Succipenoids A-C: A dimeric abietane and nor-abietane diterpenoids from fossil Chinese medicinal succinum and their anti-inflammatory potential.
An unprecedented dimeric abietane, succipenoid A (1), and two previously undescribed nor-abietane diterpenoids featuring a rarely occurring naphthalene ring or with a large conjugated system, succipenoids B and C (2 and 3), along with seven known diterpenoids (4-10) were isolated from the CH2Cl2 extract of succinum. The structures of these compounds, including their absolute configurations, were elucidated using spectroscopic and computational techniques. Notably, compounds 1-4 and 6-10 were isolated from succinum for the first time. In order to evaluate their anti-inflammatory potential, in vitro tests were conducted. The results demonstrated that compounds 1, 2, 4, and 6-10 exhibite dose-dependent inhibition of iNOS expression in lipopolysaccharide-induced RAW 264.7 cells.


Improving the evaluation of homeopathy: economic considerations and impact on health.
The financial crisis of health insurance systems sometimes drives public policy-makers to take precipitate action dominated by economic imperatives. The question addressed here consists in defining homeopathy's scope of intervention, its place in health care strategies, recourse to treatment, and especially economic data appraising homeopathy's impact on expenditures and outlay covered by health insurance in France. We used the General Evaluation Model to define the study (to whom is the evaluation made, situations, criteria, measurement of these criteria, quality and precision). The main results are in terms of costs, as follows: * For reimbursable medicines the public sales price of homeopathic products is a quarter of the average. * The total reimbursement for a prescription of allopathic products is three times more than for a prescription of homeopathic products. * Homeopathic physicians incur annual reimbursement outlays which are half those of general practitioners. The differences observed cannot be explained by the patient profile or the diseases treated. Furthermore, a study carried out in France showed that 87% of patients whose physicians had prescribed homeopathic treatment did not see another physician for the same problem. Once basic analysis has been done, so that the economic and epidemiological impact of a certain health strategy can be determined, it is necessary to proceed further, helping healthcare providers and public authorities to make decisions. Various possibilities exist and should be investigated.


Skeletal muscle differentiation of human iPSCs meets bioengineering strategies: perspectives and challenges.
Although skeletal muscle repairs itself following small injuries, genetic diseases or severe damages may hamper its ability to do so. Induced pluripotent stem cells (iPSCs) can generate myogenic progenitors, but their use in combination with bioengineering strategies to modulate their phenotype has not been sufficiently investigated. This review highlights the potential of this combination aimed at pushing the boundaries of skeletal muscle tissue engineering. First, the overall organization and the key steps in the myogenic process occurring in vivo are described. Second, transgenic and non-transgenic approaches for the myogenic induction of human iPSCs are compared. Third, technologies to provide cells with biophysical stimuli, biomaterial cues, and biofabrication strategies are discussed in terms of recreating a biomimetic environment and thus helping to engineer a myogenic phenotype. The embryonic development process and the pro-myogenic role of the muscle-resident cell populations in co-cultures are also described, highlighting the possible clinical applications of iPSCs in the skeletal muscle tissue engineering field.


Dissolution rates of uranium compounds in simulated lung fluid.
Maximum dissolution rates of uranium into simulated lung fluid were measured at 37 degrees C to estimate clearance rates from the deep lung. The materials tested included: ore and yellowcake, an airborne sample from an industrial site, and purified samples of (NH4)2U2O7, U3O8, UO2 and UF4. A batch procedure was developed to test samples containing as little as 10 micrograms of natural uranium. Values of dissolution halftimes varied from 0.01 day to several thousand days depending on the physical and chemical form of the uranium. Dissolution occurred predominantly by formation of the #UO2(CO3)3 ]4-ion; and as a result, tetravalent uranium compounds dissolved slowly. Dissolution rates of size-separated yellowcake aerosols were found to be more closely correlated with specific surface area than with aerodynamic diameter.


Regulation of body fat mass by the gut microbiota: Possible mediation by the brain.
New insight suggests gut microbiota as a component in energy balance. However, the underlying mechanisms by which gut microbiota can impact metabolic regulation is unclear. A recent study from our lab shows, for the first time, a link between gut microbiota and energy balance circuitries in the hypothalamus and brainstem. In this article we will review this study further.


Robotic Partial Nephrectomy During Pregnancy: Case Report and Special Considerations.
To report a case of robotic partial nephrectomy (RPN) during pregnancy and review the existing literature on the topic. A 35-year-old asymptomatic pregnant woman at 20 weeks gestation was found to have a large mass in the right kidney during routine anatomic ultrasound for fetal assessment. Magnetic resonance imaging demonstrated a 7.5 cm right upper-pole solid-enhancing renal mass, concerning for malignancy, without evidence of local extension or metastases. Ultimately, after shared decision-making between the patient and her physicians, the patient elected to proceed with RPN. A multidisciplinary approach was undertaken perioperatively. Notably, coordination between high-risk maternal fetal medicine, obstetrics, anesthesia, and urology were paramount to this endeavor. The patient was seen and assessed by obstetrics and maternal fetal medicine preoperatively, and fetal heart tones were monitored immediately before and after surgery and every day of her hospitalization. Total operating time was 253 minutes with an estimated blood loss of 120 cc. Warm ischemia time was 36 minutes, and 70% of normal renal parenchyma was preserved. The patient's creatinine peaked at 0.81 mg/dL, and her hemoglobin nadir reached 9.6 g/dL. She was discharged on postoperative day 6 in excellent condition. Final pathology demonstrated a 6.6 cm chromophobe renal cell carcinoma with negative margins. RPN during pregnancy is feasible but requires perioperative planning, multidisciplinary coordination, and careful operative decision-making to ensure optimal safety of mother and fetus. Herein, we report the first described case of RPN for renal neoplasm during pregnancy.


Inflammatory Pseudotumor of the Liver.
Hepatic inflammatory pseudotumor (IPT) describes a mass lesion composed of fibroblasts or myofibroblasts with a dense inflammatory infiltrate comprising lymphocyte, plasma cells, and histiocytes. These lesions are presumed to be an exuberant response to an infectious organism, although in most cases the causative agent is unknown. In specific circumstances, pathologists should consider ancillary techniques to exclude specific infections, such as mycobacteria, Candida, or syphilis. IgG4-related disease may cause a plasma-cell rich IPT. Finally, true neoplasms can mimic IPTs and must be excluded with appropriate ancillary studies, including inflammatory myofibroblastic tumor, follicular dendritic cell tumor, inflammatory angiomyolipoma, Hodgkin lymphoma, and inflammatory hepatocellular carcinoma.


Weaving public health education into the fabric of a family medicine residency.
Policymakers and accrediting bodies have recognized the importance of integrating public health, population health, and prevention into graduate medical education programs. The high prevalence of chronic illness, coupled with the impact of behavioral and societal determinants of health, necessitate an urgent call for family medicine residencies to prepare future leaders to meet these challenges. The University of Massachusetts Worcester Family Medicine Residency recently developed an integrated curriculum that strives to develop a culture of incorporating fundamental public health principles into everyday practice. This public health curriculum was designed to integrate new topics within the current residency structure through longitudinal and concentrated experiences. This strategy has substantially improved public health and prevention education without substantial impact on the already strained residency curricular structure. This paper describes the integration of public health and prevention education into a family medicine residency to help residents acquire the fundamental skills necessary to improve a population's health.


APAP Treatment Acceptance Rate and Cost-Effectiveness of Telemedicine in Patients with Obstructive Sleep Apnea: A Randomized Controlled Trial.
This study evaluated the treatment acceptance rate and cost-effectiveness of the telemedicine model in clinical practice for adult patients with obstructive sleep apnea (OSA). Patients admitted to the sleep center for snoring were randomly divided into telemedicine and control groups. Patients diagnosed with moderate-to-severe OSA using the Home Sleep Apnea Test (HSAT) were voluntarily treated with auto-adjusted positive airway pressure (APAP) therapy. The acceptance rate of the APAP treatment, cost of patient visits, time cost, and labor cost of doctors in the two groups were observed. A total of 57 subjects were included, with an average age of 40.12±11.73 years, including 47 males (82.5%); 26 patients were in the telemedicine group, and 31 were in the control group. Follow-up results showed that the acceptance rate of APAP treatment was 57.7% and 54.8% in the telemedicine and control groups, respectively, with no significant difference between the two groups (p=0.829). The cost-benefit analysis showed that the telemedicine group reduced the cost of patients' medical treatment [-457.84(-551.19,1466.87)] but increased the extra intervention frequency and time outside the doctor's office. Further analysis showed that male subjects of older age, higher education level, distant residence, no fatty liver, poor sleep quality, severe insomnia, and higher OSA severity were more likely to receive telemedicine diagnosis and treatment. The APAP treatment acceptance rate and compliance of OSA patients in the telemedicine group were similar to those in the control group, and the cost of patients' medical treatment was reduced. However, telemedicine increases the frequency and duration of additional out-of-hospital interventions.


Rho GTPases in cancer cell biology.
Rho GTPases contribute to multiple cellular processes that could affect cancer progression, including cytoskeletal dynamics, cell cycle progression, transcriptional regulation, cell survival and vesicle trafficking. In vitro several Rho GTPases have oncogenic activity and/or can promote cancer cell invasion, and this correlates with increased expression and activity in a variety of cancers. Conversely, other family members appear to act as tumour suppressors and are deleted, mutated or downregulated in some cancers. Genetic models are starting to provide new information on how Rho GTPases affect cancer development and progression. Here, we discuss how Rho GTPases could contribute to different steps of cancer progression, including proliferation, survival, invasion and metastasis.


How can a proposed Cochrane diet and nutrition field work effectively?
The Cochrane Database currently provides relatively little evidence-based guidance about nutrition relevant to general practitioners. This situation could be improved by the establishment of a new Cochrane Field to identify relevant studies, prioritize topics to include nutrition, work with Cochrane methodologists on the inclusion of observational studies, and disseminate results of Cochrane reviews to general practitioners and their patients. A Diet and Nutrition Field could be established as a separate entity or as a Subgroup of the existing Primary Health Care (PHC) Field. The Field would be appropriate if the intent is to immediately cover nutritional interventions of all sorts, in all settings. However, if the focus is nutritional evidence for use by primary care clinicians, organization as a subField would provide a simpler registration process, allow Cochrane activities to begin sooner, and would allow members to focus on primary-care-relevant nutritional issues, conserving their resources and energy. A mechanism exists for conversion to a freestanding Field if the scope later expands. Of the core Field functions, identification and assembly of relevant trials into a specialized register would be among the most important. Special registers are generated by focused literature searches augmented by hand-searching of key journals. Given the importance of studies with observational designs, a nutrition field register will require some additional work on search strategies and inclusion criteria. Other key functions would include ensuring effective communication both with members of other Cochrane entities and with the scientific and clinical community with interests in diet and nutrition.


