Design, synthesis, and biological evaluation of new territrem B analogues.
Some 23 analogues of the potent acetylcholinesterase (AChE) inhibitor territrem B (1) were designed, synthesized, and tested for their biological activities. Some of the new synthetic derivatives exhibited IC50 values for AChE inhibition in the upper micromolar range. Molecular-modeling studies indicated that a planar conformation seems to be crucial for AChE inhibition. The two N-atoms of the piperazine moieties in 5o, 5p, and 5r might further enhance the inhibitory effects. The cytotoxicities of selected compounds against six human tumor cell lines were also determined.


The role of surgery and ablative radiotherapy in oligometastatic breast cancer.
The ability to deliver precise focused radiation, combined with improved surgical techniques, has led to multiple reports of long-term survivors in patients with oligometastatic breast cancer. The removal or ablation of known metastases, often present after systemic therapy regimens has the potential to be paradigm shifting rendering many patients without evidence of disease. However, the utility of these therapies has not been proven in phase III studies. Additionally, patient selection for metastasis-directed therapies is based on clinical criteria, with many patients not benefiting from these therapies. Refinements of radiation techniques are continuing, and discoveries are uncovering the biology of breast cancer in the oligometastatic state among patients. Integrated into ongoing studies, and those in development, they have the potential to alter standard management strategies in oligometastatic patients.


VO2 and cardiac output during rest-exercise and exercise-exercise transients.
The dynamics of external gas exchange during exercise is influenced by pulmonary, cardiovascular, and metabolic factors. During rest-exercise transitions the interaction of these factors is more complex than during exercise-exercise transients. In the present study, we directly compared oxygen uptake (VO2) and cardiac output (CO) responses to step changes in exercise intensity. Nine students performed the following step changes on a bicycle ergometer in upright body position: rest-20W, 20W-80W, 20-140W. VO2 was measured breath-by-breath while CO was determined beat-by-beat by means of a Doppler device. The probe was positioned in the suprasternal notch and directed towards the aortic root. When starting from the 20 W baseline the VO2 responses showed a first, mainly cardio-vascular component over the first 30 s, followed by a second, metabolic component at constant CO. The rest-exercise transients displayed two additional early features. First, there was a very rapid VO2 increase during the initial breathing cycles of the on-transient. This was probably caused by events in the lungs or the pulmonary circulation. Second, the CO attained its steady-state level in about 10 s. This suggests a sudden increase in venous return. The present results generally show that both the VO2 and CO kinetics are faster when exercise in the upright body position is started from rest.


The comet tail artifact.
A description and explanation of an unexpected echographic appearance in a patient who had sustained an abdominal shotgun wound is presented. In the B-scans, a trail of dense continuous echoes, simulating a comet tail, is seen distal to each lead pellet. This comet tail appearance is shown to be a type of reverberation artifact. The effect of object size, shape, composition, and orientation on the appearance of this artifact is demonstrated.


Non-Linear Pharmacokinetics of Atomoxetine in Adult Japanese Patients With ADHD.
Objective: The objective was to reveal the relationship between dose and concentration of atomoxetine. Method: Fifty-five blood samples of 33 patients with ADHD were examined using high-performance liquid chromatography. Results: The plasma concentrations were 53.2 ± 67.0, 298.0 ± 390.5, and 639.3 ± 831.9 ng/mL at doses of 40 mg, 80 mg, and 120 mg, and the concentration/dose were 1.33 ± 1.67, 3.73 ± 4.88, and 5.33 ± 6.93 ng/mL/mg, respectively. Statistical analyses revealed a significant correlation between the concentration and the dose of atomoxetine (p = .004), and a trending toward significance in the difference in the concentration/dose in the three dosage groups (p = .064). The concentration/dose at 40 and 80 + 120 mg/day were 1.33 ± 1.67 and 4.22 ± 5.53 ng/mL/mg, the latter was significantly higher than the former (p = .006), which suggested non-linear pharmacokinetics. Conclusion: Clinicians should carefully titrate in high dose atomoxetine treatment.


Disseminated Intravascular Coagulation Developing After Cranioplasty.
Disseminated intravascular coagulation (DIC) developing after cranioplasty, a skull reconstructive surgical procedure, is very rare. The presently reported patient underwent cranioplasty for cranial trauma under general anaesthesia using titanium prostheses. Her laboratory data was unremarkable. She underwent three operations, each complicated by excessive postoperative bleeding. Although the patient received massive blood transfusions, but no cryoprecipitate coagulum was given during the first two re-operations, and excessive bleeding was evident. Laboratory data showed PT prolongation, APTT prolongation, thrombocytopenia and elevation of the D-dimer level, suggestive of DIC. After the third re-operation, the patient received cryoprecipitate coagulum, and there was no apparent bleeding. Administration of cryoprecipitate coagulum for excessive bleeding postcranioplasty may be required in view of this rare complication.


A case of delayed onset of threatened premature labor in association with electroconvulsive therapy in the third trimester of pregnancy.
Electroconvulsive therapy (ECT) is recommended by the American Psychiatric Association Task Force on ECT as a safe and effective treatment of depression throughout pregnancy. We report here administration of ECT in the third trimester of pregnancy in a 33-year-old patient with severe bipolar depression. The patient had a good antidepressant response to ECT. She experienced, however, delayed onset premature uterine contractions at home after her sixth session of ECT (10 hours post-ECT administration). After receiving tocolytics, the patient's contractions did not progress to premature labor. In consultation with the obstetrics team, it was decided to terminate the ECT course earlier than planned. The patient is delivered of a healthy female newborn infant spontaneously at 37 weeks' gestational age. Four months after delivery, the baby's development is progressing normally. This case illustrates that premature contractions in association with ECT during the third trimester of pregnancy may be delayed in onset. Patients and treatment team need to be aware of this possibility, particularly when ECT is conducted on an outpatient basis.


[Biological risk and health care workers: analysis of the effects of work chronobiology on the immune system].
Healthcare workers may be exposed to a variety of biological hazards. Although many studies have shown that some immunological alterations were related to work stress and sleep disorders, few studies investigated effects of shiftwork on the immunological system. The aim of the study was to compare the immune status of a group of nurses on shiftwork with that of nurses working only day shifts. A total of 138 nurses were evaluated at baseline and after a year of follow-up, via tests for perceived stress, daytime sleepiness, number of lymphocytes and subpopulation of CD3+, CD4+, CD8+-CD57+, CD19+ and CD56+, cytotoxic activity and lympho-prolferative response of NK cells, serum concentrations of IL-1beta, IL-6, INFgamma and TNFalpha. No significant alterations of any of the studied parameters were found both at baseline and after a year of follow-up. The biological hazards for nurses do not seem to be increased by shiftwork.


An end user evaluation of query formulation and results review tools in three medical meta-search engines.
Retrieving sufficient relevant information online is difficult for many people because they use too few keywords to search and search engines do not provide many support tools. To further complicate the search, users often ignore support tools when available. Our goal is to evaluate in a realistic setting when users use support tools and how they perceive these tools. We compared three medical search engines with support tools that require more or less effort from users to form a query and evaluate results. We carried out an end user study with 23 users who were asked to find information, i.e., subtopics and supporting abstracts, for a given theme. We used a balanced within-subjects design and report on the effectiveness, efficiency and usability of the support tools from the end user perspective. We found significant differences in efficiency but did not find significant differences in effectiveness between the three search engines. Dynamic user support tools requiring less effort led to higher efficiency. Fewer searches were needed and more documents were found per search when both query reformulation and result review tools dynamically adjust to the user query. The query reformulation tool that provided a long list of keywords, dynamically adjusted to the user query, was used most often and led to more subtopics. As hypothesized, the dynamic result review tools were used more often and led to more subtopics than static ones. These results were corroborated by the usability questionnaires, which showed that support tools that dynamically optimize output were preferred.


Stochastic uncertainty of advected curves in finite-time unsteady flows.
Identifying coherent structures in unsteady flows acting over a finite-time is a well-established research area, in part due to the applicability to realistic velocities obtained from experimental, observational, or numerically generated data. More recently, there is an emerging need to understand the impact of small-scale uncertainties on larger scale structures; for example, the "stochastic parametrization" problem in climate models. This article establishes a rigorous tool in this direction, specifically quantifying the uncertainty of advected curves in the presence of small stochasticity. Explicit expressions are derived for the expectation and the variance of the curves' location. The velocity field may be unsteady and compressible, and the Wiener process driving the stochasticity can have general spatiotemporal dependence. Monte Carlo simulations are used to verify the uncertainty expressions.


Functional magnetic resonance imaging for assessment of the autonomic dysfunction in patients with ANCA-associated vasculitides.
Nervous system involvement is common in ANCA-associated vasculitides (AAV). While peripheral and central nervous system involvement are well described, it is still unclear how and to what extent the autonomic nervous system (ANS) is involved. Functional magnetic resonance imaging (fMRI) can provide information on both - structure and potential damage of the brain as well as the function of the selected brain centers. The aim of this study was to investigate the ANS dysfunction in AAV patients and its correlation with fMRI results during the Valsalva maneuver. 31 patients with AAV and 30 healthy controls were enrolled in the study. Each participant completed the COMPASS-31 questionnaire. Magnetic resonance imaging (MRI) was performed using a 3T scanner. Participants were asked to perform the Valsalva maneuver according to the fixed protocol using the device measuring the pressure value in the subjects' airways. During the maneuver fMRI data were collected. The generalized least squares time series analysis and the region-of-interest (ROI) analysis were performed. AAV patients had higher COMPASS-31 questionnaire median score (12.86 vs. 2.99; p<0.01), as compared to the control group. Structural MRI investigation did not reveal any significant differences between the groups. The brain centers involved in ANS function were detected during fMRI, however the analysis of ROI in patients and controls showed no differences. Patients with AAV have symptoms related to the ANS, but no differences in the functioning of the ANS brain centers have been demonstrated in fMRI study during the Valsalva maneuver.


