires regarding demographics, physical activity, family support change, and peer support change across three waves (the data from one of the waves was retrospective). After controlling for covariates, the findings revealed that: (a) there was an increase in overall physical activity and duration, but a decrease in frequency during the transition from late adolescence (the second year of high school) to young adulthood (the third year of college); (b) family support change did not contribute to trajectories of physical activity, while peer support change significantly predicted the trajectory of overall physical activity, duration, and frequency. The findings extend the literature on physical activity from a developmental perspective by revealing different trends among physical activity duration and frequency, and unpacking different effects of family and peer support change on trajectories of physical activity.


Life and death decision in adult neurogenesis: in praise of napping.
Among the thousands of new neurons that integrate into the adult olfactory bulb each day, 50% are eliminated through apoptosis. In this issue of Neuron, Yokoyama et al. take steps toward deciphering the behavioral contexts that regulate newborn cell elimination.


Spatial distribution of soil contaminated with Toxoplasma gondii oocysts in relation to the distribution and use of domestic cat defecation sites on dairy farms.
Little information is available on the relationship between the spatial distribution of zoonotic parasites in soil and the pattern of hosts' faeces deposition at a local scale. In this study, the spatial distribution of soil contaminated by the parasite Toxoplasma gondii was investigated in relation to the distribution and use of the defecation sites of its definitive host, the domestic cat (Felis catus). The study was conducted on six dairy farms with a high number of cats (seven to 30 cats). During regular visits to the farms over a 10month period, the cat population and cat defecation sites (latrines and sites of scattered faeces) on each farm were systematically surveyed. During the last visit, 561 soil samples were collected from defecation sites and random points, and these samples were searched for T. gondii DNA using real-time quantitative PCR. Depending on the farm, T. gondii DNA was detected in 37.7-66.3% of the soil samples. The proportion of contaminated samples at a farm was positively correlated with the rate of new cat latrines replacing former cat latrines, suggesting that inconstancy in use of a latrine by cats affects the distribution of T. gondii in soil. On the farms, known cat defecation sites were significantly more often contaminated than random points, but 25-62.5% of the latter were also found to be contaminated. Lastly, the proportion of positive T. gondii samples in latrines was related to the proximity of the cats' main feeding and resting sites on the farms. This study demonstrates that T. gondii can be widely distributed in farm soil despite the heterogeneous distribution of cat faeces. This supports the hypothesis that farms are hotspot areas for the risk of T. gondii oocyst-induced infection in rural environments.


Methamphetamine pre-exposure induces steeper escalation of methamphetamine self-administration with consequent alterations in hippocampal glutamate AMPA receptor mRNAs.
Methamphetamine use disorder (MUD) is often modeled using rodent self-administration (SA) experiments. Noncontingent injections of a drug given to rodents before self-administration training can increase drug SA. In the present study, we injected methamphetamine before putting rats through methamphetamine SA to investigate SA escalation. We also measured consequent changes in the expression of glutamate receptors in the hippocampus. Experimental groups included rats that received the methamphetamine injection prior to self-administration (MM) and those that received a prior saline injection before they underwent methamphetamine SA (SM). After SA training, rats also underwent tests of relapse potentials at one day and one month after withdrawal from methamphetamine SA. We used qPCR to identify potential changes in mRNA expression of AMPA, NMDA, and mGluR glutamate receptors. MM rats showed greater escalated methamphetamine intake in comparison to SM animals. There were no differences in incubation of methamphetamine craving between the two groups. In the hippocampus, MM rats showed decreased levels of GluA2 and GluA3 mRNAs in comparison to controls and of GluN2c mRNA in comparison to SM rats. In addition, SM rats had increased mGluR3 mRNA levels in comparison to control and MM rats. These data implicate hippocampal glutamate receptors in the longterm effects of methamphetamine. Further studies are necessary to identify the specific role that changes in the expression of these receptors might play in escalated intake of methamphetamine by human users.