Development and validation of a questionnaire to evaluate lifestyle-related behaviors in elementary school children.
The SI! Program promotes cardiovascular health through a multilevel school-based intervention on four lifestyle-related components: diet, physical activity, understanding the body and heart, and management of emotions. We report here the development and validation of the KAH (knowledge, attitudes and habits)-questionnaire adapted for elementary school children (6-7 years old) as a tool for the forthcoming evaluation of the SI! Program, where the KAH scoring will be the primary outcome. The efficacy of such an intervention will be based on the improvements in children's KAH towards a healthy lifestyle. The questionnaire validation process started with a pool of items proposed by the pedagogical team who developed the SI! Program for elementary school. The questionnaire was finalized by decreasing the number of items from 155 to 48 using expert panels and statistical tests on the responses from 384 children (ages 6-7). A team of specialized psychologists administered the questionnaire at schools providing standard directions for the final administration. The internal consistency was assessed using Cronbach's α coefficients. Reliability was measured through the split-half method, and problematic items were detected applying the item response theory. Analysis of variance and Tukey's test of additivity were used for multiple comparisons. The final KAH-questionnaire for elementary school children should be administered to children individually by trained staff. The 48 items-questionnaire is divided evenly between the 4 components of the intervention, with an overall Cronbach's α = 0.791 (α = 0.526 for diet, α = 0.537 for physical activity, α = 0.523 for human body and heart, and α = 0.537 for management of emotions). The KAH-questionnaire is a reliable instrument to assess the efficacy of the SI! Program on instilling healthy lifestyle-related behaviors in elementary school children.


The thermal activity of normal and malignant tissues. Microcalorimetric response of liver cancer to hepatic artery ligation, cryosurgery, adriamycin and norcantharidin.
The usefulness of metabolic heat measurements in quantifying the response of a solid tumour to anticancer treatment was evaluated. The heat production characteristic of malignant tissues, as measured from human stomach, breast and liver cancer samples, was observed to be inconsistent, and its value could be higher or lower than that of its normal tissue of origin. The various thermal activity responses of an experimental rat hepatoma to hepatic artery ligation, cryotherapy, intra-arterial (i.a.) Adriamycin (2.4 mg/kg), i.a. Norcantharidin (0.5 mg/kg) were next studied. The tumour/liver (T/L) ratio of untreated tumour-bearing rats was 0.83 but this fell to a minimum at 24 h in both the hepatic artery ligation and the cryosurgery groups. In these two groups marked fluctuations in the heat production of normal liver occurred with poor recovery of the T/L ratio even at 2-3 weeks. In the Adriamycin group, the T/L ratio dropped to a minimum at 5 days, and in the Norcantharidin group, at 3 days. Minimal disturbances in the thermal activity of liver tissue occurred in these two chemotherapy groups and the T/L ratio recovered by 3 weeks. Norcantharidin appeared as efficacious as Adriamycin in the treatment of hepatoma when evaluated in terms of thermal activity.


Biotinidase deficiency and our champagne legacy.
Biotinidase is the enzyme that is necessary for the recycling of the vitamin, biotin. Biotinidase deficiency is an autosomal recessively inherited metabolic disorder. If untreated, individuals with biotinidase deficiency usually develop neurological and cutaneous symptoms that can result in coma or death. Symptomatic individuals can be markedly improved by treating them with pharmacological doses of biotin; however, some clinical features may be irreversible. Fortunately, essentially all symptoms can be prevented if treatment is initiated at birth or before the symptoms develop. Because of this, the disorder is currently screened for in newborns in all states in the United States and in many countries around the world. This is the story of one laboratory's work in bringing basic science research from the discovery of the disorder to its translation into clinical medicine and its impact on the individuals with the disorder and their families.


Smoking, health risks, coping mechanisms and depression in the age of COVID-19: A cross-sectional study of the Lebanese population.
We compared depression of people who smoke and those who do not, depending on whether they have an underlying disease making them at risk for COVID-19. Moreover, we analyzed the factors associated with their depression. We recruited 948 Lebanese residents, ages 18 and above. Our survey included the Patient Health Questionnaire-9 (PHQ-9) to assess depression. We divided participants, based on smoking and having a disease making one at risk for a COVID19 infection into four groups: non-smokers not at risk (NSNR), non-smokers at risk (NSR), smokers not at risk (SNR), and smokers at risk (SR). SR had PHQ-9 scores higher than other groups. The diet was not changed during the pandemic, whereas weight increased in all groups but SR. Those not at risk slept longer, while sports were decreased in NSR and SNR. Hobbies were decreased in all groups except SNR. Depending on the group, factors such as age, sex, residency, diet, exercise, sleep duration, and hobbies were associated with PHQ-9 scores. we cannot draw causal relationships. Participation required internet access, and participants might not represent the actual population due to the snowball effect. Also, recall bias might skew results. We did not inquire about sexual activity, which could be an essential coping mechanism. Factors associated with depression for one group did not necessarily do so for another. Controlling the underlying risk or smoking cessation could move a patient to a group with more options associated with depression, thereby additional methods to decrease depression.


Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) with OT-82 induces DNA damage, cell death, and suppression of tumor growth in preclinical models of Ewing sarcoma.
NAMPT mediates the rate-limiting step of the NAD salvage pathway, which maintains cellular bioenergetics and provides a necessary substrate for functions essential to rapidly proliferating cancer cells. In this study, we evaluated the efficacy and mechanisms of action of OT-82, a novel, high-potency NAMPT inhibitor with a favorable toxicity profile, in preclinical models of Ewing sarcoma (EWS), an aggressive pediatric malignancy with previously reported selective sensitivity to NAMPT inhibition. We show that OT-82 decreased NAD concentration and impaired proliferation of EWS cells in a dose-dependent manner, with IC50 values in the single-digit nanomolar range. Notably, genetic depletion of NAMPT phenocopied pharmacological inhibition. On-target activity of OT-82 was confirmed with the addition of NMN, the product of NAMPT, which rescued NAD concentration and EWS cellular viability. Mechanistically, OT-82 treatment resulted in impaired DNA damage repair through loss of PARP activity, G2 cell-cycle arrest, and apoptosis in EWS cells. Additional consequences of OT-82 treatment included reduction of glycolytic and mitochondrial activity. In vivo, OT-82 impaired tumor growth and prolonged survival in mice bearing EWS xenografts. Importantly, antitumor effect correlated with pharmacodynamic markers of target engagement. Furthermore, combining low-dose OT-82 with low doses of agents augmenting DNA damage demonstrated enhanced antitumor activity in vitro and in vivo. Thus, OT-82 treatment represents a potential novel targeted approach for the clinical treatment of EWS.


Preconception TSH and Adverse Pregnancy Outcomes in China: A Nationwide Prospective Cohort Study.
The relationship between maternal thyroid function and pregnancy outcomes remains controversial and the safe range of TSH is still unclear in women planning pregnancy. This population-based cohort study enrolled Chinese women who became pregnant in 30 provinces from 2010 to 2012 from the National Free Preconception Checkups Project. The maternal TSH level within 6 months before pregnancy and different pregnancy outcomes were collected and analyzed using restricted cubic spline regression model for dose-response relationship and potential optimal cutoff values. Logistic regression was used to reveal the relationship between different TSH groups and the risk of adverse outcomes. Among 175 112 women, a J-shaped association was revealed between TSH and large for gestational age (LGA; P < 0.001). When TSH was lower than 1.27 or 0.91 mIU/L, lower TSH was associated with higher odds ratio of low birth weight (LBW; P = 0.003) or preterm delivery (P < 0.001). There was no significant association of preconception TSH with SGA, macrosomia, fetal anomalies, stillbirth, natural or induced abortion, and cesarean delivery. The range of TSH for odds ratio lower than 1.0 was within 0.91 to 1.82 mIU/L in dose-response association. Compared with TSH 0.91 to 1.82 mIU/L, TSH low (< 0.40 mIU/L and 0.40-0.90 mIU/L) and high (1.83-2.49 mIU/L, 2.50-3.99 mIU/L, and >4.00 mIU/L) were associated with higher risk of preterm delivery and LGA. There was no significant association between TSH groups and the risk of LBW except for TSH < 0.40 mIU/L. Preconception TSH was associated with preterm delivery, LGA, and LBW. Preconception TSH had a bidirectional effect on LGA, indicating a potential mechanism regarding influence of TSH on birth weight. TSH within 0.91 to 1.82 mIU/L was the potential safe range for preconception women.


[Characteristics of the interaction of legionellae and Tetrahymena pyriformis].
L. pneumophila avirulent strains have been shown to lose their capacity for multiplication in T. pyriformis, while the concentration of the virulent strain increases 1000-fold. The loss of the hemolytic activity of L. pneumophila virulent strain leads to the loss of its capacity for multiplication in infusorians.


Effect of chronic administration of nicotine or cocaine on steroidogenesis in rat adrenocortical cells.
Rats were implanted subcutaneously with osmotic mini-pumps containing either 0.9% NaCl, nicotine (1.5 or 4.5 mg kg-1 day-1), or cocaine (30 mg kg-1 day-1), for 14 days. Neither nicotine nor cocaine treatment significantly altered the maximal rate of steroidogenesis in adrenocortical cell preparations from the animals. However, pretreatment with cocaine increased the sensitivity of the preparation to stimulation by ACTH, the ED50 was 5 pM compared with 10 pM from control animals. Addition of nicotine or cocaine at concentrations up to 100 microM to adrenal cell suspensions from naive rats did not stimulate steroidogenesis or increase the sensitivity of cells to ACTH stimulation. These results suggest that the primary chronic effect of nicotine on steroidogenesis is exerted at the level of the hypothalamus and/or pituitary and not directly on adrenocortical cells. On the contrary, pretreatment with cocaine causes persistent changes in adrenocortical cells.