What is the emotional core of the multidimensional Machiavellian personality trait?
Machiavellianism is a personality trait characterized by interpersonal manipulation and associated with specific patterns of emotional and social cognition skills. The aim of this study was to investigate its socio-cognitive characteristics by determining its association and predictors on the basis of a multidimensional approach to Machiavellianism. We used Mach IV scale to assess "Machiavellian Intelligence" skill of participants (Christie and Geis, 1970). It includes three subscales that are (1) the use of deceit in interpersonal relationships, (2) a cynical view of human nature and (3) the lack of morality. Associations were found between Machiavellianism and low levels of empathy and affective ToM, and high levels of alexithymia, anhedonia, depression, and anxiety. These associations were observed in varying proportions depending on the three subscales of Machiavellianism. The addition of anhedonia and trait-anxiety to the concepts of empathy and alexithymia made it possible to gain a better understanding of the emotional core of Machiavellianism. These findings are discussed in the light of developmental and adaptive perspectives.


Traumatic fracture in a healthy man: benign or pathologic?
To describe the challenge of determining the correct diagnosis in a healthy adult male patient with a recent femoral fracture and a history of multiple bone fractures. We present clinical, radiologic, laboratory, and histopathologic details in a patient with a history of recurrent fractures associated with minimal trauma. Moreover, the various types of osteopetrosis are reviewed. A 34-year-old African American man was in his usual state of good health when he fell hard on concrete. Immediately after the fall, he was able to bear weight, although pain prompted him to seek medical care. Besides a personal history of multiple fractures, he had no other medical problems. He had never smoked, denied illicit drug use, and had no family history of bone disorders or recurrent fractures. Findings on physical examination were unremarkable. Radiography disclosed an incomplete femoral fracture and osteosclerosis. Bone survey revealed diffuse, symmetric osteosclerosis of both the axial and the appendicular skeleton. The long bones showed areas of almost complete obliteration of the medullary canal, along with prominent hyperostosis. Additionally, a "bone-within-bone" appearance to the thickened endosteum was noted. A bone scan demonstrated numerous areas of symmetric radiotracer uptake. Laboratory analyses were unremarkable, including a complete blood cell count, electrolytes, serum protein electrophoresis, thyrotropin, and parathyroid hormone. Total alkaline phosphatase was mildly elevated at 162 U/L (normal range, 35 to 130). Seven needles were broken during attempts to perform a bone biopsy. Histologic examination showed normal bone marrow with "woven" bone and areas of primary spongiosa within mature osteoid. Autosomal dominant osteopetrosis type 2 was diagnosed on the basis of his clinical presentation and the radiologic and pathologic findings. The preliminary diagnosis for this patient's condition was Paget's disease, and determining the correct diagnosis of osteopetosis prevented the administration of inappropriate therapy. In addition, this case report reminds the clinician that genetic disease may manifest in adulthood.


Metabolites profiling and cheminformatics bioprospection of selected medicinal plants against the main protease and RNA-dependent RNA polymerase of SARS-CoV-2.
Despite the existence of some vaccines, SARS-CoV-2 (S-2) infections persist for various reasons relating to vaccine reluctance, rapid mutation rate, and an absence of specific treatments targeted to the infection. Due to their availability, low cost and low toxicity, research into potentially repurposing phytometabolites as therapeutic alternatives has gained attention. Therefore, this study explored the antiviral potential of metabolites of some medicinal plants [Spondias mombin, Macaranga barteri and Dicerocaryum eriocarpum (Sesame plant)] identified using liquid chromatography-mass spectrometry (LCMS) as possible inhibitory agents against the S-2 main protease (S-2 MP) and RNA-dependent RNA polymerase (RP) using computational approaches. Molecular docking was used to identify the compounds with the best affinities for the selected therapeutics targets. Afterwards, compounds with poor physicochemical characteristics, pharmacokinetics, and drug-likeness were screened out. The top-ranked compounds were further subjected to a 120-ns molecular dynamics (MD) simulation. Only quercetin 3-O-rhamnoside (-48.77 kcal/mol) had higher binding free energy than the reference standard (zafirlukast) (-44.99 kcal/mol) against S-2 MP. Conversely, all the top-ranked compounds (ellagic acid hexoside, spiraeoside, apigenin-4'-glucoside and chrysoeriol 7-glucuronide) except gnetin L (-24.24 kcal/mol) had higher binding free energy (-55.19 kcal/mol, -52.75 kcal/mol, -47.22 kcal/mol and -43.35 kcal/mol) respectively, against S-2 RP relative to the reference standard (-34.79 kcal/mol). The MD simulations study further revealed that the investigated inhibitors are thermodynamically stable and form structurally compatible complexes that impede the regular operation of the respective S-2 therapeutic targets. Although, these S-2 therapeutic candidates are promising, further in vitro and in vivo evaluation is required and highly recommended.Communicated by Ramaswamy H. Sarma.


Salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers selectively suppress human CD20+ melanoma stem cells.
Melanoma is the deadliest type of skin cancer. CD20+ melanoma stem cells (CSCs) are pivotal for metastasis and initiation of melanoma. Therefore, selective elimination of CD20+ melanoma CSCs represents an effective treatment to eradicate melanoma. Salinomycin has emerged as an effective drug toward various CSCs. Due to its poor solubility, its therapeutic efficacy against melanoma CSCs has never been evaluated. In order to target CD20+ melanoma CSCs, we designed salinomycin-loaded lipid-polymer nanoparticles with anti-CD20 aptamers (CD20-SA-NPs). Using a single-step nanoprecipitation method, salinomycin-loaded lipid-polymer nanoparticles (SA-NPs) were prepared, then CD20-SA-NPs were obtained through conjugation of thiolated anti-CD20 aptamers to SA-NPs via a maleimide-thiol reaction. CD20-SA-NPs displayed a small size of 96.3 nm, encapsulation efficiency higher than 60% and sustained drug release ability. The uptake of CD20-SA-NPs by CD20+ melanoma CSCs was significantly higher than that of SA-NPs and salinomycin, leading to greatly enhanced cytotoxic effects in vitro, thus the IC50 values of CD20-SA-NPs were reduced to 5.7 and 2.6 μg/mL in A375 CD+20 cells and WM266-4 CD+ cells, respectively. CD20-SA-NPs showed a selective cytotoxicity toward CD20+ melanoma CSCs, as evidenced by the best therapeutic efficacy in suppressing the formation of tumor spheres and the proportion of CD20+ cells in melanoma cell lines. In mice bearing melanoma xenografts, administration of CD20-SA-NPs (salinomycin 5 mg·kg-1·d-1, iv, for 60 d) showed a superior efficacy in inhibition of melanoma growth compared with SA-NPs and salinomycin. In conclusion, CD20 is a superior target for delivering drugs to melanoma CSCs. CD20-SA-NPs display effective delivery of salinomycin to CD20+ melanoma CSCs and represent a promising treatment for melanoma.


Shin pain in athletes - assessment and management.
Shin pain is a common complaint among running athletes and can be caused by bony, muscular, vascular or neural pathology. This article discusses the likely causes, assessment and management of shin pain in athletes presenting in the general practice setting. Accurate diagnosis is important as treatment differs depending on the cause. The characteristics of the pain and examination findings after exercise give strong clues to the diagnosis; further investigation may be unnecessary. Bony stress reactions and fractures are the most common cause of shin pain; patients describe a 'jarring' sensation along the bone margin with heel strike. Other causes include recurrent exertional compartment syndrome (RECS), tenosynovitis, neurological entrapment and rarely, vascular entrapment. Symptoms of vascular entrapment may be similar to RECS and this may cause diagnostic confusion. Increased bone stress in athletes is largely due to inappropriate training program design and can usually be alleviated by reducing impact loading until pain resolves.


Stereoselective Construction of 2,7-Disubstituted fused-Bis Tetrahydrofuran Skeletons: Biomimetic-Type Synthesis and Biological Evaluation of (±)- and (-)-Aplysiallene and Their Derivatives.
A series of trans/trans and cis/cis fused-bis tetrahydrofuran compounds have been obtained stereoselectively in high yields via a one-pot operation involving the intramolecular haloetherification of (Z,Z)-diene diol 19a and (E,E)-diene disilylether 19d, respectively. This method was subsequently applied to the biomimetic-type synthesis of (±)- and (-)-aplysiallene. The inhibitory activities of these compounds and their bromodiene isomers toward Na(+)/K(+) ATPase were determined in vitro, and gave IC50 values of approximately 15 μM in all cases.


Evidence for Behaviorally Segregated, Spatiotemporally Overlapping Subnetworks in Phantom Sound Perception.
One of the most intriguing questions in neuroscience is to understand the mechanism of information transfer between different brain areas. Recently, network theory has gained traction and is at the forefront of providing a possible explanation to not only the mechanism of information transfer but also in the identification of different neuropathologies. The perception of a phantom ringing in the ear called tinnitus, similar to other neuropathologies, has been shown to be accompanied by aberrant functional connectivity between different brain areas. Although, there have been independent studies showing that specific groups of areas encode individual symptoms of tinnitus, there has not been one study to show that tinnitus is the unified percept of distinguishable subnetworks encoding different behavioral aspects. This study combines resting-state functional connectivity obtained from the source-localized electroencephalography of 311 tinnitus patients and 264 controls, and a k-fold cross-validation machine learning algorithm to develop a predictive model that verifies the presence of behaviorally specific, spatiotemporally overlapping subnetworks in tinnitus. This reorganization is found to be exclusive to tinnitus, even when compared to physiologically similar disorders such as chronic pain, with each behavioral symptom having a unique oscillatory signature. This frequency-specific transmission of information, called multiplexing, enables different types of information to be carried between two brain regions through the same anatomical connection. In addition to understanding the efficient compensation mechanism of the brain in the presence of multisymptom disorders, the exclusivity of the prediction model presents an encouraging possibility for an objective neural marker for tinnitus.


Iridium Catalysts with f-Amphox Ligands: Asymmetric Hydrogenation of Simple Ketones.
A series of modular and rich electronic tridentate ferrocene aminophosphoxazoline ligands (f-amphox) have been successfully developed and used in iridium-catalytic asymmetric hydrogenation of simple ketones to afford corresponding enantiomerically enriched alcohols under mild conditions with superb activities and excellent enantioselectivities (up to 1 000 000 TON, almost all products up to >99% ee, full conversion). The resulting chiral alcohols and their derivatives are important intermediates in pharmaceuticals.


