The combination of chemotherapy with HVJ-E containing Rad51 siRNA elicited diverse anti-tumor effects and synergistically suppressed melanoma.
Dacarbazine (DTIC) is one of the most popular alkylating agents used for the treatment of malignant melanoma. DTIC induces apoptosis of melanoma cells via double-strand breaks (DSBs). Melanoma cells, however, tend to increase their expression of DNA repair molecules in order to be resistant to DTIC. Here, we show that DTIC increases expression of Rad51, but not Ku70, in a cultured B16-F10 mouse melanoma cell line in dose- and time-dependent manners. On introducing Rad51 short interfering RNA (siRNA) with the hemagglutinating virus of Japan envelope (HVJ-E) to B16-F10 cells, DSBs induced by DTIC treatment were not efficiently repaired and resulted in enhanced apoptotic cell death. Colony formation of B16-F10 cells that received Rad51 siRNA was significantly decreased by DTIC treatment as compared with cells that received scramble siRNA. In melanoma-bearing mice, the combination of three intratumoral injections of HVJ-E containing Rad51 siRNA and five intraperitoneal injections of DTIC at a clinical dose synergistically suppressed the tumors. Moreover, HVJ-E demonstrated anti-tumor immunity by inducing cytotoxic T lymphocytes to B16-F10 cells on administration of DTIC. These results suggest that the combination of chemotherapy with HVJ-E containing therapeutic molecules will provide a promising therapeutic strategy for patients bearing malignant tumors resistant to chemotherapeutic agents.


The effect of enkephalin dimers on body temperature in mice.
Short-lasting decrease in rectal temperature in mice after intraperitoneal administration of an enkephalin dimer, the so called double-enkephalin--(Tyr-D-Ala-Gly-Phe-NH)2 (D-ENK-O)--at dose 0.1, 0.5, 1, 2.5, 5, 10 and 20 mg/kg of body weight was observed. Another double-enkephalin--Tyr-D-Ala-Gly-Phe-NH-(CH2)3-HN-Phe-Gly-D-Ala-Tyr-- fai led to produce this effect. The hypothermic effect of D-ENK-O was almost completely reduced by naloxone which suggests an involvement of opiate receptors in the D-ENK-O produced hypothermia in mice.


Attention-deficit/hyperactivity disorder, methylphenidate use and the risk of developing schizophrenia spectrum disorders: A nationwide population-based study in Taiwan.
This study estimated the risk of developing psychotic disorders by comparing children with ADHD to non-ADHD controls, and to examine whether methylphenidate (MPH) treatment influences the risks of psychotic disorders. A nationwide cohort of patients who were newly diagnosed with ADHD (n=73,049) and age- and gender-matched controls (n=73,049) were selected from Taiwan's National Health Insurance database from January 2000 to December 2011. All participants were observed until December 31, 2011. Cox regression models were used to estimate the effects of ADHD diagnosis and MPH use on subsequent outcomes. Having a diagnosis of any psychotic disorder and of schizophrenia were set as two different outcomes and were analyzed separately. Compared to the control group, the ADHD group showed significantly increased risk of developing any psychotic disorder (adjusted hazard ratio [aHR], 5.20; 95% confidence interval [CI], 4.30-6.30) and schizophrenia (aHR, 4.65; 95% CI, 3.59-6.04). Compared to ADHD patients without psychosis, patients with ADHD who developed psychosis had significantly older age at first diagnosis of ADHD (9.4±3.3years vs. 10.6±4.0years). Among patients with ADHD, MPH use significantly increased the risk of developing any psychotic disorder (aHR, 1.20; 95% CI, 1.04-1.40), but did not increase the risk of developing schizophrenia (aHR, 1.16; 95% CI, 0.94-1.42). The results indicated that previous diagnoses of ADHD are a powerful indicator of developing psychotic disorders. Nevertheless, the specific mechanisms of the relationships between ADHD, MPH use and psychotic disorders need further elucidation in future clinical studies.