NMR structure of Dengue West Nile viruses stem-loop B: A key cis-acting element for flavivirus replication.
Flaviviruses are major emerging human pathogenic viruses that pose a persistent and growing menace to global health. They are enveloped single-stranded RNA viruses with positive polarity transmitted by arthropod vectors like mosquitoes or ticks, responsible for a significant and growing number of human deaths and illnesses. The 5'- and 3'-untranslated regions (UTRs) are highly structured and contain conserved cis-acting RNA elements that participate in viral translation, replication and host adaptation. Despite their role in fiaviviruses replication, few high-resolution structural studies have investigated the RNA elements required for viral replication. Here we report the NMR structures of stem-loop B from WNV and DENV4 viruses. Because this element is required for cyclization of the genome and the activity of the replicative viral enzymes, viral replication rates are sensitive to even small changes in these RNAs. Therefore, this work provides structural insight into a new drug target to reduce flavivirus replication rates.


Electrical thermal angioplasty: catheter design features, in vitro tissue ablation studies and in vivo experimental findings.
A prototype electrical thermal tip catheter has been developed for ablation of atherosclerotic plaques. The operating principle is based on establishing an electric arc between a central electrode and the inside of an enclosing metallic tip to convert electrical energy to thermal energy. The metal tip catheter can be heated rapidly and boils water in a saline bath with less than 1 W of power. In vitro studies, using human atherosclerotic aortic segments, demonstrated that effective tissue ablation required more power in saline than in air (more than 9 W vs less than 1 W). The rate of tissue ablation varied with the amount of power delivered and the catheter tip pressure against tissue. In a saline field, 2-mm thickness aortic wall segments were consistently perforated in 3 seconds when 15 W of power and 20 g/mm2 of pressure were applied. Using an atherosclerotic rabbit, in vivo electrical thermal angioplasty (3 W of power for 10-second treatment sequences) was performed in obstructed iliofemoral vessels after mechanical recanalization was attempted. Of the 7 vessels that were more than 50% narrowed (compared with contiguous normal vessel diameter), mechanical recanalization was effective in only 1, but thermal angioplasty resulting in an increased lumen diameter was successful in 6 others. The recanalized segments were 8 to 10 cm; gross morphologic and histologic examination of recanalized vessels demonstrated little or no thermal injury. In addition, significant cholesterol-laden plaques remained in the vessel lumen, which appeared to have been compressed and displaced laterally.(ABSTRACT TRUNCATED AT 250 WORDS)


[Differential Expression of a Foreign Gene in Arabidopsis Mitochondria In Organelle].
Genetic transformation of higher eukaryote mitochondria in vivo is an unresolved and important problem. For efficient expression of foreign genetic material in mitochondria, it is necessary to select regulatory elements that provide a high level of transcription and transcript stability. This work is aimed at studying the effectiveness of regulatory elements of mitochondrial genes flanking exogenous DNA using the phenomenon of natural competence of plant mitochondria. For this purpose, genetic constructs carrying the GFP gene under the control of the promoter regions of the RRN26 or COX1 genes and one of the two 3'-untranslated regions (3'-UTR) of mitochondrial genes were imported into isolated Arabidopsis mitochondria, followed by transcription in organello. It was shown that the level of GFP expression under the control of promoters of the RRN26 or COX1 genes in organello correlates with the level of transcription of these genes observed in vivo. At the same time, the presence of the tRNA^(Trp) sequence in the 3'-UTR leads to a higher level of the GFP transcript than the presence in this region of the 3'-UTR of the NAD4 gene containing the binding site of the MTSF1 protein. The results we obtained open prospects for creating a system for efficient transformation of the mitochondrial genome.


Pharmacokinetics of Para-Aminosalicylic Acid and Its 2 Major Metabolites: A Potential Relationship to the Development of Gastrointestinal Intolerance.
Para-aminosalicylic acid (PAS), often the last drug remaining for treatment of drug-resistant tuberculosis, is notorious for causing gastrointestinal intolerance; however, the cause of PAS intolerance is uncertain. The objective of this study was to assess relationships between peak concentrations of PAS administered as a granular slow-release enteric coated formulation, and its metabolites acetyl-PAS and glycine-PAS, and intolerance. PAS and its metabolites were measured in 29 adult patients with drug-resistant tuberculosis at Brooklyn Hospital, Cape Town, randomized to receive granular slow-release enteric-coated PAS 4 g twice daily or 8 g once daily for 1 week, followed by the alternative regimen. Concentrations of PAS and its metabolites were determined by liquid chromatography and tandem mass spectrometry, and a visual analogue scale evaluated intolerance. Spearman's correlation test assessed the relationship between maximum plasma concentrations (Cmax ) and intolerance scores. A large interindividual variability was observed for the PAS Cmax (40.42-68.55 mg/L) following 4 g twice daily; (62.69-102.41 mg/L) for 8 g once daily and a similar wide Cmax range found for the metabolites acetyl-PAS and glycine-PAS. Twenty-six patients reported at least 1 intolerance episode, but most visual analogue scale scores clustered around 0. Significant inverse associations were found between acetyl-PAS Cmax and bloating (rho = -0.448; P = .025) and diarrhea (rho = -0.407; P = .044) for the twice-daily regimen and a similar inverse association found for glycine-PAS and diarrhea (rho = -0.412; P = .041). Plasma concentrations of the metabolites did not correlate with the occurrence of gastrointestinal symptoms, but higher metabolite concentrations correlated with lower intolerance scores; slow metabolism of PAS and its continued presence in the intestinal tract may be the main cause of intolerance.


Reversible tricolour luminescence switching based on a piezochromic iridium(iii) complex.
On the basis of rational molecular design, the tricolour luminescence switching of an Ir(iii) complex is achieved for the first time. The transformation between two crystalline states and an amorphous state is responsible for the switching behaviour of this complex between blue, green and yellow states. Solvent molecules are shown to play a crucial role in the crystallization and luminescence processes.


Peter Singer's argument for utilitarianism.
The paper begins by situating Singer within the British meta-ethical tradition. It sets out the main steps in his argument for utilitarianism as the 'default setting' of ethical thought. It argues that Singer's argument depends on a hierarchy of reasons, such that the ethical viewpoint is understood to be an adaptation--an extension--of a fundamental self-interest. It concludes that the argument fails because it is impossible to get from this starting-point in self-interest to his conception of the ethical point of view. The fundamental problem is its mixing the immiscible: the Humean subordination of reason to interest with the Kantian conception of reason as universal and authoritative.


[Studying the effect of the new beta-adrenoreceptor blocker proxodolol on the ischemic model of cardiac insufficiency].
The effects of proxodolol--new beta-blocker with alpha-blocking activity--on system hemodynamics, heart function and morphology of rats with ischemia-induced congestive heart failure were studied and compared with those of carvedilol. It was shown that both drugs administered during 3 weeks after ligation of coronary artery inhibit heart remodeling and development of myocardial hypertrophy. Proxodolol was more effective than carvedilol in prevention of heart dysfunctions typical for congestive heart failure, that was especially evident during the pharmacological overload tests.


Beneficial Effects of Tannic Acid on the Quality of Bacterial Communities Present in High-Moisture Mulberry Leaf and Stylo Silage.
Tannic acid (TA), a type of polyphenol, is widely distributed in plants, especially in legumes. Not only does it possess antimicrobial properties, but it also has the ability to bind with proteins. The fermentation parameters, nitrogen fractions, antioxidant capacity, and bacterial communities present in mulberry leaves and stylo (Stylosanthes guianensis) ensiled with or without 1 and 2% TA per kilogram of fresh matter (FM) were investigated after 75 days' fermentation. The results showed that 1 and 2% TA both significantly decreased the butyric acid content (4.39 and 7.83 g/kg dry matter (DM), respectively) to an undetectable level in both mulberry leaf and stylo silage. In addition, 2% TA significantly increased the contents of lactate (24.0-39.0 and 8.50-32.3 g/kg DM), acetate (18.0-74.5 and 9.07-53.3 g/kg DM), and the antioxidant capacity of both mulberry leaf and stylo silage, respectively. With the addition of 1 and 2% TA, the pH values (5.55-5.04 and 4.87, respectively) and ammonia-N (NH3-N) content (85.5-27.5 and 16.9 g/kg total nitrogen (TN), respectively) were all significantly decreased in stylo silage. In addition, TA increased the relative abundance of Weissella, Acinetobacter, and Kosakonia spp. and decreased that of undesirable Clostridium spp. TA can thus be used to improve the silage quality of both mulberry leaf and stylo silage, with 2% TA being the better concentration of additive to use.


Empirical Dilation of Non-obstructive Dysphagia: Current Understanding and Future Directions.
Non-obstructive dysphagia (NOD) is defined as symptomatic dysphagia in patients with negative endoscopic and radiographic workup. The management of NOD remains controversial as there is a discrepancy between different guidelines and clinical practice. Despite the lack of high-quality studies, empiric dilation for NOD is a common clinical practice among endoscopists and the approach varies between different clinical centers. In this review, we summarize the published literature on empiric dilation for NOD and propose a management algorithm for offering empiric dilation to patients presenting with dysphagia.


Nutritional cofactor treatment in mitochondrial disorders.
Mitochondrial disorders are degenerative diseases characterized by a decrease in the ability of mitochondria to supply cellular energy requirements. Substantial progress has been made in defining the specific biochemical defects and underlying molecular mechanisms, but limited information is available about the development and evaluation of effective treatment approaches. The goal of nutritional cofactor therapy is to increase mitochondrial adenosine 5'-triphosphate production and slow or arrest the progression of clinical symptoms. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of antioxidants, electron transfer mediators (which bypass the defective site), and enzyme cofactors. Metabolic therapies that have been reported to produce a positive effect include Coenzyme Q(10) (ubiquinone); other antioxidants such as ascorbic acid, vitamin E, and lipoic acid; riboflavin; thiamin; niacin; vitamin K (phylloquinone and menadione); creatine; and carnitine. A literature review of the use of these supplements in mitochondrial disorders is presented.


Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease.
Hepatocyte nuclear factor 4alpha (HNF4alpha; NR2A1) is an orphan member of the nuclear receptor superfamily expressed in liver and intestine. While HNF4alpha expression is critical for liver function, its role in the gut and in the pathogenesis of inflammatory bowel disease (IBD) is unknown. Human intestinal biopsies from control and IBD patients were examined for expression of mRNAs encoding HNF4alpha and other nuclear receptors. An intestine-specific HNF4alpha null mouse line (Hnf4alpha(DeltaIEpC)) was generated using an Hnf4alpha-floxed allele and villin-Cre transgene. These mice and their control floxed counterparts (Hnf4alpha(F/F)), were subjected to a dextran sulfate sodium (DSS)-induced IBD colitis protocol and their clinical symptoms and gene expression patterns determined. In human intestinal biopsies, HNF4alpha was significantly decreased in intestinal tissues from Crohn's disease and ulcerative colitis patients. HNF4alpha expression was also suppressed in the intestine of DSS-treated mice. In Hnf4alpha(DeltaIEpC) mice, disruption of HNF4alpha expression was observed in the epithelial cells throughout the intestine. In the DSS-induced colitis model Hnf4alpha(DeltaIEpC) mice showed markedly more severe changes in clinical symptoms and pathologies associated with IBD including loss of body weight, colon length, and histological morphology as compared with Hnf4alpha(F/F) mice. Furthermore, the Hnf4alpha(DeltaIEpC) mice demonstrate a significant alteration of mucin-associated genes and increased intestinal permeability, which may play an important role in the increased susceptibility to acute colitis following an inflammatory insult. While HNF4alpha does not have a major role in normal function of the intestine, it protects the gut against DSS-induced colitis.


Concurrent bevacizumab and temozolomide alter the patterns of failure in radiation treatment of glioblastoma multiforme.
We investigated the pattern of failure in glioblastoma multiforma (GBM) patients treated with concurrent radiation, bevacizumab (BEV), and temozolomide (TMZ). Previous studies demonstrated a predominantly in-field pattern of failure for GBM patients not treated with concurrent BEV. We reviewed the treatment of 23 patients with GBM who received 30 fractions of simultaneous integrated boost IMRT. PTV60 received 2 Gy daily to the tumor bed or residual tumor while PTV54 received 1.8 Gy daily to the surrounding edema. Concurrent TMZ (75 mg/m^2) daily and BEV (10 mg/kg every 2 weeks) were given during radiation therapy. One month after RT completion, adjuvant TMZ (150 mg/m^2 × 5 days) and BEV were delivered monthly until progression or 12 months total. With a median follow-up of 12 months, the median disease-free and overall survival were not reached. Four patients discontinued therapy due to toxicity for the following reasons: bone marrow suppression (2), craniotomy wound infection (1), and pulmonary embolus (1). Five patients had grade 2 or 3 hypertension managed by oral medications. Of the 12 patients with tumor recurrence, 7 suffered distant failure with either subependymal (5/12; 41%) or deep white matter (2/12; 17%) spread detected on T2 FLAIR sequences. Five of 12 patients (41%) with a recurrence demonstrated evidence of GAD enhancement. The patterns of failure did not correlate with extent of resection or number of adjuvant cycles. Treatment of GBM patients with concurrent radiation, BEV, and TMZ was well tolerated in the current study. The majority of patients experienced an out-of-field pattern of failure with radiation, BEV, and TMZ which has not been previously reported. Further investigation is warranted to determine whether BEV alters the underlying tumor biology to improve survival. These data may indicate that the currently used clinical target volume thought to represent microscopic disease for radiation may not be appropriate in combination with TMZ and BEV.


Adjuvant activity of pollen grains.
The induction of an immune response to a biologically inert soluble protein requires an adjuvant. Here we have examined whether intact grains of pollen display such adjuvant effect, accounting for the immunogenic activity of pollen protein allergens that are devoid of intrinsic pro-inflammatory/adjuvant property. Human monocyte-derived dendritic cells (DCs) were cultured with intact grains of grass or ragweed pollen for 48 h. The state of DCs maturation was analyzed by FACS and their cytokine production by ELISA. T cell priming activity of DCs was examined in co-cultures with naïve cord blood-derived CD4(+) T cells. Contact with grains of pollen induced a distinct maturation program in immature DCs. Pollen up-regulated the expression of CD54, CD80, CD83, CD86, HLA-DR, CCR7, and CD40 on DCs. Moreover, CCR5 expression was up-regulated by pollen but suppressed by LPS. In sharp contrast to LPS-stimulated DCs, pollen-treated DCs did not produce cytokines [interleukin (IL)-10, IL-12, tumor necrosis factor (TNF)-alpha] but retained the ability to secrete high levels of these cytokines upon simulation with soluble CD40 ligand and interferon (IFN)-gamma. Pollen-primed DCs strongly stimulated the proliferation of allogeneic naïve CD4(+) T cells and promoted their development into effector cells producing high levels of IL-5 and IL-13 together with moderate levels of IFN-gamma and IL-4. Intact grains of pollen induce activation and maturation of DCs in vitro. Similar mechanisms may be effective in vivo, suggesting that pollen grain is not only an allergen carrier but also acts as an adjuvant in the induction phase of the allergic immune response.


Thrombosis of the superior sagittal sinus associated with idiopathic thrombocytosis.
An unusual association of thrombosis of the superior sagittal sinus and idiopathic thrombocytosis is reported. Etiology, clinical and radiological findings and therapeutic approach are discussed.


Binding to cellulose of IgG from patients with interstitial lung diseases.
Sera from some patients with hypersensitivity pneumonitis (HP) and lung fibrosis contain immunoglobulin G (IgG) which strongly binds to cellulose as measured by binding to paper discs. This binding is Fab-dependent. The IgG-species which binds to cellulose also binds to protein-saturated nitrocellulose membranes. This makes the detection, in patients sera, of antibodies to etiologic antigens by immunoblotting difficult. Detection by immunoblotting can, however, be performed much more precisely if patients' sera are preincubated with cellulose powder to remove cellulose-binding IgG.


Comparison of foreign language anxiety based on four language skills in Chinese college students.
Numerous studies have established that foreign language anxiety (FLA) has a significant impact on learners' language acquisition and performance. FLA is a unique form of anxiety that occurs in response to a certain circumstance. Even though a growing amount of research has extended to the examination of skill-based anxiety in specific, such as listening, speaking, reading, and writing, little used corresponding skilled-based FLA scales to assess learners' skill-based FLA at one group of learners. To fill a void in this line of research, the study aimed to explore learners' primary FLA by comparing their four language skill-specific FLAs with four different skill-based FLA scales. Additionally, we wished to investigate the variables that influence learners' FLA. All participants in the study were first-year medical students. Individual instructors delivered and collected a total of 1023 questionnaires using an open questionnaire platform during normal English lessons in the mid-semester. SPSS 24.0 (Statistical Package for Social Science 24 version) was used to analyze all statistics. Internal validity tests were undertaken on each scale to ascertain the component structure of certain modified scales. The study employed the independent sample t-test and a statistical description to investigate students' major FLA and its variables. With a mean value of 106.863, the predominant FLA arouses from English listening anxiety. English reading anxiety was the lowest, with a mean score of 62.726. Male and female students both demonstrated the greatest degree of FLA in English listening and the least anxiety in English reading. However, their mean difference was not statistically significant (t = 1.220). By comparing the mean scores for four skill-based FLAs across language proficiency groups, it became clear that the scores for the medium were much higher than the average, with average scores of ESA: 91.988, ELA: 106.864, EWA: 74.157, ERA: 62.726, respectively, and the higher-level group scored lower than the average. Students' prior English learning achievements are negatively connected with their FLA, with r values of -.207 (ELA), -.143 (EWA), and - .204 (ERA). The self-evaluation of students' English listening, writing, and reading abilities was considerably adversely connected with FLA, but the self-evaluation of their English-speaking abilities was favorably correlated with FLA. A comparison of students' FLA revealed that the primary skill-based FLA is related to English listening anxiety. Regardless of gender or language proficiency level, FLA was mainly driven by foreign language listening anxiety in all individuals. Prior language achievement and students' self-evaluation are associated with their FLA.


Normalization of the Verbal Fluency Test on the basis of results for healthy subjects, patients with schizophrenia, patients with organic lesions of the chronic nervous system and patients with type 1 and 2 diabetes.
Verbal fluency is the ability to form and express words compatible with required criteria. Verbal fluency is necessary for optimal communication and for normal social and occupational functioning. The Verbal Fluency Test is a good indicator of frontal lobe dysfunction, particularly of the left frontal cortex. The aim of the study was to compare verbal fluency in healthy subjects (n = 50), patients with paranoid schizophrenia (n = 36), patients with organic lesions of the central nervous system (CNS) (n = 33), and patients with diabetes (n = 62) - type 1 diabetes (n = 31) and type 2 diabetes (n = 31). Healthy subjects and patients with diabetes achieved the highest results in all categories of the Verbal Fluency Test. Patients with paranoid schizophrenia achieved significantly lower results. Sten norms of the Verbal Fluency Test were developed for the general population. Using these norms it was found that subjects with schizophrenia or with organic lesions of the CNS had very poor results more often and very high results less frequently compared to healthy subjects and also to patients with diabetes. This observation is consistent with the neurodevelopmental hypothesis of schizophrenia, in which cognitive functions of the frontal lobe (e.g. verbal fluency) play a major role in the psychopathological picture. We have also demonstrated that in patients with type 1 and 2 diabetes verbal fluency is comparable with healthy subjects.


Effect of the axial cysteine ligand on the electronic structure and reactivity of high-valent iron(IV) oxo-porphyrins (Compound I): a theoretical study.
The effect of axial ligands on the reactivity of high-valent iron(IV) oxo-porphyrins (Compound I) was investigated using the B3LYP hybrid density functional method. We studied alkane hydroxylation using four models: Compound I with thiolate, imidazole, phenolate, and chloride anions as axial ligands. The first three ligands were employed as models for cysteinate, histidine, and tyrosinate, respectively. Our calculations show that anionic ligands and neutral ligands favor different electronic states for stationary points in the reaction coordinate, and the calculated energy barrier and energy of several reaction intermediates show similar values. A remarkable effect of axial ligands was found in the final product release step. Our calculations show that the thiolate ligand weakens a bond between heme and an alcohol. In contrast, the imidazole ligand significantly increases the interaction between heme and an alcohol, which causes the catalytic cycle to be less efficient.