ECG abnormalities in co-proxamol (paracetamol/dextropropoxyphene) poisoning.
1) To investigate ECG changes following co-proxamol (paracetamol 325 mg and dextropropoxyphene 32.5 mg) overdose in comparison to co-codamol (paracetamol and codeine) or co-dydramol (paracetamol and dihydrocodeine) in a prospective study. 2) To examine the relationship between estimated dextropropoxyphene dose and ECG changes in a larger patient population. Co-proxamol is a common cause of drug-induced death and hospital admission in the United Kingdom. ECG changes following dextropropoxyphene have been reported in animals and man, including QRS prolongation. The prospective study was conducted on 15 patients and controls with overdose. A retrospective study of a cohort of 159 co-proxamol overdoses from a combined data set from Edinburgh and Newcastle, Australia was also conducted. The measured or estimated "four hour" plasma paracetamol level was used as a surrogate of the amount of dextropropoxyphene ingested. In the prospective study co-proxamol overdose caused statistically significant QRS prolongation (mean [95% CI] 99.36 [96.19, 102.53] msec), compared to the other combination opioid-paracetamol products (82.84 [80.81, 84.88] msec) but no effect on PR or QTc. QRS duration increase was evident soon after exposure and remained prolonged and stable over the following 24 h. In the retrospective cohort study a dose dependency of effect on QRS was documented, although the correlation coefficient relating paracetamol level to effect was relatively weak (r = 0.338, Sig. [2-tailed] 0.003, n = 74). QRS is significantly prolonged in co-proxamol overdose, and this prolongation is dose dependent. These findings have clinical relevance to the management of patients with co-proxamol poisoning.


Intraoperative assessment of reduction quality during nail fixation of intertrochanteric fractures.
The quality of intertrochanteric fracture reduction has traditionally been evaluated using simple radiographs. However, subjective intraoperative evaluation and efforts to achieve a perfect reduction are essential for optimal outcomes. This study aimed to establish criteria for the intraoperative assessment of the quality of intertrochanteric fracture reduction and also analyzed postoperative outcomes in terms of reduction quality. This study included 106 patients who received cephalo-medullary nailing for the treatment of intertrochanteric fractures between March 2012 and May 2016 and were followed-up for at least 1 year. An image intensifier was used intraoperatively to evaluate reduction quality by examining the restoration of anteromedial cortex continuity, and neck-shaft angle and anteversion. Based on the reduction quality, the patients were classified into optimal, acceptable, and unacceptable groups, with intervention provided for the unacceptable group. The need for revision surgery and the degree of blade sliding were assessed, and postoperative outcomes related to implant position were analyzed. Over 50% of patients with Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) type 31A2 and A3 fractures were assigned to the unacceptable group after closed reduction (P = 0.006), and 60 cases required additional reduction. Approximately 40% of cases classified as clinically unacceptable required revision, and the rate of sliding was ≥2-fold higher in the unacceptable group than those in the optimal and acceptable groups (P = 0.015), with an average excessive sliding of 9.85 mm. Regarding implant position, cut-out or penetration were observed in cases with superiorly-located blades (P = 0.039). Good outcomes cannot be achieved with traction alone for femoral intertrochanteric fractures. Active management is required because accurate anteromedial cortex reduction, and restoration of neck-shaft angle and anteversion are essential in femoral intertrochanteric fractures.


Quantum factorization of 143 on a dipolar-coupling nuclear magnetic resonance system.
Quantum algorithms could be much faster than classical ones in solving the factoring problem. Adiabatic quantum computation for this is an alternative approach other than Shor's algorithm. Here we report an improved adiabatic factoring algorithm and its experimental realization to factor the number 143 on a liquid-crystal NMR quantum processor with dipole-dipole couplings. We believe this to be the largest number factored in quantum-computation realizations, which shows the practical importance of adiabatic quantum algorithms.