CCGN: Centralized collaborative graphical transformer multi-agent reinforcement learning for multi-intersection signal free-corridor.
Tackling traffic signal control through multi-agent reinforcement learning is a widely-employed approach. However, current state-of-the-art models have drawbacks: intersections optimize their own local rewards and cause traffic to waste time and fuel with a start-stop mode at each intersection. They also lack information sharing among intersections and their specialized policy hinders the ability to adapt to new traffic scenarios. To overcome these limitations, This work presents a centralized collaborative graph network (CCGN) with the core objective of a signal-free corridor once the traffic flows have waited at the entry intersection of the traffic intersection network on either side, the subsequent intersection gives the open signal as the traffic flows arrive. CCGN combines local policy networks (LPN) and global policy networks, where LPN employed at each intersection predicts actions based on Transformer and Graph Convolutional Network (GCN). In contrast, GPN is based on GCN and Q-network that receives the LPN states, traffic flow and road information to manage intersections to provide a signal-free corridor. We developed the Deep Graph Convolution Q-Network (DGCQ) by combining Deep Q-Network (DQN) and GCN to achieve a signal-free corridor. DGCQ leverages GCN's intersection collaboration and DQN's information aggregation for traffic control decisions Proposed CCGN model is trained on the robust synthetic traffic network and evaluated on the real-world traffic networks that outperform the other state-of-the-art models.


Glyoxylate cycle enzymes are present in liver peroxisomes of alloxan-treated rats.
Key enzymes of the glyoxylate cycle, isocitrate lyase (ICL) and malate synthase (MS), have been detected in the liver of alloxan-treated rats. The activity of ICL in rat liver was 0.040 micromol/min/mg protein and the activity of MS was 0.022 micromol/min/mg protein. These enzymes were associated with the peroxisomal fraction. The activities of citrate synthase, malate synthase and malate dehydrogenase detected in the peroxisomal fraction were also increased by alloxan treatment. Isocitrate lyase was partially purified and displayed catalytic and regulatory properties similar to those of the enzyme isolated from the liver of starved rats (Popov, V.N. et al. (1996) FEBS Lett. 391, 87-90).


Species difference in the effects of proteolytic enzymes on red cell membrane.
Pronase and alpha-chymotrypsin digested the major glycoprotein in the human and mouse red cell membranes and in SDS gel electrophoresis the glycoprotein disappeared accompanied by the appearance of a new band of lower mol. wt. However in the membranes of sheep, rat and rabbit, no digestion was demonstrated. The effects of pronase on anion permeability were almost identical for human and animal erythrocytes.


Complementary and alternative medicine for treating amyotrophic lateral sclerosis: A narrative review.
Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that is characterized by selective motor neuron cell death in the motor cortex, brainstem, and spinal cord. Two drugs for ALS, riluzole and edaravone, have been approved by FDA for the treatment of ALS patients. However, they have many side effects, and riluzole extends the patient's life by only 2-3 months. Therefore, ALS patients seek an effective therapy for treating the symptoms or delaying the progression of ALS. Based on this, we review the effects of complementary and alternative medicine (CAM) in ALS animals or patients to verify the efficacy of CAM in incurable diseases. For this review, we searched published papers focusing on the effect of CAM in pre-clinical and clinical study in ALS. The search keywords included amyotrophic lateral sclerosis, acupuncture, herbal medicine, Traditional Chinese medicine, CAM, animals, and clinical study through electronic databases PubMed and Google Scholar from their inception until March 2019. In the ALS animal model, CAM modulated the immune system to increase motor function by reducing the expression levels of neuroinflammatory proteins in the spinal cord. Besides this, ALS patients treated with herbal medicine showed improved disease symptoms, but clinical trials with larger sample sizes are needed to develop a treatment with this herbal medicine. This review shows that CAM may be useful for ALS treatment, but more evidence regarding the efficacy and molecular mechanisms is required to establish CAM as a good therapy for the treatment of ALS patients.