Differential response to depression prevention among a sample of informal caregivers: Moderator analysis of longer-term follow-up trial data.
Depression is one of the most common mental disorders in caregivers. Therefore, preventive interventions for this population are needed, especially for caregivers with subclinical symptoms of depression. However, no study to date has identified the characteristics of caregivers that help to predict who will or will not benefit from such a preventive intervention. This study aimed to identify moderators of response to intervention comparing problem solving and usual care in indicated prevention of depression among informal caregivers. A randomized controlled trial was conducted involving 173 participants who were allocated to the problem-solving intervention (n=89) or the usual-care control-group (n=84), with 12-months follow-up. Socio-demographic, care-related and clinical variables at baseline were analyzed as potential moderators of intervention response at 12-months follow-up. Age and emotional distress emerged as significant moderators. Those caregivers younger than 65 years and with higher emotional distress at baseline were more likely to benefit from the intervention than from usual care. Simultaneous consideration of multiple moderators found that intervention was indicated for 95.4% of the sample. Considering these moderators in clinical decision-making could contribute to matching treatments and health service users in a more personalized and effective way.


Joint line obliquity after lateral closing-wedge high tibial osteotomy does not adversely affect clinical and radiological outcome: a 5-year follow-up study.
To analyze the association between change in knee joint line obliquity (KJLO) and patient-reported outcome, radiological progression of osteoarthritis, and surgical survival after lateral closing-wedge high tibial osteotomy (HTO). A cohort of 180 patients treated in one single hospital with lateral closing-wedge HTO was examined. KJLO was defined by the medial proximal tibial angle (MPTA). To assess the association between KJLO and patient-reported outcome, radiological progression of osteoarthritis, and surgical survival, patient groups were defined: I, postoperative MPTA < 95.0°; II, postoperative MPTA ≥ 95.0°; A, MPTA change < 8.0°; B, MPTA change ≥ 8.0°. Propensity score matching was used for between-groups (I and II, A and B) covariates matching, including age, gender, preoperative lower limb alignment, preoperative medial joint space width (mJSW), preoperative Western Ontario and McMaster Universities osteoarthritis Index (WOMAC) score, wedge size, and postoperative follow-up time. Patient-reported outcome was assessed by the WOMAC questionnaire, radiological progression of osteoarthritis by mJSW and Kellgren-Lawrence (KL) grade progression (≥ 1) preoperatively and at follow-ups (> 2 years). Failure was defined as revision HTO or conversion to knee arthroplasty. After propensity score matching, groups I and II contained 58 pairs of patients and groups A and B contained 50 pairs. There were no significant differences in postoperative WOMAC score or surgical failure rate between groups I and II or between groups A and B (p > 0.05). However, the postoperative mJSW was significantly lower in group I than group II (3.2 ± 1.6 mm vs 3.9 ± 1.8 mm; p = 0.018) and in group A than group B (3.0 ± 1.7 mm vs 3.7 ± 1.5 mm; p = 0.040). KL grade progression rate was significantly higher in group I than group II (53.4% vs 29.3%; p = 0.008) and in group A than group B (56.0% vs 28.0%; p = 0.005). Increased KJLO (postoperative MPTA ≥ 95.0°) or MPTA change ≥ 8.0° after lateral closing-wedge HTO does not adversely affect patient-reported outcome, radiological progression of osteoarthritis, or surgical survival at an average 5-year follow-up. III, retrospective cohort study.


SRD5A2 gene analysis in an Italian population of under-masculinized 46,XY subjects.
The differential diagnosis of male under-masculinization, including a wide spectrum of phenotypes and a heterogeneous genetic basis, is crucial for the correct management of the patients. To characterize an Italian population of under-masculinized males, we performed the molecular analysis of the SRD5A2 gene (2p23), encoding the 5alpha-reductase-2 enzyme that converts testosterone (T) to dihydrotestosterone (DHT), and is required for full masculinization of the male foetus. Twenty-six Italian patients with 46,XY kariotype and various degrees of ambiguous genitalia were retrospectively selected for this study. Twelve of these patients, 10 of whom were referred for partial androgen insensitivity syndrome (PAIS), were raised as females; 15 were raised as males and all had a severe hypospadias. For most of the patients, the case histories and hormonal findings were incomplete but all could be included in the clinical characteristics of under-masculinization. For hormonal evaluation, T and DHT were measured by means of radioimmunoassay (RIA) and high-performance liquid chromatography (HPLC)-RIA methods, respectively. Genomic DNA of all patients and relatives was extracted from peripheral blood, the five exons of the SRD5A2 gene were amplified by polymerase chain reaction (PCR) and submitted to automatic sequencing. Five known mutations affecting the NADPH binding function and one new mutation affecting the enzyme C-terminus were identified in a total of eight patients (two of whom were sisters). Five families were characterized, and in two patients only one affected allele was observed. The extension of the analysis to the regions flanking exons allowed the identification of a new polymorphism in intron 2, whose frequency was determined. This first report of an Italian population underlines the importance of differential diagnoses in patients with under-masculinization. The lack of precise genotype-phenotype correlation in some of the mutations highlights the necessity to improve knowledge about the biochemical aspects of steroid 5alpha-reductase action and about the interactions of genetic and environmental factors.


The bead process for beta ensembles.
The bead process introduced by Boutillier is a countable interlacing of the Sine 2 point processes. We construct the bead process for general Sine β processes as an infinite dimensional Markov chain whose transition mechanism is explicitly described. We show that this process is the microscopic scaling limit in the bulk of the Hermite β corner process introduced by Gorin and Shkolnikov, generalizing the process of the minors of the Gaussian Unitary and Orthogonal Ensembles. In order to prove our results, we use bounds on the variance of the point counting of the circular and the Gaussian beta ensembles, proven in a companion paper (Najnudel and Virág in Some estimates on the point counting of the Circular and the Gaussian Beta Ensemble, 2019).


Inhibition by indomethacin of spontaneous mammary tumorigenesis in SHN mice.
This experiment was designed to examine the effects of indomethacin, a potent prostaglandin synthesis inhibitor, on spontaneous mammary tumors in mice. The growth of established mammary tumors and the appearance of new tumors in multiparous SHN mice were significantly suppressed by the subcutaneous implantation of pellets of indomethacin diluted to 1/12 with cholesterol. Furthermore, the same treatment inhibited normal and preneoplastic mammary gland growth in virgin SHN mice. The pattern of estrous cycles, ovarian structure, and plasma prolactin levels were not affected significantly by the treatment. All results have demonstrated that indomethacin inhibits mammary tumorigenesis of mice primarily by route(s) other than the endocrine system under the present experimental conditions. Indomethacin would be the first agent that appears to inhibit the growth of spontaneous mammary tumors of palpable size in mice.


The importance of water exchange rates in the design of responsive agents for MRI.
The rate of water exchange in lanthanide complexes is often overlooked as an important parameter in the design of responsive MR imaging agents. Most often, the number of inner-sphere water coordination sites or the rotational mobility of the complex is considered as the central theme while water exchange is either assumed to be "fast enough" or entirely ignored. On the contrary, relaxation and shift theories predict that water exchange rates may indeed be the key parameter one should consider in any new molecular design. In this short review, the impact of water exchange rates on three classes of lanthanide-based MRI contrast agents, T₁-based relaxation agents, T₂ exchange line-broadening agents and chemical exchange saturation transfer (CEST) agents, is illustrated and discussed.


[A case of congenital hepatic fibrosis presented with symptom of acute cholangitis].
Congenital hepatic fibrosis (CHF) is an autosomal recessive disease, presenting principally in children or young adults with portal hypertension, and infrequently associated with cholangitis. It is associated with renal malformation and Caroli's disease. The diagnosis of CHF is usually confirmed by its typical histological features. Cholangitis is a severe and frequently fatal complication. We report a 22-year-old man with congenital hepatic fibrosis who showed the cholangitis without radiological features of cystic dilatation or stone of intrahepatic ducts.


Endocavitary (laparoscopic) pelvic lymphadenectomy with specific indications in urologic surgery.
Recent reports have established the feasibility and minimal morbidity of laparoscopic pelvic lymph node dissection in the staging of prostate and bladder cancer. In addition, a prospective study recently published established the completeness and efficacy of this form of endocavitary surgical lymphadenectomy with respect to the standard modified open procedure. The method's utility prior to definitive radiation therapy or radical perineal prostatectomy is obvious. However, clear indications of its utility in identifying men with positive nodes prior to radical retropubic prostatectomy are less clear. A description of the surgical technique as well as a review of the existing literature, and our present indications for its use are presented. In addition, possible future applications of endocavitary node dissection will be put in context.


Trophic provisioning and parental trade-offs lead to successful reproductive performance in corals after a bleaching event.
Warming ocean temperatures are severely compromising the health and resilience of coral reefs worldwide. Coral bleaching can affect coral physiology and the energy available for corals to reproduce. Mechanisms associated with reproductive allocation in corals are poorly understood, especially after a bleaching event occurs. Using isotopic labeling techniques, we traced the acquisition and allocation of carbon from adults to gametes by autotrophy and heterotrophy in previously bleached and non-bleached Montipora capitata and Porites compressa corals. Experiments revealed that both species: (1) relied only on autotrophy to allocate carbon to gametes, while heterotrophy was less relied upon as a carbon source; (2) experienced a trade-off with less carbon available for adult tissues when provisioning gametes, especially when previously bleached; and (3) used different strategies for allocating carbon to gametes. Over time, M. capitata allocated 10% more carbon to gametes despite bleaching by limiting the allocation of carbon to adult tissues, with 50-80% less carbon allocated to bleached compared to non-bleached colonies. Over the same time period, P. compressa maintained carbon allocation to adult tissues, before allocating carbon to gametes. Our study highlights the importance of autotrophy for carbon allocation from adult corals to gametes, and species-specific differences in carbon allocation depending on bleaching susceptibility.


Do we truly understand vaccine reactions and vaccinosis?
There is a crucial difference between vaccinosis and a vaccine reaction, which can have significant clinical implications. Unfortunately, in much of the discussion around vaccination, this distinction becomes blurred. A vaccine reaction, if properly managed, need have no adverse effects, but failure to recognise it and act accordingly can lead to the creation of a vaccinosis. Vaccinosis can also be established as a primary condition. The imperatives and protocols involved with vaccination vary considerably between the medical and veterinary professions, but our common homeopathic approach provides us with the means of assessing every situation from the perspective of the body's reaction, and thus to appreciate the true significance of what is happening to our patient.