Mechatronic Device Control by Artificial Intelligence.
Nowadays, artificial intelligence is used everywhere in the world and is becoming a key factor for innovation and progress in many areas of human life. From medicine to industry to consumer electronics, its influence is ever-expanding and permeates all aspects of our modern society. This article presents the use of artificial intelligence (prediction) for the control of three motors used for effector control in a spherical parallel kinematic structure of a designed device. The kinematic model used was the "Agile eye" which can achieve high dynamics and has three degrees of freedom. A prototype of this device was designed and built, on which experiments were carried out in the framework of motor control. As the prototype was created through the means of the available equipment (3D printing and lathe), the clearances of the kinematic mechanism were made and then calibrated through prediction. The paper also presents a method for motor control calibration. On the one hand, using AI is an efficient way to achieve higher precision in positioning the optical axis of the effector. On the other hand, such calibration would be rendered unnecessary if the clearances and inaccuracies in the mechanism could be eliminated mechanically. The device was designed with imperfections such as clearances in mind so the effectiveness of the calibration could be tested and evaluated. The resulting control of the achieved movements of the axis of the device (effector) took place when obtaining the exact location of the tracked point. There are several methods for controlling the motors of mechatronic devices (e.g., Matlab-Simscape). This paper presents an experiment performed to verify the possibility of controlling the kinematic mechanism through neural networks and eliminating inaccuracies caused by imprecisely produced mechanical parts.


Coverage & missed opportunity for Japanese encephalitis vaccine, Gorakhpur division, Uttar Pradesh, India, 2015: Implications for Japanese encephalitis control.
Japanese encephalitis (JE) is an important aetiology of acute encephalitis syndrome in Gorakhpur division, Uttar Pradesh, India. Two doses of JE vaccine ( first during 9-12 months and second during 16-24 months of age) are administered under the Universal Immunization Programme. We conducted surveys to estimate the coverage of JE vaccine and magnitude of missed opportunity for vaccination (MoV) for JE in Gorakhpur division. To estimate the JE vaccine coverage, cluster surveys were conducted in four districts of Gorakhpur division by selecting 30 clusters by probability proportional to size method in each district, seven children aged 25-36 months were selected from each cluster and their mothers were interviewed about JE vaccination. To estimate the magnitude of MoV, exit surveys were conducted in vaccination clinics in selected health facilities, mothers were interviewed about the vaccination status of their children and vaccines administered to the child on the day of interview. A total of 840 children were surveyed, 210 from each district. The coverages of one and two doses of JE vaccine in Gorakhpur division were 75 per cent [95% confidence interval (CI): 71.0-78.9] and 42.3 per cent (95% CI: 37.8-46.8), respectively. Facility-based exit survey indicated that 32.7 per cent of the eligible children missed JE vaccine. The survey results showed that three of the four children aged 25-36 months in Gorakhpur division had received at least one dose of JE vaccine. The coverage of second dose of JE vaccine, however, was low. Failure to administer vaccination simultaneously was the most common reason for MoV for JE vaccine. Training vaccinators about correct vaccination schedule and removing their misconception about administering vaccines simultaneously would substantially improve JE vaccine coverage in Gorakhpur.


The Application of Finite Element Method for Analysis of Cross-Wedge Rolling Processes-A Review.
The aim of this article is to review the application of the finite element method (FEM) to cross-wedge rolling (CWR) modeling. CWR is a manufacturing process which is used to produce stepped axles and shafts as well as forged parts for further processing on forging presses. Although the concept of CWR was developed 140 years ago, it was not used in industry until after World War 2. This was due to the limitations connected with wedge tool design and the high costs of their construction. As a result, until the end of the twentieth century, CWR tools were constructed by rolling mill manufacturers as they employed engineers with the most considerable experience in CWR process design. The situation has only changed recently when FEM became widely used in CWR analysis. A vast number of theoretical studies have been carried out in recent years, and their findings are described in this overview article. This paper describes nine research areas in which FEM is effectively applied, namely: the states of stress and strain; force parameters; failure modes in CWR; material fracture; microstructure modeling; the formation of concavities on the workpiece ends; CWR formation of hollow parts; CWR formation of parts made of non-ferrous materials; and new CWR methods. Finally, to show the potential of FEM on CWR modeling, a CWR process for manufacturing a stepped shaft used in car gearboxes is simulated numerically. This numerical simulation example shows that FEM can be used to model very complex cases of CWR, which should lead to a growing interest in this advanced manufacturing technique in the future.


Identification and characterization of Streptomyces flavogriseus NJ-4 as a novel producer of actinomycin D and holomycin.
This paper is the first public report that Streptomyces flavogriseus can produce both actinomycin D and holomycin. The actinomycete strain NJ-4 isolated from the soil of Nanjing Agricultural University was identified as S. flavogriseus. This S. flavogriseus strain was found for the first time to produce two antimicrobial compounds that were identified as actinomycin D and holomycin. GS medium, CS medium and GSS medium were used for the production experiments. All three media supported the production of actinomycin D, while holomycin was detected only in GS medium and was undetectable by HPLC in the CS and GSS media. The antimicrobial activity against B. pumilus, S. aureus, Escherichia coli, F. moniliforme, F. graminearum and A. niger was tested using the agar well diffusion method. Actinomycin D exhibited strong antagonistic activities against all the indicator strains. Holomycin exhibited strong antagonistic activities against B. pumilus, S. aureus and E. coli and had antifungal activity against F. moniliforme and F. graminearum but had no antifungal activity against A. niger. The cell viability was determined using an MTT assay. Holomycin exhibited cytotoxic activity against A549 lung cancer cells, BGC823 gastric cancer cells and HepG2 hepatocellular carcinoma cells. The yield of actinomycin D from S. flavogriseus NJ-4 was 960 mg/l. S. flavogriseus NJ-4 exhibits a distinct capability and has the industrial potential to produce considerable yields of actinomycin D under unoptimized conditions.


Conserved intragenic elements were critical for the evolution of the floral C-function.
The floral C-function, which specifies stamen and carpel development, played a pivotal role in the evolution of flowers. An important aspect of this was the establishment of mechanisms regulating the temporal and spatial expression domain of the C-function genes. Transcription of the Arabidopsis C-function gene AGAMOUS (AG) is tightly controlled by factors that interact with cis-elements within its large second intron. Little is known about the regulatory role of intragenic elements in C-function genes from species other than Arabidopsis. We show that a binding site for the LEAFY (LFY) transcription factor, present in the AG intron, is conserved in the introns of diverse C-function genes and is positioned close to other conserved motifs. Using an in planta mutagenesis approach, we targeted evolutionarily conserved sequences in the intron of the Antirrhinum PLENA (PLE) gene to establish whether they regulate PLE expression. Small sequence deletions resulted in a novel class of heterochronic C-function mutants with delayed onset of PLE expression and loss of stamen identity. These phenotypes differ significantly from weak C-function mutant alleles in Antirrhinum and Arabidopsis. Our findings demonstrate that the PLE intron contains regulatory cis-elements, including a LFY-binding site, critical for establishing the correct C-function expression domain. We show that the LFY site, and other conserved intron elements, pre-date the divergence of the monocot and dicot lineages, suggesting that they were a determinant in the evolution of the C-function, and propose a threshold model to explain phenotypic divergence observed between C-function mutants.


Familial risk and cancer control.
An intensive study of the family history of cancer in 4,515 patients screened consecutively by a multiphasic mobile cancer detection unit showed, after age correction, that cancer had developed in 8.9% of the probands when there was one cancer in a single first-degree relative, 16.2% had cancer with two family members affected, and 27.4% had cancer when three or more family members had been affected. This constituted a significant correlation between family and personal histories of cancer in these patients. Extrapolation to the United States population with cancer-control implications are given.


Combined ACL reconstruction and Segond fracture fixation fails to abolish anterolateral rotatory instability.
The Segond fracture (SF) is considered pathognomonic of an anterior cruciate ligament (ACL) tear. However, the anatomy of the soft-tissue attachments responsible for the avulsion of SFs has been a cause of controversy. A 31-year-old male patient presented with an injury to his right knee that resulted in ACL tear and a SF. Open SF fixation and arthroscopic ACL reconstruction were performed. The anatomical dissection demonstrated that the avulsion of SFs had occurred because of the tibial attachment of the anterolateral ligament (ALL) with an intact Iliotibial band. At 1-year postoperative follow-up, the ACL graft had restored anterior tibial translation to within normal limits. However, residual rotational knee laxity was observed. This finding highlights that patients with SF may be at increased risk of persistent instability after ACL reconstruction. Consideration should be given to recession of the fixation or augmentation of the ALL when dealing with this injury pattern.


Deletion of the aryl hydrocarbon receptor-associated protein 9 leads to cardiac malformation and embryonic lethality.
The aryl hydrocarbon receptor-associated protein 9, ARA9 (also known as XAP2 or AIP1), is a chaperone that is found in complexes with certain xenobiotic receptors, such as the aryl hydrocarbon receptor (AHR) and the peroxisome proliferator-activated receptor alpha (PPARalpha). In an effort to better understand the physiological role of ARA9 outside of its role in xenobiotic signal transduction, we generated a null allele at the Ara9 locus in mice. Mice with a homozygous deletion of this gene die at various time points throughout embryonic development. Embryonic lethality is accompanied by decreased blood flow to head and limbs, as well as a range of heart deformations, including double outlet right ventricle, ventricular-septal defects, and pericardial edema. The early cardiovascular defects observed in Ara9-null mice suggest an essential role for the ARA9 protein in cardiac development. The observation that the developmental aberrations in Ara9-null mice are distinct from those observed for disrupted alleles at Ahr or Pparalpha indicates that the role of ARA9 in cardiac development is independent of its interactions with its known xenobiotic receptor partners.


Heterogeneous Domain Adaptation by Information Capturing and Distribution Matching.
Heterogeneous domain adaptation (HDA) is a challenging problem because of the different feature representations in the source and target domains. Most HDA methods search for mapping matrices from the source and target domains to discover latent features for learning. However, these methods barely consider the reconstruction error to measure the information loss during the mapping procedure. In this paper, we propose to jointly capture the information and match the source and target domain distributions in the latent feature space. In the learning model, we propose to minimize the reconstruction loss between the original and reconstructed representations to preserve information during transformation and reduce the Maximum Mean Discrepancy between the source and target domains to align their distributions. The resulting minimization problem involves two projection variables with orthogonal constraints that can be solved by the generalized gradient flow method, which can preserve orthogonal constraints in the computational procedure. We conduct extensive experiments on several image classification datasets to demonstrate that the effectiveness and efficiency of the proposed method are better than those of state-of-the-art HDA methods.