Polymorphisms in Genes Involved in the Leptin-Melanocortin Pathway are Associated with Obesity-Related Cardiometabolic Alterations in a Southern Chilean Population.
Polymorphisms in genes encoding proteins of the leptin-melanocortin pathway have been associated with obesity. The involvement of these polymorphisms with changes in body mass index (BMI) and anthropometric measures could also imply a contribution to the risk of metabolic syndrome (MetS) and metabolic alterations. We evaluated the relationship of leptin-melanocortin system polymorphisms with obesity, MetS, and other metabolic alterations in Southern Chilean individuals. Two-hundred individuals were grouped as normoweight (BMI 18.0-24.9 kg/m2), overweight (BMI 25.0-29.9 kg/m2), and obese (BMI ≥ 30 kg/m2) or according to MetS status. Anthropometric measures (BMI, abdominal circumference, waist-to-hip ratio [WHR]) and biochemical parameters (glycemia and lipid profile) were evaluated. Polymorphisms LEP rs7799039, LEPR rs1137101, MC3R rs3746619 and rs3827103, and MC4R rs17782313 were evaluated by real-time PCR using allelic discrimination assays. LEPR rs1137101 GG genotype was related to reduced risk of obesity (odds ratio [OR] 0.26, 95% confidence interval [CI] 0.08-0.79; p = 0.018) and MetS (OR 0.36, 95% CI 0.15-0.88; p = 0.024), but it was not significant after Bonferroni correction for multiple tests as compared to the AA genotype (p > 0.01). Moreover, LEPR rs1137101 allele G (AG + GG) was related to lower BMI and WHR (p < 0.01). Further multiple linear regression analysis demonstrated that this genotype was also responsible for reduced BMI in 2.44 kg/m2 and WHR in 0.033 units. MC4R rs17782313 allele C (TC + CC) was slightly associated with diminished risk of MetS (OR 0.48, 95% CI 0.23-0.98; p = 0.040) and reduced BMI values in 1.95 kg/m2 (p < 0.05). Regarding lipid profile, LEPR rs1137101 allele G carriers had lower triglycerides and very-low-density lipoprotein (VLDL) cholesterol, whereas individuals carrying the MC4R rs17782313 allele C had higher high-density lipoprotein (HDL) cholesterol (p < 0.01). LEP rs7799039 allele A (GA + AA) was slightly associated with reduced total and low-density lipoprotein (LDL) cholesterol (p < 0.05). These results suggest that polymorphisms at LEP, LEPR, and MC4R may be useful biomarkers of obesity-related cardiometabolic alterations in our population.


Trimming flow, plasticity, and mechanical properties by cubic silsesquioxane chemistry.
In this work, the possibility of managing the rheological and mechanical parameters of composites based on PLA with the use of cubic structures of organofunctional spherosilicates was verified. To accurately observe the effect of various organosilicon modifier substitutions on changes in composites' properties, we synthesized and used monofunctional octasubstituted derivatives as reference systems. The OSS/PLA systems were tested with concentrations of 0.1-2.5% (w/w) using extrusion to obtain a filament with a diameter of 1.75 mm. The printed samples underwent comprehensive tests including microscopic (SEM-EDS, optical microscope), rheological, thermal (TG, DSC, HDT), mechanical (impact and strength) as well as water contact angle tests. The work is interdisciplinary in nature and combines elements of organosilicon synthesis, materials engineering, and materials processing and characterization technology.


Expression of the novel murine homeobox gene Sax-1 in the developing nervous system.
We have isolated the novel murine Sax-1 gene, a member of the NK-1 class of homeobox genes, and report its expression pattern in the developing central nervous system (CNS) in comparison to two other homeobox genes, Evx-1 and Pax-6. Sax-1 was found to be transiently expressed in the developing posterior CNS. First seen in the ectoderm lateral to the primitive streak, the signal later encompassed the neural plate. Posteriorly, the expression domain overlapped with the Evx-1 expression in the streak, while anteriorly it was delimited by the Pax-6 signal in the neural tube. This early phase starting at day 9.5 pc, Sax-1 was expressed in distinct areas of spinal cord, hindbrain and forebrain. Particularly strong signals were detected in rhombomere 1 and in the pretectum. In these areas, subsets of neurons may be marked and specified. In addition to the normal pattern of Sax-1 during development, the expression in different mouse mutants was analysed. In Brachyury curtailed homozygotes, the expression of Sax-1 was found to be reduced during neurulation and even lost at day 9.0 pc. Ventral shift and finally loss of the signal in the ventral spinal cord was observed in Danforth's short tail homozygotes.


Affective temperaments and obesity: Is there an association with binge eating episodes and multiple weight cycling?
affective temperaments have been so far understudied in the field of obesity. Therefore, we aimed to assess affective temperaments in outpatients with obesity reporting symptoms of binge eating (BE) and multiple weight cycling (MWC) and to investigate the likelihood of an association between affective temperaments and risk of both conditions. A total of 300 individuals with obesity seeking treatment at the Obesity Unit of an academic hospital were asked to complete self-report measures of affective temperaments, BE, depressive and anxiety symptoms, and quality of life. Even in the absence of full-blown mental disorders, symptoms of anxiety and depression emerged in the sample; 197 individuals (65.6%) reported BE and 162 (54%) MWC. The most frequent affective temperament was the depressive one. Depression symptoms and cyclothymic scores (directly), and age and hyperthymic score (inversely) were significantly associated with BE risk, while being an active smoker (directly) and hyperthymic score (inversely) were significantly associated with MWC risk, after controlling for confounders in a multiple logistic regression. sample size was small, the study was limited to a single center, no formal definition of weight cycling exists and MWC was self-reported. A substantial number of outpatients with obesity reported BE and MWC notwithstanding the absence of a formal psychiatric diagnosis. Cyclothymic scores were positively associated with BE while the hyperthymic temperament showed a protective effect on both BE and MWC. These findings suggest the need for multidisciplinary treatments for people with obesity enhancing research on temperament-based psychological interventions.