Clinico-pathological correlations in Parkinson's disease.
Based on comparative clinical and morphometric studies in 45 autopsy cases of Parkinson's disease (PD), 27 clinically presenting with akinesia and rigidity (AR-type), 18 with predominant resting tremor (T-type), the neurobiological basis of the major clinical subtypes in PD is discussed. The AR-type showed higher neuronal losses in locus coeruleus (LC) and in medial and lateral parts of substantia nigra (SNM, SNL), suggesting lesion patterns different from the T-type. More severe cell loss in the serotonergic dorsal raphe nucleus was observed in PD patients with depression than in non-depressed ones. Demented PD subjects showed higher cell loss in SNM than non-demented ones indicating dysfunction of the mesocortical dopamine system, and significantly more severe Alzheimer lesions in isocortex and hippocampus. These and other recent data from the literature indicate that some major clinical features of PD are related to lesions of distinct neuronal systems.


The remote distractor effect of saccade latencies in fixation-offset and overlap conditions.
Saccadic responses to a visual target are delayed if another visual stimulus (distractor) is presented in the visual field opposite to the target (remote distractor effect). In the present study, two experiments were conducted to investigate how the remote distractor effect is modulated by the presence or absence of a central fixation stimulus. In both experiments, when a fixation stimulus was continuously presented even after target presentation, the remote distractor effect decreased. The reduction of the remote distractor effect was observed for all distractor positions examined (1.5 degrees -9.0 degrees eccentricity), and prominent especially when targets were presented at more peripheral positions (9.0 degrees and 10 degrees eccentricity). It was concluded that these results can be well explained by recent findings on inhibitory interactions among subpopulations of neurons in the superior colliculus.


Sporadic amyotrophic lateral sclerosis: two pathological patterns shown by analysis of distribution of TDP-43-immunoreactive neuronal and glial cytoplasmic inclusions.
A nuclear protein, 43-kDa TAR DNA-binding protein (TDP-43), was recently identified as a component of the ubiquitinated inclusions (UIs) in frontotemporal lobar degeneration (FTLD-U) and sporadic amyotrophic lateral sclerosis (SALS). In the present study using immunohistochemistry, we examined various regions of the nervous system in a series of 35 SALS cases using a polyclonal antibody against TDP-43. Seven of the 35 cases had disease durations of more than 10 years with artificial respiratory support (ARS; duration: 69-156 months). In all cases, TDP-43-immunoreactive (ir) neuronal and glial cytoplasmic inclusions (NCIs and GCIs) were found together in many regions, including the histologically affected lower motor neuron nuclei. Cluster analysis of the distribution pattern of TDP-43-ir NCIs for cases without ARS (n = 28) identified two types (type 1, n = 16; type 2, n = 12). Type 2 was distinguished from type 1 by the presence of TDP-43-ir NCIs in the frontotemporal cortex, hippocampal formation, neostriatum and substantia nigra, and was significantly associated with dementia. Eleven of the 28 cases showed UIs in the hippocampal dentate granule cells, all of which had type-2 distribution pattern. Cases with ARS (n = 7) were also classified into the same types (type 1, n = 5; type 2, n = 2). Cases having type-1 distribution pattern (n = 21) showed no evident neuronal loss in most of the non-motor neuron nuclei where TDP-43-ir NCIs were present, whereas cases having type-2 distribution pattern (n = 14) often showed evident neuronal loss in the frontotemporal cortices, amygdaloid nuclei and substantia nigra. These findings indicate that SALS is a multisystem degenerative disease widely affecting both neurons and glial cells with a heterogeneous pattern of TDP-43-ir NCI distribution (SALS showing type-2 distribution pattern being closely linked to FTLD-U), and that long-term survival supported by a respirator has no apparent influence on the TDP-43 neuronal distribution pattern.


Characterization of the L1NH repeat family of Novikoff hepatoma.
Long interspersed repeated sequences of the Novikoff hepatoma rat tumour cell genome were cloned and studied. No basic differences were found when the genomic organization of the Novikoff hepatoma was compared with that of other mammalian L1 families. The nucleotide sequence of the central approximately 4 kb (1 kb = 10(3) bases) part of the Novikoff hepatoma LINE (L1NH) appeared to be more highly conserved than the sequences found at the 5' and 3' ends. Moreover, the central approximately 4 kb core fragments were not always associated with the same end sequences. Thus, the occurrence of the more-conserved and more-abundant central portion in L1NH suggest that: (1) besides reverse transcription, other DNA- and/or RNA-mediated mechanisms might be involved in the dispersal of LINE families; and that (2) L1 sequences can sometimes consist of a compound unit made up of members of different L1 subunits and sequences with different genomic copy numbers.


How to ensure the survival of the surgeon-scientist? The Homburg Program.
Academic surgery requires competence in research, teaching, and patient care. Because of the increasing complexity of both surgical research and clinical surgery, and additional skills necessary for adequate patient care, including economics, management, and organization, it becomes more and more difficult to provide an attractive education for surgeon-scientists. This has resulted in a dramatic decline in the number of surgeon-scientists in the past and alarms us to systematically restructure our research training system. We herein introduce a program involving the clinical departments of surgery, trauma surgery, and cardiac-thoracic surgery as well as a surgical research institution. The program allows the clinical departments to sharpen their overall research profile and facilitates the establishment of competent working groups, guaranteeing long-term research activities on a high scientific level. The program involves both surgical residents and medical students, who will represent our future generation of academic surgeons, ensuring the survival of the surgeon-scientist.


Primary and secondary measurements of 222Rn.
In the past few years, a primary measurement system has been established at the PTB allowing absolute measurements of 222Rn. The activity can be determined by counting the emitted alpha particles in a defined solid angle after condensing the radon at a cold point under vacuum conditions. This primary measurement system is connected to a solid 226Ra source, where 222Rn can be produced up to an activity of about 2MBq. After the measurement, radon can be completely transferred into a glass bulb or a stainless steel cylinder for use as a transfer standard. The results of the measurements, the uncertainties and the realization of the primary measurement system are described. For quality assurance and fast determination of radon activity, a secondary measurement system with an NaI(Tl) detector is also used. Together, both systems provide a reliable tool for the production of gaseous 222Rn activity standards with relative uncertainties of less than 1%.


Primary immune effects of eukaryotic expression plasmids encoding two hyperactive mutants of human soluble B lymphocyte stimulator.
B lymphocyte stimulator (BLyS), a ligand belonging to the tumor necrosis factor (TNF) family, plays a critical role in regulating survival and activation of peripheral B cell populations during humeral immune responses. Among the TNF family members, BLyS is unique in that it contains an unpaired Cys residue (Cys146) at the corresponding position where some other members have about 37.5% (6/16) Ala or 37.5% (6/16) Val. Here, with eukaryotic expression vector pcDNA3.1(-), we mutated Cys146 to Ala or Val and constructed two mutant eukaryotic expression plasmids of the human soluble BLyS, pcDNA3.1BY-A and pcDNA3.1BY-V. Following repetitive subcutaneous injection of these expression plasmids in BALb/C mice, the wild-type and mutant BLyS proteins were detectable in the blood of treated animals over several weeks. In addition, the expression of these proteins induced specific IgG but not IgM responses. The implications of the results are discussed.


A standardized boundary element method volume conductor model.
We used a 3-compartment boundary element method (BEM) model from an averaged magnetic resonance image (MRI) data set (Montreal Neurological Institute) in order to provide simple access to realistically shaped volume conductor models for source reconstruction, as compared to individually derived models. The electrode positions were transformed into the model's coordinate system, and the best fit dipole results were transformed back to the original coordinate system. The localization accuracy of the new approach was tested in a comparison with simulated data and with individual BEM models of epileptic spike data from several patients. The standard BEM model consisted of a total of 4770 nodes, which describe the smoothed cortical envelope, the outside of the skull, and the outside of the skin. The electrode positions were transformed to the model coordinate system by using 3-5 fiducials (nasion, left and right preauricular points, vertex, and inion). The transformation consisted of an averaged scaling factor and a rigid transformation (translation and rotation). The potential values at the transformed electrode positions were calculated by linear interpolation from the stored transfer matrix of the outer BEM compartment triangle net. After source reconstruction the best fit dipole results were transformed back into the original coordinate system by applying the inverse of the first transformation matrix. Test-dipoles at random locations and with random orientations inside of a highly refined reference BEM model were used to simulate noise-free data. Source reconstruction results using a spherical and the standardized BEM volume conductor model were compared to the known dipole positions. Spherical head models resulted in mislocation errors at the base of the brain. The standardized BEM model was applied to averaged and unaveraged epileptic spike data from 7 patients. Source reconstruction results were compared to those achieved by 3 spherical shell models and individual BEM models derived from the individual MRI data sets. Similar errors to that evident with simulations were noted with spherical head models. Standardized and individualized BEM models were comparable. This new approach to head modeling performed significantly better than a simple spherical shell approximation, especially in basal brain areas, including the temporal lobe. By using a standardized head for the BEM setup, it offered an easier and faster access to realistically shaped volume conductor models as compared to deriving specific models from individual 3-dimensional MRI data.


Binding of transcription factor TFIID to the major late promoter during in vitro nucleosome assembly potentiates subsequent initiation by RNA polymerase II.
A plasmid containing the major late promoter was assembled into nucleosomes in a Xenopus oocyte extract, isolated by gel filtration, and found to be refractory to transcription initiation in vitro. However, exposure of the promoter to HeLa nuclear extract or to a mixture of isolated transcription factors prior to nucleosome assembly prevented nucleosome-mediated repression of the promoter. Inactivation or elimination of the TATA box-binding factor (TFIID) abolished the ability of these treatments to preserve promoter function. Preincubation with TFIID alone prevented repression and resulted in TFIID being sequestered into the nucleosome-assembled templates. Preincubation with all the transcription factors resulted in the assembly of nucleosome templates containing a near complete preinitiation complex, which required only the addition of TFIIE for transcription initiation.


Dissociation of self-reported and observed pleasure in depression.
Anhedonia, or the inability to experience pleasure, is an important component of depressive symptomatology. Observer ratings of positive affect and self-ratings of pleasurable experience were collected from ten depressed inpatients and ten ward staff members during the patients' base-line, medication-free period. Depressives were observed to display significantly lower degrees of positive affect than the normal group, but they reported significantly higher degrees of experienced pleasure. The normal group displayed positive affective behavior that was consistent with self-reported data. Thus, normal subjects showed synchronous, or associated self-reported and observed activity, whereas depressives appeared to be dissociated along those same dimensions. A dissociation also appeared in self-reports of positive versus negative mood states, suggesting the existence of a malfunction in these normally inhibitory affective mechanisms.