Schooling experiences in children with long-gap esophageal atresia compared with children with esophageal atresia and primary anastomosis: a Swedish study.
Children with long-gap esophageal atresia (LGEA) risk living with aerodigestive morbidity and mental health difficulties. No previous study has investigated their experiences of schooling, despite the importance of schools in children's development, learning and social relationships. We aimed to describe experiences of schooling in children with LGEA in Sweden in comparison with children with EA who had primary anastomosis. Children with LGEA aged 3-17 were recruited nationwide in Sweden. One parent completed a survey on their child's school-based supports (according to definitions from the Swedish National Agency for Education), school absence, school satisfaction, school functioning (PedsQL 4.0), mental health (Strength and Difficulties Questionnaire) and current symptomatology. School data were compared between 26 children with LGEA to that from 95 children with EA who had PA, a hypothesized milder affected group. Mental health level was determined using validated norms; abnormal ≥ 90 percentile. Data were analyzed using descriptives, correlation and Mann-Whitney-U test. Significance level was p < 0.05. Formal school-based support was reported in 17 (65.4%) children with LGEA and concerned support with nutritional intake (60%), education (50%) and medical/special health needs (35%). The prevalence of school-based support was significantly higher compared to children with PA overall (36.8%, p = 0.013) and regarding nutritional intake support (20%, p < 0.001). In children with LGEA, school-based support was related to low birth weight (p = 0.036), young child age (p = 0.014), height ≤ -2SD for age/sex (p = 0.024) and an increased number of aerodigestive symptoms (p < 0.05). All children with LGEA who had abnormal mental health scores had school-based support, except for one child. Nine children with LGEA (36%) had school absence ≥ 1times/month the past year, more frequently because of colds/airway infections (p = 0.045) and GI-specific problems compared to PA (p = 0.003). School functioning scores were not significantly different from children with PA (p = 0.34) but correlated negatively with school-based support (< 0.001) and school absence (p = 0.002). One parent out of 26 reported their child's school satisfaction as "not good". Children with LGEA commonly receive school-based support, reflecting multifaceted daily needs and disease severity. School absence is frequent and related to poorer school functioning. Future research focusing on academic achievement in children with EA is needed.


Perfusion pressure does not affect neurologic outcome in axillary artery side graft cannulation in type a aortic dissection.
Antegrade selective cerebral perfusion (ASCP) through the right axillary is a safe and effective method for cerebral protection in aortic surgery. In the present study, we evaluated whether or not pressure control in ASCP affected the neurologic outcome. Sixty-two patients (17 female, 45 male) with a mean age of 53.9 +/- 9.4 years (range, 23-74 years) with a diagnosis of Type A aortic dissection were operated on by using the right axillary artery side graft cannulation technique. ASCP with pressure control was used in the first 37 (59.6%) patients (group 1), whereas ASCP with flow control was used in the consecutive 25 patients (39.4%) (group 2). The groups were compared according to postoperative neurologic outcomes. The hospital mortality rate was 9.7% with 6 patients. The mean ASCP flows of group 1 was 663 +/- 76 mL/min and 692 +/- 51 mL/min in group 2. This difference was not statistically significant (P = .120). The neurological dysfunction rates were 2.7% in group 1 with 1 patient and 8% in group 2 with 2 patients (P = .560). In this study, we could not find a statistically significant difference in patients treated with ASCP through the right axillary applicated with pressure control versus flow control.


The TFDP1 gene coding for DP1, the heterodimeric partner of the transcription factor E2F, is a target of deregulated E2F.
The TFDP1 gene codes for the heterodimeric partner DP1 of the transcription factor E2F. E2F, principal target of the tumor suppressor pRB, plays central roles in cell proliferation by activating a group of growth-related genes. E2F also mediates tumor suppression by activating tumor suppressor genes such as ARF, an upstream activator of the tumor suppressor p53, when deregulated from pRB upon oncogenic changes. Among 8 E2F family members (E2F1∼E2F8), expression of activator E2Fs (E2F1∼E2F3a) is induced at the G1/S boundary of the cell cycle after growth stimulation by E2F itself. However, mechanisms regulating DP1 expression are not known. We show here that over-expression of E2F1 and forced inactivation of pRB, by adenovirus E1a, induced TFDP1 gene expression in human normal fibroblast HFFs, suggesting that the TFDP1 gene is a target of E2F. Serum stimulation of HFFs also induced TFDP1 gene expression, but with different kinetics from that of the CDC6 gene, a typical growth-related E2F target. Both over-expression of E2F1 and serum stimulation activated the TFDP1 promoter. We searched for E2F1-responsive regions by 5' and 3' deletion of the TFDP1 promoter and by introducing point mutations in putative E2F1-responsive elements. Promoter analysis identified several GC-rich elements, mutation of which reduced E2F1-responsiveness but not serum-responsiveness. ChIP assays showed that the GC-rich elements bound deregulated E2F1 but not physiological E2F1 induced by serum stimulation. These results suggest that the TFDP1 gene is a target of deregulated E2F. In addition, knockdown of DP1 expression by shRNA enhanced ARF gene expression, which is specifically induced by deregulated E2F activity, suggesting that activation of the TFDP1 gene by deregulated E2F may function as a failsafe feedback mechanism to suppress deregulated E2F and maintain normal cell growth in the event that DP1 expression is insufficient relative to that of its partner activator E2Fs. a maximum of 6 keywords: E2F, DP1, TFDP1 gene, pRB, gene expression.