Managing change in health care organizations.
The forces for change seem more potent today than ever before; increased technological advancement and rapid "societal upheavals" create a more critical need for change and a more significant need for skills to manage and channel change toward meaningful ends. The area of health care delivery is probably one of the fields most impinged upon and most affected by these turbulent times. Organizational development is presented herein as an approach to assist people in health care organizations with the problems of adaptation and change. A specific change strategy, action research, is discussed and a concrete case example is presented to illustrate the ways in which the action research model can be applied. Advantages and pitfalls are discussed in the concluding section.


The branching of insulin-like growth factor 1 and insulin: an immunohistochemical analysis during phylogeny.
The co-existence of insulin-like growth factor 1 (IGF-1) with the classical islet hormones insulin (INS), glucagon (GLUC), somatostatin (SOM) and pancreatic polypeptide (PP) in the endocrine pancreas of representative species of cyclostomes (Myxine glutinosa), cartilaginous fish (Raja clavata, Squalus acanthias) and bony fish (Cottus scorpius, Carassius auratus, Cyprinus carpio, Anguilla anguilla) was studied by the use of monoclonal and polyclonal antisera and the double immunofluorescence technique. In all species investigated, IGF-1-like-immunoreactive cells were found in the endocrine pancreas, however, in varying localization. In Myxine glutinosa, all INS-immunoreactive cells and some of the SOM-immunoreactive cells contained IGF-1-like-immunoreactivity. In Raja and Squalus, only a minority of the INS-immunoreactive cells also displayed IGF-1-like-immunoreactivity. The majority of the IGF-1-like-immunoreactivity was observed in SOM- and in GLUC-immunoreactive cells. Different results were obtained in bony fish. In Cottus, in the Brockmann bodies and the small islets IGF-1-like- and INS-immunoreactivities co-existed to 100%. In contrast, in the other bony fish studied IGF-1-like-immunoreactivity was not observed in INS-immunoreactive cells: in Cyprinus, IGF-1-like-immunoreactivity was found in GLUC-, PP- and SOM-immunoreactive cells and in Carassius and Anguilla, in SOM-immunoreactive cells only. Thus, in all bony fish species with the exception of Cottus, IGF-1 and insulin display a distinct cellular distribution, similar to that of mammals. The present results, thus, may indicate that the branching of IGF-1 and insulin has occurred at the phylogenetic level of bony fish.


A novel mutation in the KCNJ11 gene (p.Val36Glu), predisposes to congenital hyperinsulinemia.
The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in neonates. Inactivating mutations in the genes encoding KATP channel (ABCC8 and KCNJ11) as well as HNF4A, HNF1A, HADH, UCP2, and activating mutations in GLUD1, GCK, and SLC16A1 have been identified as causal. A 3-month-old male infant presenting tonic-clonic seizures and hyperinsulinemia was clinically assessed and subjected to genetic analysis. Besides the index patient, his parents were clinically investigated, and a detailed family history was also recorded. The laboratory investigations and the genetic test results of the parents were compared with the index patient. The biochemical and hormonal profile of the patient confirmed his suffering from CHI and did not respond to diazoxide treatment. The genetic testing revealed that the subject harbored a novel homozygous missense mutation in the KCNJ11 gene, (c.107T>A, p.Val36Glu.). The bioinformatic analysis revealed that valine is highly conserved and predicted that the variant allele (p.Val36Glu) is likely pathogenic and causal for CHI. Parents were heterozygous carriers and did not report any abnormal metabolic profile. Identification of such mutations is critical and likely to change the therapeutic interventions for such patients in the future.


Genetic basis of photopigment variations in human dichromats.
The spectral sensitivities of the X-encoded pigments in dichromats were studied using the electroretinogram. The action spectra measured for these subjects correspond to four distinctly different X-encoded visual pigments, two different middle-wave pigments spectrally separated by 7 nm and two different long-wave pigments separated by 5 nm. Amino acid sequences were deduced from examination of the genes encoding the pigments. Pairwise comparisons of the opsin structures and pigment spectra confirm and clarify earlier conclusions. Substitutions in exon 5 of the genes produce the spectral difference that separates human X-encoded pigments into middle- and long-wave classes. Polymorphisms in exons 2-4 produce subtypes of pigments that fall within those major classes. Substitution of half of a middle-wave gene with long-wave sequence (exons 1-3) does not shift the middle-wave spectrum. Combined substitutions at positions 230, 233 and 180 produce a 7 nm shift in the in the middle-wave pigment spectrum. Two subtypes of long-wave pigments that differ in the presence of serine or alanine at position 180 and occur in dichromats, deuteranomalous trichromats, and color normals are spectrally separated by 5-7 nm.