MtDNA and Y-chromosomal diversity in the Chachapoya, a population from the northeast Peruvian Andes-Amazon divide.
The ancient Chachapoya were an aggregate of several ethnic groups that shared a common language, religion, and material culture. They inhabited a territory at the juncture of the Andes and the Amazon basin. Their position between those ecozones most likely influenced their genetic composition. We attempted to better understand their population history by assessing the contemporary genetic diversity in the Chachapoya and three of their immediate neighbors (Huancas, Jivaro, and Cajamarca). We inferred signatures of demographic history and genetic affinities, and contrasted the findings with data from other populations on local and continental scales. We studied mitochondrial DNA (mtDNA; hypervariable segment [HVSI and HVSII]) and Y chromosome (23 short tandem repeats (STRs)) marker data in 382 modern individuals. We used Sanger sequencing for mtDNA and a commercially available kit for Y-chromosomal STR typing. The Chachapoya had affinities with various populations of Andean and Amazonian origin. When examining the Native American component, the Chachapoya displayed high levels of genetic diversity. Together with other parameters, for example, large Tajima's D and Fu's Fs, the data indicated no drastic reduction of the population size in the past. The high level of diversity in the Chachapoya, the lack of evidence of drift in the past, and genetic affinities with a broad range of populations in the Americas reflects an intricate population history in the region. The new genetic data from the Chachapoya indeed seems to point to a genetic complexity that is not yet resolved but beginning to be elucidated. Am. J. Hum. Biol. 28:857-867, 2016. © 2016Wiley Periodicals, Inc.


Interventional treatment of hepatic arterial and venous pathology: a commentary.
Hepatic aneurysms, pseudoaneurysms and fistulas (arterial biliary and arterial portal) causing bleeding or portal hypertension, and arteriovenous malformations causing high output cardiac failure in adults can be successfully managed by embolization techniques. Results of embolization in infantile hemangioendotheliomas are less uniform and tumors with massive arteriovenous shunting are difficult to manage. Transjugular intrahepatic portal systemic shunts using expendable stents have been successfully created in patients and have effectively controlled portal hypertension and variceal bleeding.


A comparison of developmental changes in surface charge in mouse blastocysts and uterine epithelium using DEAE beads and dextran sulfate in vitro.
The ability of 3.5-day mouse blastocysts and vesicles prepared from maternal uterine epithelium to adhere to surfaces by charge interactions was compared by observing their adhesion to DEAE-Sephadex beads in the presence of increasing concentrations of dextran sulfate. The adhesion frequency for both the blastocysts and epithelium declined in a manner suggesting that predominantly ionic sites were being titrated, but differences between the two tissues in characteristics of the titration curve and susceptibility to neuraminidase digestion indicated that nonionic interactions were relatively more important for blastocysts. Because the threshold concentration of dextran sulfate required to initiate displacement of uterine epithelium from the DEAE beads was at least 4X that required to initiate the displacement of blastocysts, we argue that the uterine epithelium had at least 4X more interactive charged groups on its surface than the blastocysts. These differences were even more pronounced 4.5 days after mating, a time when attachment to the uterine epithelium is normally first seen in vivo. Blastocysts isolated at this time showed a marked increase in resistance to polyanion competition, but the epithelium showed a nearly 50% decline in surface negative charge that was not compensated by nonionic mechanisms. These observations support the conclusion that the initial adhesion of blastocysts in vivo is accompanied by a reduction in negativity of the uterine epithelial surface and by the formation of new trophoblast cell surfaces that adhere by nonelectrostatic interactions.


Next-generation deep learning based on simulators and synthetic data.
Deep learning (DL) is being successfully applied across multiple domains, yet these models learn in a most artificial way: they require large quantities of labeled data to grasp even simple concepts. Thus, the main bottleneck is often access to supervised data. Here, we highlight a trend in a potential solution to this challenge: synthetic data. Synthetic data are becoming accessible due to progress in rendering pipelines, generative adversarial models, and fusion models. Moreover, advancements in domain adaptation techniques help close the statistical gap between synthetic and real data. Paradoxically, this artificial solution is also likely to enable more natural learning, as seen in biological systems, including continual, multimodal, and embodied learning. Complementary to this, simulators and deep neural networks (DNNs) will also have a critical role in providing insight into the cognitive and neural functioning of biological systems. We also review the strengths of, and opportunities and novel challenges associated with, synthetic data.


Intraoperative factors and the risk of respiratory complications after pneumonectomy.
The potential effect of intraoperative factors on respiratory complications after pneumonectomy is still unclear. We conducted a retrospective cohort study; charts of 129 patients who underwent elective pneumonectomy at the University of Virginia were reviewed. Logistic regression was used to estimate the effect of anesthetic factors on the odds of at least one respiratory complication. Linear regression models were fit to assess the impact of these outcomes on length of stay (LOS). The incidence of respiratory complications in this cohort was 21%. In univariate analysis total nonblood fluids (p = 0.001), and the blood products packed red blood cells (p < 0.001), plasma (p < 0.001), and platelets (p = 0.044) were significantly associated with respiratory complications. In a multivariable logistic regression analysis, single unit transfusion of any blood product (packed red blood cells, plasma, or platelets) was identified as a major risk factor for respiratory complications after controlling for covariates (odds ratio = 1.47, 95% confidence interval 1.06 to 2.05). Respiratory failure and complications were closely related to LOS, increasing the LOS by a factor of 4.7 (95% confidence interval 3.51 to 6.18) and 3.5 (95% confidence interval 2.69 to 4.41), respectively. Blood product transfusion affects respiratory function and is an independent risk factor for respiratory complications after pneumonectomy.


Forkhead box O1 promotes INS‑1 cell apoptosis by reducing the expression of CD24.
Type 2 diabetes seriously affects human health and burdens public health systems. Pancreatic β‑cell apoptosis contributes to a reduction in β‑cell mass, which is responsible for the occurrence of type 2 diabetes. However, the mechanism that underlies this effect remains unclear. In the present study, the role of forkhead box O1 (Foxo1) was investigated (which is a key regulatory factor in β‑cell function) in the apoptotic behavior of β‑cells and a potential underlying mechanism was determined. It was demonstrated that Foxo1 overexpression significantly reduced the proliferation of INS‑1 cells and increased the apoptosis of INS‑1 cells, in contrast to foxm1, foxp, foxa1, foxc and foxb1 overexpression. The present study aimed to investigate potential underlying mechanisms using bioinformatics, including Gene Set Enrichment Analysis, and biological experiments, including flow cytometry, cell counting kit‑8, immunofluorescence, western blotting, reverse transcription‑quantitative polymerase chain reaction analysis and lentiviral transfection. Further experiments conclusively showed that cluster of differentiation (CD)24 expression was significantly decreased when INS‑1 cells were treated with Foxo1. Animal experiments showed high CD24 expression in the pancreatic islets of diabetic Goto‑Kakizaki rats. Moreover, Gene Set Enrichment Analysis showed that CD24 expression was associated with the adaptive immune response of β‑cells. Finally, no significant differences in the proliferation and apoptosis of CD24 overexpressing INS‑1 cells were observed after Foxo1 treatment. These results suggested that Foxo1 overexpression in β‑cells was able to increase apoptosis by inhibiting CD24 expression. This study may provide an approach for the treatment and prevention of type 2 diabetes.


Are astroglial cells involved in morphine tolerance?
Morphine gives rise to a cascade of events in the nervous system affecting, among others, neurotransmitter metabolism. Tolerance develops for various effects shortly after administration of the drug. Also, physical dependence develops and can be demonstrated by precipitation of withdrawal reactions. Biochemical events in nervous tissue have been extensively studied during morphine treatment. This overview will focus upon brain protein metabolism since macromolecular events might be of importance for development of long-term effects, such as tolerance and physical dependence. Both dose- and time-dependent changes in brain protein synthesis and the syntheses of specific proteins have been demonstrated after morphine treatment, although methodological considerations are important. Different experimental models (animal and tissue culture models) are presented. It might be interesting to note that astroglial protein synthesis and the secretion of proteins to the extracellular medium are both changed after morphine treatment, these having been evaluated in astroglial enriched primary cultures and in brain tissue slices. The possibility is suggested that proteins released from astroglial cells participate in the communication with other cells, including via synaptic regions, and that such communication might of significance in modifying the synaptic membranes during morphine intoxication.


A comparative study of oxygen consumption for conventional and energy-storing prosthetic feet in transfemoral amputees.
To compare oxygen consumption for traumatic high-functioning transfemoral amputees wearing initially a conventional prosthetic foot (Multiflex) and then an energy-storing prosthetic foot (Vari-Flex). A regional prosthetic and amputee rehabilitation tertiary referral centre in a teaching hospital. Experimental crossover trial. Six established unilateral transfemoral prosthetic users. Oxygen consumption breath-by-breath analysis at multiple speeds on a treadmill for each amputee wearing initially the Multiflex foot and then repeated wearing the Vari-Flex foot. Mean oxygen consumption across all subjects was lower for the Vari-Flex foot than for the Multiflex foot at all speeds, although the differences were only significant at speeds of 0.83 and 1.1 m/s (P < 0.05). ANCOVA analysis across all speeds showed that oxygen consumption with the Vari-Flex foot was significantly lower (P < 0.001). The estimated difference across all speeds was 3.54 mL/kg.min. A high functioning transfemoral amputee who wears an energy-storing prosthetic foot may have significantly reduced oxygen consumption at normal walking speeds.


A highly bone marrow metastatic murine breast cancer model established through in vivo selection exhibits enhanced anchorage-independent growth and cell migration mediated by ICAM-1.
To understand the mechanisms underlying bone marrow metastasis precisely, we established the highly metastatic 4T1E/M3 murine breast cancer cell line. 4T1 murine breast cancer cells were transfected with the neomycin resistance gene, selected in G418, intravenously injected into mice, and harvested from bone marrow. By repeating this protocol three times, we established the 4T1E/M3 cells. The clonality of 4T1E/M3 cells was markedly high confirmed by genomic southern analysis using neo-gene probe. When tissues harvested from mice after intravenous injection of 4T1E/M3 cells were examined histologically, markedly enhanced bone marrow metastasis was observed; 77% of spines from 4T1E/M3-injected mouse showed metastasis as compared to 14% metastasis seen with the parent cells. In vitro, 4T1E/M3 cells attached more strongly to the plastic plate and to bone marrow-derived endothelial cells. DNA micro arrays, real time RT-PCR and FACS analyses revealed that the expression of ICAM-1 and beta2 integrin was upregulated in 4T1E/M3 cells at both the mRNA and cell surface protein levels. 4T1E/M3 cells also showed greater anchorage-independent proliferation in soft agar, and migrated markedly faster than the parent cells in wound healing assays. Anti-ICAM-1 antibodies strongly inhibited both the colony formation and the migration activity of 4T1E/M3 suggesting the importance of the role of ICAM-1. Our newly established highly metastatic 4T1E/M3 cells may provide a potentially powerful tool to study the molecular mechanisms of bone marrow metastasis and to identify new molecular targets for therapeutic interventions.