Bacillus cereus meningoencephalitis in preterm infants: neuroimaging characteristics.
Meningoencephalitis can severely damage the developing brain. Preterms are more prone for nosocomial infections with pathogens other than Group B streptococci and Escherichia coli. In this report we focus on the deleterious clinical course and imaging characteristics of proven Bacillus cereus meningoencephalitis. We collected 3 cases of proven Bacillus cereus meningoencephalitis. In the medical records we focused on prenatal, perinatal, and postnatal risk factors. Imaging data of several brain ultrasounds, MR images, and diffusion-weighted images were reevaluated. The ultrasound and MR images show a typical pattern of mainly hemorrhagic and early cavitating, selective white matter destruction. Knowledge of this paradigm of acquired brain injury may help to better understand the natural course of these severe neonatal infections.


Pain and its modulation. Part 1. Afferent mechanisms.
Our understanding of pain and its afferent modulation has undergone a great deal of modification in recent years as our knowledge of the sensory nervous system has expanded. In this review, current concepts are detailed in the perspective of present and potential clinical applications of basic science principles and theories to neurosurgical interventions. Beginning with peripheral receptors and fibers and traversing the peripheral nervous system to ultimately reach the central nervous system, the nociceptive information undergoes much integration and modification to affect the ultimate response of the organism to the original stimulus. At each point in the afferent pathways, various alternative neurosurgical ablative or augmentive approaches are available and might be appropriate for pain relief. For a variety of reasons many ablative procedures are being used less often in the treatment of chronic pain of a noncancerous origin, while the newer augmentive techniques are becoming more popular. On the other hand, at present ablative procedures are still used frequently for chronic pain associated with cancer, although the newer augmentive approaches are being tried in this area as well.


Application and prospects of nucleic acid nanomaterials in tumor therapy.
Cancer poses a great threat to human life, and current cancer treatments, such as radiotherapy, chemotherapy, and surgery, have significant side effects and limitations that hinder their application. Nucleic acid nanomaterials have specific spatial configurations and can be used as nanocarriers to deliver different therapeutic drugs, thereby enabling various biomedical applications, such as biosensors and cancer therapy. In recent decades, a variety of DNA nanostructures have been synthesized, and they have demonstrated remarkable potential in cancer therapy related applications, such as DNA origami structures, tetrahedral framework nucleic acids, and dynamic DNA nanostructures. Importantly, more attention is also being paid to RNA nanostructures, which play an important role in gene therapy. Therefore, this review introduces the developmental history of nucleic acid nanotechnology, summarizes the applications of DNA and RNA nanostructures for tumor treatment, and discusses the development opportunities for nucleic acid nanomaterials in the future.


[Late effects of mass acute phosphine poisoning - Case report].
This paper reports the case of collective acute phosphide (PH3) intoxication among the crew aboard a merchant ship. All the intoxicated individuals were hospitalized 3 months after the accident. The aim of examinations was to identify late health effects of the accident. Laboratory tests and consultations were performed during their stay in the hospital. There were 5 cases of toxic liver damage. other 5 patients were diagnosed with posttraumatic stress disorder and adjustment disorders. The results of the study suggest that in cases of acute phosphide intoxication, the assessment of patients' psychological functioning should be an indispensable part of diagnostic procedure. Med Pr 2018;69(3):337-344.


[Ovarian tumors with endocrine function].
To analyze the clinicopathological features of ovarian tumors with endocrine function. Twenty-four cases of ovarian tumor with endocrine manifestation were collected from the hospital. Their clinical presentation and histopathologic features were reviewed, along with a panel immunohistochemistry stainings (EnVision method). The antibodies were AE1/AE3, epithelial membrane antibody (EMA), alpha-inhibin, calretini and smooth myoglobin (SMA). The main clinical endocrinological manifestations were related to an excess production of sex steroids. Histologically, the principle histological subtype of these tumors was ovarian sex cord-stroma tumors, including 13 cases ovarian type (8 granulosa cell tumors, 2 thecofibromas, 3 sclerosing stromal tumors), 7 cases testicular type (1 sertoli cell tumors, 5 sertoli-Leydig cell tumors, 1 Leydig cell tumor, and 2 cases of steroid cell tumor (NOS). Another 2 cases were ovarian epithelial tumors. Grossly, 50% (11/22) ovarian sex cord-stromal tumors were less than 5 cm in diameter. However, 4 tumors were quite larger, up to 18 cm in diameter. Most of these tumors were solid or solid-cystic and their cut surfaces were brown, pink, yellow or grey in color. The 2 primary ovarian epithelial tumors were larger, being 12 cm and 14 cm in diameter, respectively. Immunohistochemically, ovarian sex cord-stromal tumors showed positive staining for alpha-inhibin in all cases (22/22) and for calretinin in majority cases (18/22), and that the intensity of reactivity correlated with the degree of tumor differentiation. The non-neoplastic, luteinized stromal cells in 2 ovarian primary epithelial tumors also showed positive staining. Five cases of fibrothecomas and sclerosing stroma tumors were all positive for SMA. Although 6 of the 22 ovarian sex cord-stromal tumors were AE1/AE3 positive, all were EMA negative. Most endocrinological syndromes in ovarian neoplasia reflect an overproduction of sex steroids, but the clinical manifestations do not correlate with the tumor histological subtypes. Most functional ovarian tumors are sex cord-stromal tumors and are usually of small to medium in size, but few are larger or giant. The size of the tumor does not correlate with the duration and the degree of clinical manifestations. Ovarian tumors of non-sex cord-stromal type may also be clinically functional. The immunohistochemical results suggests that alpha-inhibin and/or calretinin expression are useful markers in support of a diagnosis of sex cord-stromal tumor of the ovary. Although some of these tumors are AE1/AE3 positive, EMA negativity may be useful for the differential diagnosis with epithelial ovarian tumors.


A novel cold-active lipase from Candida albicans: cloning, expression and characterization of the recombinant enzyme.
A novel lipase gene lip5 from the yeast Candida albicans was cloned and sequenced. Alignment of amino acid sequences revealed that 86-34% identity exists with lipases from other Candida species. The lipase and its mutants were expressed in the yeast Pichia pastoris, where alternative codon usage caused the mistranslation of 154-Ser and 293-Ser as leucine. 154-Ser to leucine resulted in loss of expression of Lip5, and 293-Ser to leucine caused a marked reduction in the lipase activity. Lip5-DM, which has double mutations that revert 154 and 293 to serine residues, showed good lipase activity, and was overexpressed and purified by (NH(4))(2)SO(4) precipitation and ion-exchange chromatography. The pure Lip5-DM was stable at low temperatures ranging from 15-35 °C and pH 5-9, with the optimal conditions being 15-25 °C and pH 5-6. The activation energy of recombinant lipase was 8.5 Kcal/mol between 5 and 25 °C, suggesting that Lip5-DM was a cold-active lipase. Its activity was found to increase in the presence of Zn(2+), but it was strongly inhibited by Fe(2+), Fe(3+), Hg(2+) and some surfactants. In addition, the Lip5-DM could not tolerate water-miscible organic solvents. Lip5-DM exhibited a preference for the short-and medium-chain length p-nitrophenyl (C4 and C8 acyl group) esters rather than the long chain length p-nitrophenyl esters (C12, C16 and C18 acyl group) with highest activity observed with the C8 derivatives. The recombinant enzyme displayed activity toward triacylglycerols, such as olive oil and safflower oil.


Bezafibrate regulates the expression and enzyme activity of 11beta-hydroxysteroid dehydrogenase type 1 in murine adipose tissue and 3T3-L1 adipocytes.
A clinically employed antihyperlipidemic drug, bezafibrate, has been characterized as a PPAR(alpha, -gamma, and -delta) pan-agonist in vitro. Recent extended trials have highlighted its antidiabetic properties in humans. However, the underlying molecular mechanism is not fully elucidated. The present study was designed to explore potential regulatory mechanisms of intracellular glucocorticoid reactivating enzyme, 11beta-HSD1 and anti-diabetic hormone, adiponectin by bezafibrate in murine adipose tissue, and cultured adipocytes. Treatment of db/db mice with bezafibrate significantly ameliorated hyperglycemia and insulin resistance, accompanied by a marked reduction of triglyceride and nonesterified fatty acids. Despite equipotent in lipid-lowering effects, another fibrate, fenofibrate, did not show such beneficial effects on glycemic control. Treatment of bezafibrate caused a marked decrease in the mRNA level of 11beta-HSD1 preferentially in adipose tissue of db/db mice (-47%, P<0.05), concomitant with a significant increase in plasma adiponectin level (+37%, P<0.01). Notably, treatment of bezafibrate caused a marked decrease in the mRNA level (-34%, P<0.01) and enzyme activity (-32%, P<0.01) of 11beta-HSD1, whereas the treatment substantially augmented the expression (+71%, P<0.01) and secretion (+27%, P<0.01) of adiponectin in 3T3-L1 adipocytes. Knockdown of 11beta-HSD1 by siRNA confirmed that 11beta-HSD1 acts as a distinct oxoreductase in adipocytes and validated the enzyme activity assays in the present study. Effects of bezafibrate on regulation of 11beta-HSD1 and adiponectin in murine adipocytes were comparable with those in thiazolidinediones. This is the first demonstration that bezafibrate directly regulates 11beta-HSD1 and adiponectin in murine adipocytes, both of which may contribute to metabolically-beneficial effects by bezafibrate.


Variational Quantum Simulators Based on Waveguide QED.
Waveguide QED simulators are analog quantum simulators made by quantum emitters interacting with one-dimensional photonic band gap materials. One of their remarkable features is that they can be used to engineer tunable-range emitter interactions. Here, we demonstrate how these interactions can be a resource to develop more efficient variational quantum algorithms for certain problems. In particular, we illustrate their power in creating wave function Ansätze that capture accurately the ground state of quantum critical spin models (XXZ and Ising) with fewer gates and optimization parameters than other variational Ansätze based on nearest-neighbor or infinite-range entangling gates. Finally, we study the potential advantages of these waveguide Ansätze in the presence of noise. Overall, these results evidence the potential of using the interaction range as a variational parameter and place waveguide QED simulators as a promising platform for variational quantum algorithms.