Postconfluency MDCK monolayers as an in vitro model of solid tumor chemosensitivity.
Shortly after reaching confluency, canine MDCK cells enter a prolonged state of basal growth with doubling times of 200-300 hours. These values are similar to those commonly exhibited by in vivo solid tumors at clinically relevant sizes. By comparison with rapidly growing sparse density cultures, the postconfluent monolayers displayed a pronounced resistance to deazauridine, deoxyspergualin, and 5-fluorouridine. Drug concentrations required for unit levels of effect increased from several fold to several orders of magnitude as cells entered high density basal growth. This high density chemoresistance was observed for both growth inhibition and cytotoxicity, but was much more pronounced with the former. Dose-response curves were biphasic, suggesting that growth inhibition and cytotoxicity may be mediated by different mechanisms of drug action. The pronounced chemoresistance of postconfluent MDCK monolayers is similar to that encountered with many clinical solid neoplasms. It suggests that postconfluency monolayers, like multicellular spheroids and cellular multilayers, may provide better in vitro models of solid tumor chemosensitivity than subconfluent monolayer and suspension cultures.


Local Nogo-66 administration reduces neuropathic pain after sciatic nerve transection in rat.
Neuropathic pain after periphery nerve injury is frequently accompanied by the regeneration of the injured nerve fibers. We tested in this study whether local administration of Nogo-66, a well-studied axon growth inhibiting peptide in the central nerve system, could reduce the pain related behavior after sciatic nerve transection in rat. Nogo-66 peptide was purified as a GST fusion protein. Its inhibitory function was testified by neurite outgrowth assay of primary cultured neurons, and then it was given directly at the lesion site by a minipump for 2 weeks. Mechanical nociceptive withdrawal responses and heat hyperalgesia responses were assessed during a 4-week period, and autotomy was evaluated during a 6-week period. The results showed that the mechanical allodynia and heat hyperalgesia scores of the rats treated with GST-Nogo-66 were significantly higher than the controls between 7 and 14 days after sciatic nerve transection. The autotomy scores in the GST-Nogo-66 group were significantly lower than the controls from 28 days after surgery. Taken together, the results of our present study suggest that Nogo-66 may be utilized to decrease the neuropathic pain after periphery nerve injury.


Motor unit number estimation of the tibialis anterior muscle in spinal cord injury.
Case-control study. To investigate the number of motor units from the tibialis anterior (TA) muscle in normal subject and its change after SCI. China Rehabilitation Research Center, Beijing, China. Motor unit number estimation (MUNE) in 45 control subjects (35 young subjects with an average age of 36 years, and 10 elderly subjects with an average age of 65 years) was performed by using adapted multiple point stimulation method (AMPS). Twenty patients with SCI (10 subacute patients with an average age of 39 years, and 10 chronic patients with an average age of 34 years) were also examined for three times in 3 months with the same method. The mean MUNE value of the TA muscle was 188+/-20 in the control group, and 40+/-33 in subacute SCI patients (P<0.01 vs young controls). A continuous increase in the MUNE value was observed in subacute SCI patients during the later follow-up period. In the chronic SCI group, the mean MUNE value was 173+/-29 which was similar to that of young control group. AMPS could be a useful procedure for quantifying changes of MUNE values after SCI. Changes in functional motor unit number may occur distal to the site of lesion in SCI patients. These phenomena may be caused by neuronal plasticity in motor units, reversible transsynaptic degeneration and/or local functional depression. Owing to the limited sample size and a wide age range of subjects recruited in this study, future study are warranted for revealing detailed changes of MUNE parameters after SCI and exploring the underlying mechanisms.


Rapamycin sensitive mTOR activation mediates nerve growth factor (NGF) induced cell migration and pro-survival effects against hydrogen peroxide in retinal pigment epithelial cells.
Patients with age related macular degeneration (AMD) have a loss of vision in the center of the visual field. Oxidative stress plays an important role in this progress. Nerve growth factor (NGF) is important for the survival and maintenance of sympathetic and sensory neurons and NGF eye drops improve visual acuity and electro-functional activity in patients with AMD. However, the molecular mechanisms and signaling events involved in this have not been fully investigated. Using cultured human retinal pigment epithelial (RPE) cells, we demonstrate here that NGF protects RPE cells against hydrogen peroxide (H(2)O(2))-induced cell apoptosis. NGF also induces RPE cell migration, the latter is important for retinal regeneration and the recovery from AMD. H(2)O(2) decreases S6 phosphorylation and cell viability, which is restored by NGF. Rapamycin, the pharmacologic inhibitor of mammalian target of rapamycin (mTOR), diminished NGF-induced S6 phosphorylation, cell migration and protective effects against oxidative stress. Collectively, we conclude that activation of rapamycin sensitive mTOR signaling mediates NGF induced cell migration and pro-survival effects in H(2)O(2) treated RPE cells.