Plasminogen activator Inhibitor-2 inhibits pulmonary arterial smooth muscle cell proliferation in pulmonary arterial hypertension via PI3K/Akt and ERK signaling.
The proliferation of pulmonary arterial smooth muscle cells (PASMCs) and subsequent pulmonary vascular remodeling leads to pulmonary arterial hypertension (PAH). Understanding the underlying mechanisms and identifying molecules that can suppress PASMCs proliferation is critical for developing effective pharmacological treatment. We previously showed that plasminogen activator inhibitor-2 (PAI-2) inhibited human PASMC (hPASMCs) proliferation in vitro. However, its inhibitory effect on PAH remains to be determined, and the mechanism remains to be illustrated. We compared serum PAI-2 levels between PAH patients and healthy controls, and examined the correlation between PAI-2 level and disease severity. In monocrotaline-induced PAH rats, we examined the effects of exogenous PAI-2 administration on pulmonary vascular remodeling and PAH development. The effect of PAI-2 and potential mechanisms was further examined in cultured hPASMCs. The serum PAI-2 was decreased in PAH patients compared with controls. PAI-2 level was negatively correlated with mean pulmonary arterial pressure and estimated systolic pulmonary arterial pressure in ultrasonic cardiogram, while positively correlated with 6-min walking distance. In rats, administration of exogenous PAI-2 significantly reversed monocrotaline-induced PAH, as indicated by the decrease in right ventricle systolic pressure, right ventricular hypertrophy index and percent media thickness of pulmonary arterioles. Further mechanistic investigation in hPASMCs showed that PAI-2 inhibited cell proliferation by preventing the activation of PI3K/Akt and ERK pathways. PAI-2 is downregulated in PAH patients. PAI-2 attenuates PAH development by suppressing hPASMCs proliferation via the inhibition of PI3K/Akt and ERK pathways. PAI-2 may serve as a potential biomarker and therapeutic target for PAH.


Intraindividual Comparison of Contrast-Enhanced Ultrasound Using Perfluorobutane With Modified Criteria Versus CT/MRI LI-RADS Version 2018 for Diagnosing HCC in High-Risk Patients.
BACKGROUND. Previously proposed modifications to LI-RADS criteria for contrast-enhanced ultrasound (CEUS) performed using perfluorobutane contrast agent yielded increased sensitivity for hepatocellular carcinoma (HCC) without a significant decrease in specificity. OBJECTIVE. The purpose of our study was to compare the diagnostic performance of CEUS with perfluorobutane using modified LI-RADS criteria versus contrast-enhanced CT or MRI using LI-RADS version 2018 (v2018) for characterizing lesions as HCC in high-risk patients. METHODS. This retrospective study included 171 patients (140 men, 31 women; mean age, 54 ± 12 [SD] years) at high-risk for HCC with a pathologically confirmed liver observation evaluated by both CEUS using perfluorobutane and contrast-enhanced CT or MRI between March 2020 and May 2021. A matching algorithm was used to select two patients with HCC for each patient with a non-HCC lesion. Two readers evaluated observations using previously proposed modifications to CEUS LI-RADS version 2017 that classify certain observations as LR-5 rather than as LR-4 or LR-M on the basis of the presence of Kupffer phase defect after perfluorobutane administration; two different readers evaluated observations using CT/MRI LI-RADS v2018. Each reader pair reached consensus. Diagnostic performance was evaluated. RESULTS. A total of 114 patients had HCC, 43 had a non-HCC malignancy, and 14 had a benign lesion. Modified CEUS criteria using perfluorobutane and CT/MRI LI-RADS v2018 showed no significant difference (p > .05) in sensitivity (92.1% vs 89.5%), specificity (87.7% vs 84.2%), or accuracy (90.6% vs 87.7%) of LR-5 for diagnosis of HCC. Of six observations assessed as LR-4 only by CT/MRI LI-RADS v2018, modified CEUS criteria using perfluorobutane assessed one as LR-3 (benign lesion) and five as LR-5 (all HCC). Of seven observations assessed as LR-M only by CT/MRI LI-RADS v2018, modified CEUS criteria using perfluorobutane assessed one as LR-3 (non-HCC malignancy) and six as LR-5 (all HCC). Eight of 12 observations assessed as LR-5 only by CT/MRI LI-RADS v2018 and 11 of 13 observations assessed as LR-5 only by modified CEUS criteria using perfluorobutane were HCC. CONCLUSION. The diagnostic performance of LR-5 for HCC diagnosis was not significantly different between modified CEUS criteria using perfluorobutane and CT/MRI LI-RADS v2018. CLINICAL IMPACT. The findings support the application of modified CEUS criteria using perfluorobutane for diagnosing HCC in high-risk patients.