The assessment of the clinical impact of using a single set of radiotherapy planning data for two kilovoltage therapy units.
Kilovoltage therapy units are used for superficial radiotherapy treatment delivery. Peer reviewed studies for MV linear accelerators describe tolerances to dosimetrically match multiple linear accelerators enabling patient treatment on any matched machine. There is an absence of literature on using a single planning data set for multiple kilovoltage units which have limited ability for beam adjustment. This study reviewed kilovoltage dosimetry and treatment planning scenarios to evaluate the feasibility of using ACPSEM annual QA tolerances to determine whether two units (of the same make and model) were dosimetrically matched. The dosimetric characteristics, such as measured half value layer (HVL), percentage depth dose (PDD), applicator factor and output variation with stand-off distance for each kV unit were compared to assess the agreement. Independent planning data based on the measured HVL for each beam energy from each kV unit was prepared. Monitor unit (MU) calculations were performed using both sets of planning data for approximately 200 clinical scenarios and compared with an overall agreement between units of < 2%. Additionally, a dosimetry measurement comparison was completed at each site for a subset of nine scenarios. All machine characterisation measurements were within the ACPSEM Annual QA tolerances, and dosimetric testing was within 2.5%. This work demonstrates that using a single set of planning data for two kilovoltage units is feasible, resulting in a clinical impact within published uncertainty.


[New drug delivery systems for the therapy of bronchial asthma].
Inhalation therapy gives us ideal topical therapy for the airway diseases without significant major side-effects. As new century approaches, a major goal for asthma therapy will be to provide more effective therapeutic drugs to prevent airway inflammation and its spasmus. It is also important to produce excellent inhalant devices that are easy to use and do not contain substances that are harmful to the environment. Future inhalers should target the drug to the correct sites in the airways and thus enable optimal therapeutic effects to be achieved. There are many exciting new developments available in this field. And we should finally obtain special therapeutic drugs to prevent the process to the sudden-onset of asthmatic death.


Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance.
Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8+ T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors.


Local Light-Controlled Generation of Calcium Carbonate and Barium Carbonate Biomorphs via Photochemical Stimulation.
Photochemical activation is proposed as a general method for controlling the crystallization of sparingly soluble carbonates in space and time. The photogeneration of carbonate in an alkaline environment is achieved upon photo-decarboxylation of an organic precursor by using a conventional 365 nm UV LED. Local irradiation was conducted focusing the LED light on a 300 μm radius spot on a closed glass crystallization cell. The precursor solution was optimized to avoid the precipitation of the photoreaction organic byproducts and prevent photo-induced pH changes to achieve the formation of calcium carbonate only in the corresponding irradiated area. The crystallization was monitored in real-time by time-lapse imaging. The method is also shown to work in gels. Similarly, it was also shown to photo-activate locally the formation of barium carbonate biomorphs. In the last case, the morphology of these biomimetic structures was tuned by changing the irradiation intensity.


Tissue distribution of morphine in the newborns of addicted monkeys and humans. Clinical implications.
The distribution of morphine in various tissues of 6 addicted monkey fetuses and in 2 infants of drug-dependent mothers (IDDM) show that significant concentrations of the drug are in the gastrointestines (tissue plus content), liver, cerebellum, lungs, heart, spleen and thymus. The high concentration of morphine in the gastrointestinal tract may be secondary to the excretion of the drug through the bile or by the repeated swallowing by the fetus of amniotic fluid which contains morphine (1.9 +/- 1.0 micrograms/dl). Meconium, taken from 2 IDDMs show a significant concentration of morphine for up to 2-3 days after birth. Thus, meconium is a useful material to analyze postnatally for the diagnosis of neonatal narcotic addiction.


Poststroke upper limb recovery.
Upper limb recovery after a stroke is suboptimal. Only a few individuals achieve full functional use of the hemiparetic arm. Complex primary and secondary impairments may affect recovery of upper limb function in stroke survivors. In addition, multiple personal, social, behavioral, economic, and environmental factors may interact to positively or negatively influence recovery during the different stages of rehabilitation. The current management of upper limb dysfunction poststroke has become more evidence based. In this article, we review the standard of care for upper limb poststroke rehabilitation, the evidence supporting the treatment modalities that currently exist and the exciting new developments in the therapeutic pipeline.


Pathophysiological evaluation associated with sustained delivery of danazol and dihydrotestosterone in adult male rodents.
The objective of this investigation was to evaluate histologically and pathologically the effect of long-term sustained release of D and DHT on the reproductive system of male rats. A total of 120 Sprague-Dawley male albino rats were distributed equally into three groups. Two CDD, one nonimpregnated and the other impregnated with PLA, were implanted in each rat in groups I and II. Capsules implanted in group I rats were loaded with 20 mg DHT and 20 mg D each. Group II rats were implanted with two empty capsules (sham group), and group III animals served as unimplanted controls. Blood samples were withdrawn weekly via tail artery from all animals. Eight rats from each group were euthanized at the end of the one, three, six, nine, and twelve months following the implantation of the devices. No significant changes in the weights of vital (spleen, kidneys, heart, adrenals, lungs) organs of rats were observed among any of the three different groups. Vas deferens and epididymal fluid were devoid of normal spermatozoa within three months of implanting the D+DHT containing devices. Testes weights decreased significantly in the rats implanted with CDD containing D+DHT and the seminiferous tubules became oligospermic after one month and azoospermic after three months.(ABSTRACT TRUNCATED AT 250 WORDS)


Rashba spin-splitting in Janus SnXY/WXY (X, Y = S, Se, Te; X ≠ Y) heterostructures.
Janus transition metal dichalcogenide monolayers have shown a lack of mirror symmetry perpendicular to the 2D plane. The breaking of out-of-plane symmetry, along with the spin-orbit coupling, induces Rashba spin-splitting (RSS) in these materials. In this work, RSS in Janus tin dichalcogenide monolayers are studied. In addition, the heterostructures (HSs) of Janus SnXY and WXY (X, Y = S, Se, Te; X ≠ Y) monolayers are discussed. A RSS energy of about 43 meV, more significant than the room temperature energy, is observed in the Janus SnSSe/WSSe HS. The consequences of vertical strain on the semiconducting HS are examined. Compressive vertical strain enhances and tensile strain reduces, the spin-splitting. For the compressive strain of 10.4%, Janus SnSSe/WSSe HS remains semiconductor with only Rashba bands surrounding near the Fermi level. Enhanced Rashba parameter of about 0.96 eV Å and splitting energy of about 72 meV are observed. These findings confirm that Janus SnSSe/WSSe HS is a productive Rashba material for spintronic device applications.


Ia.W39 expression correlates with a specific Ir function.
The xid- defective mouse (N X B6)F1 male and the I-Ab mutant of the B6 mouse bm12 have mutations on different chromosomes, and therefore in separate genes. However, both variant strains have a trait in common; namely, they are unresponsive to the A chain loop determinant(s) of beef insulin to which mice of the H-2b haplotype respond. We show here that in both mutant strains, this unresponsiveness is concurrent with the absence of the Ia.W39 specificity from the M phi and B cell surface. The concordance is specific for Ia specificity W39 and no other Ia determinant, suggesting that Ia.W39 is identical with the Ir epitope necessary for generating an immune response to a particular amino acid sequence of beef insulin. In the xid-defective mouse, the molecule carrying this antigen is synthesized but not expressed on the plasma membrane, presumably because a mature M phi and B cell subset is missing. By comparison, the bm12 mouse has mature B lymphocytes, but is unable to synthesize Ia.W39. Thus, bm12 has a structural mutation in the gene coding for Ia.W39, whereas xid is a mutant regulatory or maturation gene controlling the membrane expression of Ia.W39.


The abdominoscrotal hydrocele.
While hydrocele is among the commonest inguinal anomalies in children, less than 20 cases have been reported of its extreme form, the abdominoscrotal hydrocele (ASH). This anomaly consists of a large inguinoscrotal hydrocele which communicates in an hour-glass fashion with a large "intra-abdominal" component. The latter lies deep to the narrow internal inguinal ring, but superficial to the peritoneal cavity proper, which is displaced superiorly and medially. The abdominal component of the ASH thus lies latero- and retroperitoneally, sometimes reaching the lower pole of the kidney. We report five ASH in four children under one year old. All four underwent complete resection of the ASH. If the abdominal portion of the hydrocele can not be delivered through a standard approach, we advocate a properitoneal approach as described for recurrent adult hernias. The external oblique, internal oblique and transversalis muscles are divided horizontally above the level of the internal inguinal ring. The peritoneal cavity is retracted superiorly, separating it from the ASH. By decompressing the scrotal component of the ASH, its abdominal part can be emptied through the narrow communication at the internal ring. In this fashion, the processus vaginalis can be identified and ligated deep to internal ring, and the floor of the inguinal canal is left intact. The pathophysiology of ASH is not clear. A one-way valve effect of the patent processus vaginalis may be one cause of the massive accumulation of peritoneal fluid in the ASH. Complete resection is curative, and the properitoneal approach should be considered.


Histologic Lung Cancer Incidence Rates and Trends Vary by Race/Ethnicity and Residential County.
Lung cancer incidence is higher among non-Hispanic (NH) blacks than among the NH white and Hispanic populations in the United States. However, national cancer estimates may not always reflect the cancer burden in terms of disparities and incidence in small geographic areas, especially urban-rural disparities. Moreover, there is a gap in the literature regarding rural-urban disparities in terms of cancer histologic type. Using population-based cancer registry data-Surveillance, Epidemiology and End Results and National Program of Cancer Registries data-we present age-adjusted histologic rates and trends by race/ethnicity and residential county location at the time of first cancer diagnosis. Rate ratios were calculated to examine racial/ethnic differences in rates. Annual percent change was calculated to measure changes in rates over time. We found that declines in squamous cell carcinoma are occurring fastest in metropolitan counties, whereas rates of adenocarcinoma increased fastest in counties nonadjacent to metropolitan areas. Further, although NH black men have increased lung cancer incidence compared with NH white and Hispanic men in all geographic locations, we found that the degree of the disparity increases with increasing rurality of residence. Finally, we discovered that among women whose lung cancer was diagnosed when they were younger than 55 years, the incidence of squamous cell carcinoma and adenocarcinoma was higher for NH blacks than for NH whites. Our results highlight disparities among NH blacks in nonadjacent rural areas. These findings may have significant impact for the implementation of smoking cessation and lung cancer screening programs.