Elevated oxidative stress and sensorimotor deficits but normal cognition in mice that cannot synthesize ascorbic acid.
Oxidative stress is implicated in the cognitive deterioration associated with normal aging as well as neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. We investigated the effect of ascorbic acid (vitamin C) on oxidative stress, cognition, and motor abilities in mice null for gulono-gamma-lactone oxidase (Gulo). Gulo-/- mice are unable to synthesize ascorbic acid and depend on dietary ascorbic acid for survival. Gulo-/- mice were given supplements that provided them either with ascorbic acid levels equal to- or slightly higher than wild-type mice (Gulo-sufficient), or lower than physiological levels (Gulo-low) that were just enough to prevent scurvy. Ascorbic acid is a major anti-oxidant in mice and any reduction in ascorbic acid level is therefore likely to result in increased oxidative stress. Ascorbic acid levels in the brain and liver were higher in Gulo-sufficient mice than in Gulo-low mice. F(4)-neuroprostanes were elevated in cortex and cerebellum in Gulo-low mice and in the cortex of Gulo-sufficient mice. All Gulo-/- mice were cognitively normal but had a strength and agility deficit that was worse in Gulo-low mice. This suggests that low levels of ascorbic acid and elevated oxidative stress as measured by F(4)-neuroprostanes alone are insufficient to impair memory in the knockouts but may be responsible for the exacerbated motor deficits in Gulo-low mice, and ascorbic acid may have a vital role in maintaining motor abilities.


Production of nisin with continuous adsorption to Amberlite XAD-4 resin using Lactococcus lactis N8 and L. lactis LAC48.
The production of nisin, biomass and lactic acid in pH-controlled and uncontrolled batch fermentation and batch fermentation (pH 5.5) with continuous removal of nisin was examined in the parent strain Lactococcus lactis N8 and LAC48. Strain LAC48 in batch fermentor (pH not controlled) gave a maximum nisin concentration of 2.5 x 10(6) IU g dcw(-1). The nisin concentration remained high (2.0 x 10(6) IU g dcw(-1)) after the logarithmic growth phase (10-22 h), whereas nisin production of strain N8 decreased after the logarithmic growth phase. The maximum nisin production of strain LAC48 was not directly related to the biomass formation and not associated with growth. In order to study end product inhibition in nisin production, a system was built for adsorption of nisin during fermentation. The adsorbent Amberlite XAD-4 was found to have an effective binding capacity for nisin. Cells of LAC48 and N8 compensated for the removal of nisin, indicating that nisin production also occurs in the stationary phase.


Photo and biocatalytic activities along with UV protection properties on polyester fabric through green in-situ synthesis of cauliflower-like CuO nanoparticles.
In this paper, a facile environmentally friendly method is introduced for in-situ synthesis and fabrication of cauliflower-like CuO nanoparticles on the polyester fabric to produce photo and biocatalytic activities with UV protection properties on polyester fabric. The ash of burnt leaves and stems of Seidlitzia rosmarinus plant called Keliab was used as a natural and nontoxic alkaline source for simultaneous synthesis of CuO nanoparticles and surface modification of polyester without using any other compounds. The images of field-emission scanning electron microscopy, patterns of energy-dispersive spectroscopy, UV-visible spectrum and X-ray diffraction confirmed successful synthesis and loading of CuO nanoparticles on the polyester fabric. The treated fabrics showed very good antibacterial activities toward two pathogen bacteria including Staphylococcus aureus as a Gram-positive and Escherichia coli as a Gram-negative bacteria with no adverse effects on human dermal fibroblasts based on MTT test. The treated fabrics confirmed significant photocatalytic activity for degradation of methylene blue under sunlight, self-cleaning properties under UV light and also UV protection properties. Further a colorant effect along with an improvement in the wettability and mechanical properties of the treated fabrics were indicated. Overall, this method can be applied as a clean route for producing photo and bio active textiles protecting against UV irradiation.