Grassland production in response to changes in biological metrics over the Tibetan Plateau.
A clear interannual variability in annual production of grasslands (termed AEVI) has been reported over the Tibetan Plateau (TP), but the underlying mechanism has not been fully understood. Here, we explained the interannual variability of AEVI during 2001-2015 by two phenological metrics (the start and end of the growing season, termed SOS and EOS, respectively) and one physiological metric (the maximum capacity of canopy light absorbance, termed MEVI) using MODIS Enhanced Vegetation Index (EVI) data over the TP. The results showed that the interannual variability of AEVI can be well attributed to not only the trends of, but also the sensitivities of AEVI to, the selected biological metrics. On the one hand, the advancing SOS and delaying EOS dominated the study area while both increased and decreased MEVI were observed. On the other hand, the AEVI responded negatively to the SOS and positively to the EOS and MEVI, exhibiting significant variations along the temperature and precipitation gradients. Hence, the current interannual variability of SOS and EOS mainly increased the AEVI; meanwhile, both enhancement and suppression of the interannual variability of MEVI to the AEVI were widespread over the TP. Overall, the interannual variability of MEVI mostly contributed to that of the AEVI, indicating a dominant role of the physiological metric rather than phenological metrics in carbon gain of TP grasslands. The achievements of this study are helpful to understand the underlying biological causes of the interannual variability of grassland production over the TP.


Expression and localization of amelotin, laminin γ2 and odontogenesis-associated phosphoprotein (ODAPH) on the basal lamina and junctional epithelium.
At maturation stage of enamel development, a specialized basal lamina (sBL) was built between ameloblasts and enamel. After the teeth eruption, the ameloblasts transform into the inner cell layer of junctional epithelium. The inner cell layer forms the internal basal lamina of junctional epithelium. However, the composition of the sBL and internal basal lamina was not clarified. The objective of our study was to make a description of the localization of amelotin (AMTN), laminin γ2 (LAMC2) and Odontogenesis-associated phosphoprotein (ODAPH) on the sBL and internal basal lamina. In immunohistochemical study, AMTN, LAMC2 and ODAPH were detected on the sBL at maturation stage. AMTN was also detected in ameloblasts at maturation stage. The expression of AMTN decreased from early-to-late maturation stage. In contrast, the expression of LAMC2 and ODAPH was stable. Immunofluorescence double-staining showed the localization of AMTN was close to enamel surface. However, the localization of ODAPH was close to ameloblasts. LAMC2 and ODAPH were observed on internal basal lamina of junctional epithelium. In contrast, no expression of AMTN was detected on internal basal lamina of junctional epithelium. Our results suggested that ODAPH might participate in enamel maturation and periodontal health, which might provide a better understanding of enamel defects and periodontal disease in clinic.


CT and MRI of acute thoracic cardiovascular emergencies.
A wide spectrum of acute cardiovascular disorders is seen in patients who are hospitalized in a critical care setting. Imaging plays a central role in the diagnosis and management of these conditions. The most frequently used imaging remains chest radiography; however, more advanced modalities, including coronary angiography, echocardiography, and radioisotope scintigraphy, have well established roles in the assessment of patients in the critical care setting. More recently, multidetector row CT (MDCT) and MRI are being used increasingly for evaluation of coronary artery disease, cardiac structure and function, coronary artery anomalies, cardiac masses, pericardial disease, valvular disease, postoperative cardiovascular abnormalities, venous thromboembolism and acute aortic syndromes, often with other ancillary findings that can provide important clinical information. The three most common life-threatening cardiovascular processes in which advanced imaging plays a role, particularly CT, are discussed, including pulmonary embolism, aortic dissection, and coronary artery disease.