Long-Term Oncological Outcome After Conventional Radical Hysterectomy Versus 2 Nerve-Sparing Modalities for Early Stage Cervical Cancer.
Nerve-sparing radical hysterectomy for early stage cervical cancer was introduced to improve quality of life after treatment. Sparing the pelvic autonomic nerves reduces bladder, bowel, and sexual dysfunction. The Leiden nerve-sparing radical hysterectomy (LNSRH) was modified to the Swift procedure, the latter being more radical regarding the sacrouterine and parametrial resection. We investigate whether nerve-sparing surgery has comparable oncological outcomes as the conventional radical hysterectomy (CRH). Concurrently, we investigate whether there is a difference regarding the oncological outcomes of the 2 nerve-sparing techniques. This is a single-center, observational prospective cohort study analyzing oncological outcomes in women undergoing CRH (1994-1999), LNSRH (2001-2005), or Swift procedure (2006-2010) for early stage cervical cancer (International Federation of Gynecology and Obstetrics IA2-IIA). Three hundred sixty-three patients (124 CRH, 122 LNSRH, and 117 Swift) were included. International Federation of Gynecology and Obstetrics stage IB2 or higher (P = 0.005) was significantly more prevalent in the CRH cohort. The 5-year pelvic relapse-free survival and overall survival were not significantly different between the 3 cohorts (P = 0.116). Regarding the nerve-sparing cohorts, the Swift cohort showed a significant better 5-year overall survival (87.2%) compared with the LNSRH cohort (78.8%) (P = 0.04). In the LNSRH cohort, resection planes less than 5 mm free and need for adjuvant therapy were significantly higher than in the Swift cohort (P = 0.026 and 0.046, respectively). The nerve-sparing radical hysterectomy shows a similar oncological outcome compared with the CRH. The more radical Swift version of nerve-sparing techniques is preferable to the former LNSRH procedure.


Radiation dose response simulation for biomechanical-based deformable image registration of head and neck cancer treatment.
Biomechanical-based deformable image registration is conducted on the head and neck region. Patient specific 3D finite element models consisting of parotid glands (PG), submandibular glands (SG), tumor, vertebrae (VB), mandible, and external body are used to register pre-treatment MRI to post-treatment MR images to model the dose response using image data of five patients. The images are registered using combinations of vertebrae and mandible alignments, and surface projection of the external body as boundary conditions. In addition, the dose response is simulated by applying a new loading technique in the form of a dose-induced shrinkage using the dose-volume relationship. The dose-induced load is applied as dose-induced shrinkage of the tumor and four salivary glands. The Dice Similarity Coefficient (DSC) is calculated for the four salivary glands, and tumor to calculate the volume overlap of the structures after deformable registration. A substantial improvement in the registration is found by including the dose-induced shrinkage. The greatest registration improvement is found in the four glands where the average DSC increases from 0.53, 0.55, 0.32, and 0.37 to 0.68, 0.68, 0.51, and 0.49 in the left PG, right PG, left SG, and right SG, respectively by using bony alignment of vertebrae and mandible (M), body (B) surface projection and dose (D) (VB+M+B+D).


Views on online self-help programmes from people with eating disorders and their carers in UK.
Digitalizing the healthcare system has been declared a priority by the UK government. People with eating disorders (EDs), especially those with bulimia nervosa (BN) or binge eating disorder (BED), and ED carers may benefit from online self-help programmes, due to the shame and stigma associated with EDs and barriers in accessing treatment, skills-training or support. Qualitative studies are needed to explore stakeholders' needs, attitudes to and views about online self-help, to optimize intervention design and delivery. Focus groups and telephone interviews were conducted with people with BN or BED, and carers of people with anorexia nervosa, between March and September 2018 in the UK. People with EDs and carers perceived online self-help positively in the context of barriers to seeking and accessing treatment and support, despite some seeing it as inferior to face-to-face support. Most reported little experience with online interventions. Participants thought the disadvantages of online interventions could be overcome by reminders, progress summaries, regular engagement and engaging with peers. Receiving guidance was seen as an important functionality in the intervention by people with EDs. People with EDs and their carers are aware of the potential benefits of online self-help despite having little experience with this form of intervention. A stepped-care approach that utilizes technology-based interventions as a first step and makes such interventions available directly to the consumer may fit the attitudes and needs of stakeholders. The study provides a foundation for future research on design and delivery of ED online self-help.


Recovery of phosphorus from dairy manure: a pilot-scale study.
Phosphorus was recovered from dairy manure via a microwave-enhanced advanced oxidation process (MW/H2O2-AOP) followed by struvite crystallization in a pilot-scale continuous flow operation. Soluble phosphorus in dairy manure increased by over 50% after the MW/H2O2-AOP, and the settleability of suspended solids was greatly improved. More than 50% of clear supernatant was obtained after microwave treatment, and the maximum volume of supernatant was obtained at a hydrogen peroxide dosage of 0.3% and pH 3.5. By adding oxalic acid into the supernatant, about 90% of calcium was removed, while more than 90% of magnesium was retained. As a result, the resulting solution was well suited for struvite crystallization. Nearly 95% of phosphorus in the treated supernatant was removed and recovered as struvite.


A Time and Place for Everything: Developmental Differences in the Building Blocks of Episodic Memory.
This research investigated whether episodic memory development can be explained by improvements in relational binding processes, involved in forming novel associations between events and the context in which they occurred. Memory for item-space, item-time, and item-item relations was assessed in an ethnically diverse sample of 151 children aged 7-11 years and 28 young adults. Item-space memory reached adult performance by 9½ years, whereas item-time and item-item memory improved into adulthood. In path analysis, item-space, but not item-time best explained item-item memory. Across age groups, relational binding related to source memory and performance on standardized memory assessments. In conclusion, relational binding development depends on relation type, but relational binding overall supports episodic memory development.


Suprarenal mass due to a gastric diverticulum.
Suprarenal masses shown on CT scan should be diagnosed with caution. In fact normal structures, anatomic variations, and lesions of adjacent organs may mimic actual adrenal tumors. A gastric diverticulum simulating an adrenal metastasis is reported.


Cancer Therapeutic Effects of Titanium Dioxide Nanoparticles Are Associated with Oxidative Stress and Cytokine Induction.
Nanoparticles (NPs) are considered to influence the inflammatory process; however, the precise mechanism and the significance in tumors are still not clear. In this study, when CT26 and LL2 mouse cancer cells were treated with 6-nm anatase titanium dioxide NPs (TDNPs) without ultraviolet irradiation, oxidative stress and induction of inflammatory cytokines were observed. Oxidative stress was further increased by disease-associated conditions such as high glucose concentrations and hypoxia. Inhaled or orally administered TDNPs generated granulomatous lesions in the lungs and colon of the rodent models tested, with increased oxidative stress and inflammatory cytokines. Oxidative stress and inflammatory cytokines were also found in cancer cells treated with gold or carbon black NPs. Treatment of CT26 cells with 10- to 70-nm rutile TDNPs showed that smaller NPs produced more oxidative stress and inflammatory cytokines than larger ones did. To avoid diffusion of TDNPs and to minimize toxicity, 10-nm TDNPs were suspended in a collagen gel inserted into a subcutaneous tumor in a CT26 mouse. A single TDNP treatment via this method inhibited tumor growth in a size- and dose-dependent manner, and resulted in lower levels of urinary 8-OHdG when compared to systemically administered TDNPs. These findings suggest that TDNPs might be useful for the local treatment of tumors.


Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency.
Epidermal growth factor receptor (EGFR) blockade and radiation are efficacious in the treatment of cancer, but resistance is commonly reported. Studies have suggested that dysregulation of Notch signaling and enrichment of the cancer stem cell population underlie these treatment challenges. Our data show that dual targeting of EGFR and Notch2/3 receptors with antibody CT16 not only inhibited signaling mediated by these receptors but also showed a strong anti-stem cell effect both in vitro and in vivo. Treatment with CT16 prevented acquired resistance to EGFR inhibitors and radiation in non-small cell lung cancer (NSCLC) cell line models and patient-derived xenograft tumors. CT16 also had a superior radiosensitizing impact compared with EGFR inhibitors. CT16 in combination with radiation had a larger antitumor effect than the combination of radiation with EGFR inhibitors or tarextumab. Mechanistically, CT16 treatment inhibits the stem cell-like subpopulation, which has a high mesenchymal gene expression and DNA repair activity, and reduces tumor-initiating cell frequency. This finding highlights the capacity of a combined blockade of EGFR and Notch signaling to augment the response to radiation and suggests that CT16 may achieve clinical efficacy when combined with radiation in NSCLC treatment.


Cytochromes P450: Role in Carcinogenesis and Relevance to Cancers.
Cancer is a leading cause of mortality globally. Cytochrome P450 (CYP) enzymes play a pivotal role in the biotransformation of both endogenous and exogenous compounds. Various lines of evidence from epidemiological, animal, and clinical studies point to the instrumental role of CYPs in cancer initiation, metastasis, and prevention. Substantial research has found that CYPs are involved in activating different carcinogenic chemicals in the environment, such as polycyclic aromatic hydrocarbons and tobacco-related nitrosamines. Electrophilic intermediates produced from these chemicals can covalently bind to DNA, inducing mutation and cellular transformation that collectively result in cancer development. While bioactivation of procarcinogens and promutagens by CYPs has long been established, the role of CYP-derived endobiotics in carcinogenesis has only emerged in recent years. Eicosanoids derived from arachidonic acid via CYP oxidative pathways have been implicated in tumorigenesis, cancer progression and metastasis. The purpose of this review is to update the current state of knowledge about the molecular cancer mechanism involving CYPs with a focus on the biochemical and biotransformation mechanisms in the various CYP-mediated carcinogenesis and the role of CYP-derived reactive metabolites, from both external and endogenous sources, in cancer growth and tumor formation.