[Observation of course of placental separation by continuous dynamic ultrasonography during third stage of labor].
To investigate the physiologic course of third stage of labor, and to judge the optimal time of natural placental separation permitted. To observe and record the course of third stage of labor by continuous dynamic ultrasonography and to estimate the total amount of blood loss from placental separation within two hours after delivery by the method of weighing lost blood. Third stage of labor can be divided into four phases: the latent phase (4.37 +/- 3.78) min, the contraction phase (1.48 +/- 0.97) min, the detachment phase (0.50 +/- 0.00) min, and the expulsion phase (0.62 +/- 2.23) min. In 85% of the puerperas the third stage of labor takes about 10 minutes (average 6.94 minutes). The amount of postpartum hemorrhage and the risk of the patient increased prominently if the time of stage of labor was longer than 10 minutes (P < 0.01). The third stage of labor must be limited in 10 minutes to prevent postpartum hemorrhage.


The influence of infant characteristics and attention to social cues on early vocabulary.
Individual differences in early language development are related to a number of infant characteristics and skills, including temperament traits, cognitive ability, and social cognition. The current study aimed to assess the complex mechanisms underlying these relations by evaluating the ability to use social cues in a word-learning context along with temperament, cognitive ability, and expressive vocabulary in 71 18-month-old infants. A moderated mediation analysis indicated that infants' nonverbal cognitive ability affects their early vocabulary through its effect on their ability to use social cues, but only in infants with low nonverbal cognitive ability. Implications for both typical and atypical development are discussed.


The new imperative: reducing adolescent-related violence by building resilient adolescents.
Involvement in violence is affected by a variety of risk factors and timing, duration, number of risks, and intensity of risk factors. The earlier the exposure to risk starts, the longer the exposure continues, the number of risks one is exposed to, and intensity of the risk factors experienced are all important. A child who is severely beaten, sexually abused, or both; one who grows up witnessing intimate partner or family violence; one who attends a failing school or is not involved in structured after-school activities; or one who lives in a violent neighborhood is at increased risk of becoming involved in violent behavior. The nature of the violence is worsened by the impact of shifting family structure and other risk factors such as alcohol and drugs. Adolescents who are exposed to positive parenting and supportive individuals, receive relevant education, are literate, possess life skills, and participate in structured, supervised activities become empowered young people who can resist violence.


Performance of gene-expression profiling test score variability to predict future clinical events in heart transplant recipients.
A single non-invasive gene expression profiling (GEP) test (AlloMap®) is often used to discriminate if a heart transplant recipient is at a low risk of acute cellular rejection at time of testing. In a randomized trial, use of the test (a GEP score from 0-40) has been shown to be non-inferior to a routine endomyocardial biopsy for surveillance after heart transplantation in selected low-risk patients with respect to clinical outcomes. Recently, it was suggested that the within-patient variability of consecutive GEP scores may be used to independently predict future clinical events; however, future studies were recommended. Here we performed an analysis of an independent patient population to determine the prognostic utility of within-patient variability of GEP scores in predicting future clinical events. We defined the GEP score variability as the standard deviation of four GEP scores collected ≥315 days post-transplantation. Of the 737 patients from the Cardiac Allograft Rejection Gene Expression Observational (CARGO) II trial, 36 were assigned to the composite event group (death, re-transplantation or graft failure ≥315 days post-transplantation and within 3 years of the final GEP test) and 55 were assigned to the control group (non-event patients). In this case-controlled study, the performance of GEP score variability to predict future events was evaluated by the area under the receiver operator characteristics curve (AUC ROC). The negative predictive values (NPV) and positive predictive values (PPV) including 95 % confidence intervals (CI) of GEP score variability were calculated. The estimated prevalence of events was 17 %. Events occurred at a median of 391 (inter-quartile range 376) days after the final GEP test. The GEP variability AUC ROC for the prediction of a composite event was 0.72 (95 % CI 0.6-0.8). The NPV for GEP score variability of 0.6 was 97 % (95 % CI 91.4-100.0); the PPV for GEP score variability of 1.5 was 35.4 % (95 % CI 13.5-75.8). In heart transplant recipients, a GEP score variability may be used to predict the probability that a composite event will occur within 3 years after the last GEP score. Clinicaltrials.gov identifier NCT00761787.