Patterns of spatial distortions in human amblyopia are invariant to stimulus duration and instruction modality.
We investigated the patterns of two-dimensional spatial distortions in human amblyopia, using three different psychophysical mapping procedures. Strabismic and strabismic-anisometropic amblyopes showed consistent distortions, consisting in enlargement, shrinkage, or torsion of portions of the tested visual field. Purely anisometropic amblyopes and strabismics with alternating fixation showed increased spatial uncertainty, but no consistent distortions. For all groups of subjects, there was a very good correspondence between the patterns of distortion obtained with the three methods. We conclude that the spatial distortions are robust across different procedures. They might reflect a genuine rearrangement of the cortical topography as a result of strabismus.


31P magnetization transfer studies of creatine kinase kinetics in living rabbit brain.
The kinetics of the CK reaction in the living rabbit brain was studied by three 31P magnetization transfer methods: inversion recovery (IR), inversion transfer (IT), and steady-state saturation transfer (SSST). Longitudinal relaxation rates (tau -1) were determined from IR and IT experiments. The values were 0.88 +/- 0.08 s-1 for PCr and 2.45 +/- 0.39 s-1 for gamma-ATP. Analysis of the results of SSST experiments in which gamma-ATP was saturated yielded a forward rate constant kF of 0.53 +/- 0.07 s-1. Upon saturation of PCr no change in the gamma-ATP signal could be detected in SSST. An average reverse rate constant (kR +/- S.D.) of 0.52 +/- 0.04 s-1 was estimated by analyzing IT data from three experiments with selective inversion of gamma-ATP. The standard error of kR was 50%. The average [PCr]/[ATP] of 1.21 +/- 0.16 together with the values of kF and kR yielded a forward-to-reverse flux ratio of 1.23. Within our limits of accuracy this ratio was not significantly different from 1.0, thus suggesting that in the brain the forward and reverse CK fluxes are equal.


Characteristics of facial nerve palsy in 112 children and risk factors for ocular complications.
To report the ophthalmic findings and ocular complications in a large cohort of pediatric patients with facial nerve palsy (FNP). Ocular data of children (≤16 years of age) diagnosed with FNP presenting to an eye care network from 2012 to 2021 were analyzed. Study parameters were etiology of FNP, ocular and imaging findings, degree of lagophthalmos, and degree of vision loss. Clinical characteristics were compared between those with and without moderate-to-severe vision impairment (best-corrected visual acuity <20/50) and those with and without exposure keratopathy at presentation. A total of 112 patients were included. Mean age at presentation was 8.3 ± 5.0 years. The most common etiology was idiopathic (57%) followed by congenital (22.3%) and traumatic (13.4%). There was bilateral involvement in 8% of children, multiple cranial nerve involvement in 15.2%, and exposure keratopathy at presentation in 38.4%. One-fifth (20.5%) of children (29.6% of affected eyes with known visual acuity) had moderate-to-severe visual impairment. Multiple cranial nerve involvement was present in 31% of eyes with visual impairment compared with 14% of those without. Corneal scarring and strabismic amblyopia were both frequent causes of visual impairment. Most children with exposure keratopathy had lagophthalmos (76.6%), whereas it was less common in those without keratopathy (49.2%). Pediatric FNP was most commonly idiopathic, secondarily congenital. Strabismic amblyopia and corneal scarring were the most common causes of visual impairment in our cohort.


European Association for the Study of Diabetes 2019 Conference: Podcast Overview of the Conference.
Podcast recording of Editorial Board Members Uazman Alam and Shazli Azmi live from the EASD 2019 conference in Barcelona (MP4 377292 kb).


Transcriptional silencing of hedgehog-interacting protein by CpG hypermethylation and chromatic structure in human gastrointestinal cancer.
Hedgehog-interacting protein (HHIP) was identified as a putative antagonist of the Hh pathway and as a target of Hh signalling. Our aim was to clarify the expression profiles and epigenetic alterations of the HHIP gene in gastrointestinal cancer. The expression and promoter epigenetic status of HHIP in cancer cell lines and freshly resected gastrointestinal cancer tissues were examined using RT-PCR, tissue microarray analysis, methylation-specific PCR, and chromatin immunoprecipitation assay. Cells were treated with the demethylating agent 5-aza-2'-deoxycytidine and/or histone deacetylase inhibitor trichostatin A. WST-8 assays and in vitro invasion assays after treatment with HHIP-specific siRNA were performed. HHIP expression levels were reduced in most of the gastrointestinal cancer cell lines and in a certain subset of cancer tissues, and these were correlated with promoter hypermethylation. A heterochromatic structure characterized by neither acetylated H3 nor acetylated H4, and histone H3 lysine 9 hypermethylation and histone H3 lysine 4 hypomethylation was observed in cancer cells in which the HHIP gene was aberrantly silenced. On the other hand, overexpression of the HHIP gene was also found in some cancer tissues and there were significant correlations between protein expression levels of HHIP and those of Sonic hedgehog (Shh), Indian hedgehog, Patched, and glioma-associated oncogene homologue-1. An association was found between lymph node metastasis and HHIP silencing in colorectal cancer tissues with strong Shh expression and between advanced TNM stage and HHIP silencing in diffuse-type gastric cancer tissues with strong Shh expression. Down-regulation of HHIP expression by siRNA resulted in a significant increase in colon cancer cell growth and invasion in vitro. Silencing of the HHIP gene due to hypermethylation and chromatin remodelling appears to be frequently involved in gastrointestinal tumourigenesis.


Computational assessment on the impact of collagen fiber orientation in cartilages on healthy and arthritic knee kinetics/kinematics.
The inhomogeneous distribution of collagen fiber in cartilage can substantially influence the knee kinematics. This becomes vital for understanding the mechanical response of soft tissues, and cartilage deterioration including osteoarthritis (OA). Though the conventional computational models consider geometrical heterogeneity along with fiber reinforcements in the cartilage model as material heterogeneity, the influence of fiber orientation on knee kinetics and kinematics is not fully explored. This work examines how the collagen fiber orientation in the cartilage affects the healthy (intact knee) and arthritic knee response over multiple gait activities like running and walking. A 3D finite element knee joint model is used to compute the articular cartilage response during the gait cycle. A fiber-reinforced porous hyper elastic (FRPHE) material is used to model the soft tissue. A split-line pattern is used to implement the fiber orientation in femoral and tibial cartilage. Four distinct intact cartilage models and three OA models are simulated to assess the impact of the orientation of collagen fibers in a depth wise direction. The cartilage models with fibers oriented in parallel, perpendicular, and inclined to the articular surface are investigated for multiple knee kinematics and kinetics. The comparison of models with fiber orientation parallel to articulating surface for walking and running gait has the highest elastic stress and fluid pressure compared with inclined and perpendicular fiber-oriented models. Also, the maximum contact pressure is observed to be higher in the case of intact models during the walking cycle than for OA models. In contrast, the maximum contact pressure is higher during running in OA models than in intact models. Additionally, parallel-oriented models produce higher maximum stresses and fluid pressure for walking and running gait than proximal-distal-oriented models. Interestingly, during the walking cycle, the maximum contact pressure with intact models is approximately three times higher than on OA models. In contrast, the OA models exhibit higher contact pressure during the running cycle. Overall, the study indicates that collagen orientation is crucial for tissue responsiveness. This investigation provides insights into the development of tailored implants.


Clearance of hepatitis B virus DNA and pre-S surface antigens in patients with markers of acute viral replication.
To clarify the relationship between the pre-S antigens and other serological markers of hepatitis B virus (HBV) replication, we followed up 27 patients: 21 presented with symptoms of acute hepatitis (two progressed to chronicity) and six suffered from chronic hepatitis. Pre-S1, pre-S2, HBV DNA, IgM antihepatitis core antigen (HBc), hepatitis B e antigen (HBeAg), and anti-HBe were detected in about 200 sera serially collected at different times for at least 6-12 months from the onset of clinical observation. In the early symptomatic phase of acute hepatitis, the pre-S1 and pre-S2 antigens were present in 95% of the cases and correlated well with high levels of alanine-transferase (ALT) and IgM anti-HBc, while HBV DNA was present in the sera of only six (28.6%) patients (P less than 0.0001). This was the first marker to disappear (1 month after the initial stage). All of the HBV DNA-positive patients were also HBeAg positive, whereas no HBeAg-negative subjects were found with serum HBV DNA. In the six chronic patients, pre-S antigens were always present independently of the HBeAg/anti-HBe status; HBV DNA was detected in three of them, even if transiently, and in two of these it reappeared together with pre-S2 epitope. The follow-up data suggest that, in acute hepatitis, the clearance of pre-S antigens can be considered as a prognostic index of clinical resolution and that, in chronic hepatitis, the persistence of pre-S antigens seems to indicate progression of the disease. In particular, pre-S2, in patients in whom it is intermittent, can be considered as an index of reactivation.


Two subtypes of nucleoproteins (NP) of influenza A viruses.
The nucleoprotein (NP) genes of nine influenza A virus strains isolated from different species have been sequenced and the deduced amino acid sequences have been compared to published NP sequences and sequences in press. Two "subtypes" of NPs can clearly be defined, one "subtype" comprises the NPs found with all tested human and one porcine strain, and another "subtype" comprises the NPs found with all tested avian and equine, and some porcine strains and a mink virus. There are no significant differences between these two groups concerning secondary structure predictions. Pig viruses were the only ones whose NP can belong to the one or the other "subtype." Therefore, pigs can be regarded as "mixing vessels," where the two independently evolving reservoirs of influenza A viruses can meet for the creation of new pandemic strains by reassortment.