Protected Stroke Mechanical Thrombectomy Code During the Coronavirus (COVID-19) Pandemic: Southwestern Part of Saudi Arabia Stroke Unit Local Protocol.
Cerebrovascular diseases are a significant cause of mortality and morbidity worldwide, in particular those with large vessels occlusion (LVO). Coronavirus disease 2019 (COVID-19) has become a global crisis rapidly since its initial outbreak in Wuhan, China, in December, 2019. Stroke due to LVO needs rapid assessment and timely endovascular intervention which can be very challenging during the time of pandemic where you need to deliver proper, safe, and timely care to acute ischemic stroke (AIS) patients with LVO, yet, protecting healthcare workers and existing patients at the medical facility. In this article, we share our local experience in the stroke unit at Aseer Central Hospital which is the main hub of stroke patients in the southwestern part of Saudi Arabia and the primary regional COVID center to provide guidance to perform smooth, safe, and swift mechanical thrombectomy during the coronavirus (COVID-19) pandemic as well as possible similar future situations.


Poly(l-lysine)-Coated Liquid Crystal Droplets for Cell-Based Sensing Applications.
Exploring intermolecular interactions in the presence of biomolecules that dictate director configurations of liquid crystals (LCs) enables new techniques for optically probing complex biological phenomena and realizing new classes of sensors and actuators. However, the design of a new approach by probing direct protein-LC interactions (in aqueous media) that can mimic chemico-biological interactions at the cellular level remains elusive. Here, we present a simple method to produce biocompatible LC droplets through poly(l-lysine) (PLL)-LC interactions in situ for reporting the presence of cells and monitoring the real-time interaction of cells with their environments that are mediated by topological defects in those droplets. In addition, responsive PLL droplets have been found to be useful as a template for reporting Annexin V-phosphatidylserine interactions, providing a simple measure of the harmful effect on cell health.


Does formal vs home-based physical therapy predict outcomes after ankle fracture or ankle fracture-dislocation?
Ankle fractures are among the most common injuries treated by orthopaedic surgeons. Various postoperative rehabilitation strategies have been promoted, but the ability to improve patient-reported functional outcome has not been clearly demonstrated. We aim to evaluate outcomes associated with clinic-based, physical therapist-supervised rehabilitation (Formal-PT) compared to surgeon-directed rehabilitation (Home-PT). This prospective observational study included patients with operative bimalleolar or trimalleolar ankle fractures with or without dislocation (n = 80) at a Level I trauma center. Patients were prescribed PT per the surgeon's practice pattern. Patient-reported functional outcomes at 6 months and complication rates were compared between groups. Of the 80 patients, 38 (47.5%) patients received Formal-PT; the remaining received Home-PT. Thirty-four patients (89.5%) attended ≥1 PT session. Number of sessions attended ranged from 1 to 36 (mean = 16). Receipt of Formal-PT did not differ by injury characteristics or demographics. Of patients with private insurance, 57% were prescribed Formal-PT vs 7% of uninsured patients (P = .033). FAAM and Combination SMFA scores at 6 months were similar between groups (Formal-PT: 69.7, 20.1; Home-PT: 70.9, 24.4; P = .868, .454, respectively). Postoperative complications were rare and equivalent between groups. Comparison of outcomes between patients with operatively treated displaced ankle fractures/dislocations with Formal-PT vs Home-PT showed no difference in SMFA and FAAM scores. These findings suggest patients receiving supervised PT produced a similar outcome to those under routine physician-directed rehabilitation at 6 months. The cost for therapy averaged $2012.96 per patient receiving Formal-PT.


Epigenetic landscape analysis of lncRNAs in acute myeloid leukemia with DNMT3A mutations.
Acute myeloid leukemia (AML) is a type of cancer that consists of a group of hematological malignancies with high heterogeneity. DNA methyltransferase 3A (DNMT3A)-mutated AML patients have a poor prognosis. Some long non-coding RNAs (lncRNAs) have been reported to enhance therapeutic sensitivity, and so could affect the overall survival rate of elderly cytogenetically normal acute myeloid leukemia (CN-AML) patients; however, studies on the lncRNA signature in DNMT3A-mutated AML are rare. The DNMT3A R878H conditional knock-in mouse model was constructed to explore the lncRNAs of DNMT3A mutation by using the Cuffcomparison method. Cis and trans regulation networks were used to predict candidate genes. The expression levels in leukemic cell lines and the prognostic index of these candidate genes were analyzed with the Broad Institute Cancer Cell Line Encyclopedia (CCLE) and OncoLnc databases. The data for each sample were statistically analyzed using GraphPad Prism. In this study, we applied the DNMT3A R878H conditional knock-in mouse model to explore the lncRNA epigenetic landscape of DNMT3A mutation by using the Cuffcomparison method. Twenty-three differentially expressed lncRNAs were identified in Dnmt3aR878H/WTMx1-Cre+ mice. We next predicted the downstream targetable genes regulated by these lncRNAs through cis and trans regulation networks and found 124 candidate genes are related to these lncRNAs. In further analysis of 124 genes, we found that increased mRNA expression levels of interleukin 1 receptor type 2 (IL1R2), Krüppel-like factor 13 (KLF13), ATPase H+ transporting V1 subunit A (ATP6V1A), proteasome 26S Subunit, non-ATPase 3 (PSMD3), and pyrroline-5-carboxylate reductase 2 (PYCR2) were associated with poor prognosis in AML. Functional analysis of these genes demonstrated that the pathways involved in autophagy, cell cycle, and hematopoietic stem cell differentiation were more enriched in Dnmt3aR878H/WTMx1-Cre+ mice. Our study was the first to use DNMT3A R878H conditional knock-in mouse model to predict the specific lncRNAs regulated by the DNMT3A mutation in AML. Six candidate genes were found to be associated with DNMT3A mutation with poor prognosis. Our results provided a possible treatment strategy for this disease.


Effective reinnervation of the quadriceps femoris by spinal ventral root cross-anastomosis in rats.
To study the effective recovery of the quadriceps femoris by spinal ventral root cross-anastomosis in rats. End-to-end anastomosis was performed between the left L(1) and L(3) ventral roots using autogenous nerve graft, and the right L(1) and L(3) roots were left intact. In control animals, the left L(3) ventral root was cut and shortened, and anastomosis was not performed. Six months postoperatively, the movement of low extremities was detected by electrophysiological examination, hindlimb locomotion and basso, beattie and bresnahan (BBB) scoring at one, three, seven, 14, 21 and 28 days after SCI. Fluorescence retrograde tracing with TRUE BLUE (TB) and HE staining were performed to observe the nerve regeneration. Six months after surgery, the anastomotic nerve was smooth and not atrophic. The amplitudes of action potential were 7.63 ± 1.86 mV and 6.0 ± 1.92 mV respectively before and after the spinal cord hemisection. The contraction of left quadriceps femoris was induced by a single stimulation of the anastomotic nerve. The locomotion of left hindlimb was partially restored after spinal cord hemisection while creeping and climbing. In addition, there was significant difference in the BBB score at one, three and seven days after SCI. TB retrograde tracing and neurophysiologic observation indicated efficient reinnervation of the quadriceps femoris. The cross-anastomosis between spinal ventral root can partially reconstruct the function of quadriceps femoris following SCI and may have clinical implication for the treatment of human SCI.


Remote monitoring of implantable devices: Should we continue to ignore it?
The number of patients with implantable cardioverter defibrillators (ICDs) is increasing. In addition to improve survival, ICD can collect data related to device function and physiological parameters. Remote monitoring (RM) of these data allows early detection of technical or clinical problems and a prompt intervention (reprogramming device or therapy adjustment) before the patient require hospitalization. RM is not a substitute for emergency service and its consultation is now limited during working hours. Thus, a consent form is required to inform patients about benefits and limitations. The available studies indicate that remote monitoring is more effective than traditional calendar face to face based encounters. RM is safe, highly reliable, cost efficient, allows quick reply to failures, and reduces the number of scheduled visits and the incidence of inappropriate shocks with a positive impact on survival. It follows that RM has the credentials to be the standard of care for ICD management; however, unfortunately, there is a delay in physician acceptance and implementation. The recent observations from randomized IN-TIME study that showed a clear survival benefit with RM in heart failure patients have encouraged us to review both the negative and positive aspects of RM collected in a little more than a decade.


Bioequivalence evaluation of two brands of enalapril 20 mg tablets (Narapril and Renitec) in healthy human volunteers.
The bioequivalence of two brands of enalapril 20 mg tablets was demonstrated in 24 healthy human volunteers after a single oral dose in a randomized cross-over study, conducted at IPRC, Amman, Jordan. Reference (Renitec, MSD, Netherlands) and test (Narapril, Julphar, UAE) products were administered to fasted male volunteers; blood samples were collected at specified time intervals, plasma separated and analysed for enalapril and its active metabolite (enalaprilat) using a validated LC-MS/MS method at Cartesius Analytical Unit, Institute of Biomedical Sciences, USP, Sao Paulo, Brazil. The pharmacokinetic parameters AUC(0-t), AUC(0-infinity), Cmax, Tmax, T(1/2) and elimination rate constant were determined from plasma concentration-time profile for both formulations and were compared statistically to evaluate bioequivalence between the two brands, using the statistical modules recommended by FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetic profiles and that Julphar's Narapril is bioequivalent to Renitec of MSD, Netherlands.


Carcinoma cuniculatum: a distinctive variant of penile squamous cell carcinoma: report of 7 cases.
We are reporting a peculiar variant of penile squamous cell carcinoma (SCC) characterized by its peculiar deeply penetrating and burrowing pattern of growth. This low grade, verruciform penile neoplasm is similar to the plantar epithelioma cuniculatum originally described by Ayrd in 1954. Clinical and pathologic features of 7 patients are presented. There were 7 partial penectomies and 4 bilateral inguinal node dissections. The mean patient's age was 77 years. Grossly, the tumors were white to gray, exo-endophytic, and papillomatous with a cobblestone or spiky appearance. All cases affected the glans and extended to coronal sulcus and foreskin (average size was 6.3 cm). The hallmark of the lesion was noted on cut surface where there were deep tumoral invaginations forming irregular, narrow, and elongated neoplastic sinus tracts connecting the surface of the neoplasm to deep anatomic structures. The neoplasm invaded through lamina propria and corpus spongiosum and grew along the loose connective tissue of Buck fascia to involve the tunica albuginea and corpora cavernosa (average depth was 32 mm). Deeply invasive keratin filled cysts or crypts, on serial sections, showed to be connected to the surface tumor. Fistulization to the skin was also noted. Microscopically, the lesions corresponded to well-differentiated carcinomas with bulbous front of invasion. There were focal areas of higher histologic grade and more infiltrative and jagged borders in 4 cases. Inguinal nodes were negative in 4 patients in which groin dissection was performed. Carcinoma cuniculatum is a variant of penile SCC with distinctive growth pattern and should be distinguished from other verruciform tumors such as the verrucous, papillary, and warty carcinomas. Unlike most subtypes of penile SCCs and despite the deep invasion, none of the tumors showed groin or systemic dissemination at time of diagnosis.


Applications of cold temperature stress to age fractionate Caenorhabditis elegans: a simple inexpensive technique.
The nematode Caenorhabditis elegans's (CE) successful use in studies of aging is well documented. Cold temperature stress of mixed populations of CE provides a rapid inexpensive means of obtaining three life stage-specific cohorts. Cohorts are obtained in quantities that allow acquisition of replicate metabolite profiles of changes associated with development, aging, and senescence. The fractionation technique is effective with monoxenic and axenic CE cultures. Cohort Y contains 100% young worms, and Cohort A contains 75% adult worms. Cohort M, prereproductive and reproductive, contains some A and Y due to continuous egg laying and hatch. Principal component analysis of normalized data from metabolite profiles obtained using high-performance liquid chromatography electrochemical analysis clearly separates Cohort Y from Cohort A and monoxenic from axenic cultured worms. Access to replicate quantities of age-defined worms will aid studies of alterations in homeostatic controls associated with aging and senescence.


Calcium and ROS-mediated activation of transcription factors and TNF-alpha cytokine gene expression in macrophages exposed to ultrafine particles.
Ultrafine (Uf) particles are a component of particulate air pollution suggested to be responsible for the health effects associated with elevations of this pollutant. We have previously suggested that Uf particles, through the induction of oxidative stress, may induce inflammation in the lung, thus exacerbating preexisting illness in susceptible individuals. Alveolar macrophages are considered to play a key role in particlemediated inflammation and lung disease. The effect of Uf particles on rat alveolar macrophages and human blood monocytes was investigated with reference to the roles of calcium and reactive oxygen species (ROS). TNF-alpha protein release, intracellular calcium concentration, TNF-alpha mRNA expression, and transcription factor activation were studied as end points after treatment of rat alveolar macrophages or peripheral blood monocytes. The calcium channel blocker verapamil, the intracellular calcium chelator BAPTA-AM, the calmodulin inhibitor W-7, and the antioxidants Trolox and Nacystelin (NAL) were included in combination with Uf particles. Verapamil reduced intracellular calcium concentration in rat alveolar macrophages on stimulation with Uf particles. This effect was also apparent with transcription factor AP-1 activation. All antagonists and antioxidants reduced Uf-stimulated nuclear localization of the p50 and p65 subunits of NF-kappaB in human monocytes. Verapamil, BAPTA-AM, and NAL reduced Uf-stimulated TNF-alpha protein release, whereas only verapamil reduced Uf-stimulated mRNA expression in rat alveolar macrophages. In human monocytes, verapamil, Trolox, BAPTA-AM, and W-7 reduced Uf-stimulated TNF-alpha protein release. These findings suggest that Uf particles may exert proinflammatory effects by modulating intracellular calcium concentrations, activation of transcription factors, and cytokine production through a ROS-mediated mechanism.


[Effects of plasma lipopolysaccharide changes on platelet release of vascular endothelial growth factor and thromobospondin-1 in patients with cirrhotic portal hypertension after TIPS procedure].
Objective: To investigate the effects of plasma lipopolysaccharide (LPS) concentration changes on platelet release of vascular endothelial growth factor (VEGF) and thrombospondin (TSP)-1 in patients with decompensated cirrhotic portal hypertension after transjugular intrahepatic portosystemic shunt (TIPS) procedure. Methods: 169 cases with cirrhotic portal hypertension were enrolled, of which 81 cases received TIPS treatment. LPS, VEGF, and TSP-1 concentrations with different Child-Pugh class in peripheral blood plasma of patients were measured. After pre-incubation of normal human platelets with different concentrations of LPS and stimulated by collagen in vitro, platelet PAC-1 expression rate, VEGF, and TSP-1 concentrations were detected. PAC-1 expression rate and the concentrations of LPS, VEGF and TSP-1 in peripheral blood plasma of patients before and after TIPS procedure were detected. The relationship between plasma LPS, VEGF and TSP-1 concentrations and Child-Pugh score changes in patients after TIPS procedure was analyzed. Statistical analysis was performed by t-test, one-way ANOVA or Pearson's rho according to different data. Results: Plasma LPS and TSP-1 concentrations were significantly higher in Child-Pugh class C patients than class A and B, but the concentration of plasma VEGF was significantly lower than class A and B (P < 0.01). In vitro experiments showed that concentration of LPS, TSP-1, and platelet PAC-1 expression rate was higher in the supernatant, but the difference in the concentration of VEGF in the supernatant was not statistically significant. Portal vein pressure and platelet activation were significantly decreased (P < 0.01) in patients after TIPS procedure. Portal venous pressure, platelet activation, plasma LPS, and TSP-1 levels were significantly decreased continuously, while VEGF levels were significantly increased continuously after TIPS procedure. Plasma LPS concentration was positively correlated with TSP-1 concentration (r = 0.506, P < 0.001), and negatively correlated with VEGF concentration (r = -0.167, P = 0.010). Child-Pugh score change range was negatively correlated with change range of plasma VEGF concentration (r = -0.297, P = 0.016), and positively correlated with change range of plasma TSP-1 concentration (r = 0.145, P = 0.031) after TIPS. Conclusion: Portal venous pressure gradient, plasma LPS concentration and corresponding platelet activation was decreased in cirrhotic portal hypertension after TIPS procedure, and with TSP-1 reduction and VEGF elevation it is possible to reduce the liver function injury caused by portal venous shunt.


Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease.
Nonalcoholic fatty liver disease (NAFLD) is estimated to afflict approximately 1 billion individuals worldwide. In a subset of NAFLD patients, who have the progressive form of NAFLD termed nonalcoholic steatohepatitis (NASH), it can progress to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related morbidity and mortality. NASH is typically characterized by a specific pattern on liver histology, including steatosis, lobular inflammation, and ballooning with or without peri-sinusoidal fibrosis. Thus, key issues in NAFLD patients are the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis. Until now, liver biopsy has been the gold standard for identifying these 2 critical end points, but has well-known limitations, including invasiveness; rare but potentially life-threatening complications; poor acceptability; sampling variability; and cost. Furthermore, due to the epidemic proportion of individuals with NAFLD worldwide, liver biopsy evaluation is impractical, and noninvasive assessment for the diagnosis of NASH and fibrosis is needed. Although much of the work remains to be done in establishing cost-effective strategies for screening for NASH, advanced fibrosis, and cirrhosis, in this review, we summarize the current state of the noninvasive assessment of liver disease in NAFLD, and we provide an expert synthesis of how these noninvasive tools could be utilized in clinical practice. Finally, we also list the key areas of research priorities in this area to move forward clinical practice.


Calcium antagonism and the vasorelaxation of the rat aorta induced by rotundifolone.
The vasorelaxing activity of rotundifolone (ROT), a major constituent (63.5%) of the essential oil of Mentha x villosa, was tested in male Wistar rats (300-350 g). In isolated rat aortic rings, increasing ROT concentrations (0.3, 1, 10, 100, 300, and 500 microg/ml) inhibited the contractile effects of 1 microM phenylephrine and of 80 or 30 mM KCl (IC50 values, reported as means +/- SEM = 184 +/- 6, 185 +/- 3 and 188 +/- 19 microg/ml, N = 6, respectively). In aortic rings pre-contracted with 1 microM phenylephrine, the smooth muscle-relaxant activity of ROT was inhibited by removal of the vascular endothelium (IC50 value = 235 +/- 7 microg/ml, N = 6). Furthermore, ROT inhibited (pD2 = 6.04, N = 6) the CaCl2-induced contraction in depolarizing medium in a concentration-dependent manner. In Ca2+-free solution, ROT inhibited 1 microM phenylephrine-induced contraction in a concentration-dependent manner and did not modify the phasic contractile response evoked by caffeine (20 mM). In conclusion, in the present study we have shown that ROT produces an endothelium-independent vasorelaxing effect in the rat aorta. The results further indicated that in the rat aorta ROT is able to induce vasorelaxation, at least in part, by inhibiting both: a) voltage-dependent Ca2 channels, and b) intracellular Ca2+ release selectively due to inositol 1,4,5-triphosphate activation. Additional studies are required to elucidate the mechanisms underlying ROT-induced relaxation.


[A variant of transvesical extraurethral adenomectomy].
To facilitate extraurethral adenomectomy, we used a semicylindric scalpel and metallic tube (tubus) to make a semioval cut parallel to proximal prostatic portion of the urethra along the posterior semicircle of the bladder neck in 260 patients with prostatic adenoma (PA). The urethra was isolated from the adenomatous tissues. The vesicular cut was prolonged left and right to the level of ureteral ostia. This manipulation was followed with bimanual index finger enucleation of adenomatous tissue. The defect of the vesicourethral segment was sutured with catgut or monocril. Extra-urethral adenomectomy with semicylindric scalpel injured prostatic urethra in lesser extent than endourethral adenomectomy, it reduced the risk of hemorrhage, entailed neither stricture of the posterior urethra nor incontinence of urine in the postoperative period.


Incorporation of acetate into fatty acids and lecithin by lung slices from fetal and newborn lambs.
Incorporation of acetate-1-(14)C into phospholipids and fatty acids by lung slices from fetal and newborn lambs and from ewes was studied in vitro. The distribution of radioactivity in the fatty acids of neutral lipids, phospholipids, and lecithin was determined. Acetate-1-(14)C was incorporated into myristic, palmitic, and C(18) fatty acids. Of the lecithin fatty acids, myristic and palmitic were the major radioactive fatty acids. The results indicate that the lung of fetal lambs is able to synthesize lecithin containing saturated fatty acids, a major constituent of pulmonary surfactant. A marked increase in the rate of acetate incorporation into lecithin was observed during maturation, and these rates were higher than those obtained in the ewes. A possible relationship between developmental changes in lecithin biosynthesis and pulmonary surfactant is discussed.