Tacrolimus therapy for dermal arteritis of the nasal philtrum refractory to surgery and anti-inflammatory therapy (doxycycline/niacinamide and topical fluocinolone) in a dog.
Dermal arteritis of the nasal philtrum is a rarely reported condition commonly affecting large breed dogs. To describe the effective treatment of nasal philtrum arteritis with topical tacrolimus in one dog. A 9-year-old, intact male German shorthair pointer dog was presented with well-demarcated deep erythematous ulcers targeting exclusively the skin of the nasal philtrum, accompanied by frequent series of haemorrhage. Complete blood count, serum chemistry profile, urinalysis, histopathological examination and immunohistochemistry of skin biopsies. The presence of a V-shaped ulcer with subendothelial spindle cell proliferation resulting in stenosis of dermal arteries and arterioles on histological evaluation, together with a well-demarcated deep nasal philtrum ulcer was consistent with arteritis of the nasal philtrum. Treatment was initiated with twice daily oral doxycycline and niacinamide in conjunction with topical fluocinolone cream. Over the course of two years, the lesions progressed with frequent bleeding episodes. A novel surgical approach provided deep resection of all grossly affected tissue; four months later a recurrence of fissures and occasional mild bleeding from the original site was noted and there was no improvement after another two months of oral doxycycline/niacinamide and topical fluocinolone treatment. Topical application of 0.1% tacrolimus twice daily resulted in complete healing of the ulceration and normalization of the epidermis. Over the subsequent 15 months, the dog's lesions remained in remission with topical tacrolimus application twice daily. Topical tacrolimus ointment appeared effective at inducing and maintaining lesion remission in this dog with nasal philtrum arteritis.


Development and use of modified live Edwardsiella ictaluri vaccine against enteric septicemia of catfish.
The present study showed that E. ictaluri RE-33 vaccine does not cause ESC but does stimulate protective immunity. The RE-33 vaccinates were protected against ESC for at least 4 months following a single bath immersion in a low number of E. ictaluri RE-33 without booster vaccination. Antibody responses are weak after RE-33 vaccination. Edwardsiella ictaluri RE-33 vaccine presents no risk or hazard to catfish. RE-33 vaccine will prevent ESC caused by most isolates of E. ictaluri in catfish. We recently obtained from USDA, Animal Plant Health Inspection Service (APHIS), and the state veterinarians of Alabama and Mississippi, approval to field test the RE-33 vaccine in young catfish. About 2-3 million 10- to 30-day-old channel catfish in Alabama and Mississippi have been vaccinated since June 1997 with no adverse effects of vaccination.


Mean platelet volume is an independent risk factor for myocardial infarction but not for coronary artery disease.
After rupture of an arteriosclerotic plaque in a coronary artery, platelets play a crucial role in the subsequent thrombus formation, leading to myocardial infarction. An increased mean platelet volume (MPV), as an indicator of larger, more reactive platelets, may represent a risk factor for myocardial infarction. However, this hypothesis is still controversial and most studies addressing the role of MPV were performed comparing patients suffering from myocardial infarction with healthy controls. We intended to identify patients at high risk of suffering myocardial infarction in a group of patients with known coronary artery disease. One hundred and eighty-five consecutive patients with stable coronary artery disease were compared with 188 individuals who had suffered myocardial infarction. Patients within the highest quintile of MPV (> or = 11.6 fl) had a significantly higher risk of experiencing a myocardial infarction compared with patients within the lowest quintile (OR = 2.6, 95% CI 1.3-5.1) in a multivariate analysis that included sex, age, body mass index, hyperlipidaemia, hypertension, smoking and diabetes mellitus. Our results indicate that patients with pre-existing coronary artery disease and an increased MPV (> or = 11.6 fl) are at higher risk of myocardial infarction. These patients can be easily identified during routine haematological analysis and could possibly benefit from preventive treatment.


Application of microscope-based scanning software (Panoptiq) for the interpretation of cervicovaginal cytology specimens.
Digital pathology increasingly has been gaining the attention of pathologists worldwide. However, the application of digital cytology by Panoptiq (ViewsIQ, Vancouver, Canada) microscope-based scanning software is relatively unexplored. Panoptiq enables the operator to combine low-power panoramic digital images with z-stacks at regions of interest with a significantly smaller image size than that obtained by whole-slide scanning. The current study aimed to evaluate the feasibility of the use of Panoptiq in the digital interpretation of cervicovaginal cytology specimens in comparison with conventional light microscopy. A total of 100 liquid-based cytology slides were selected sequentially. The dotted slides were reviewed and scanned, in which all dotted areas were scanned further by the ×20 objective with z-stacks. The cases were reviewed by 4 pathologists and a cytotechnologist using conventional light microscopy and digital cytology images acquired by Panoptiq and interpreted based on the Bethesda classification system. The washout time was set as 3 weeks. The Cohen kappa coefficient was calculated to measure the agreement between the 2 modalities. Digital cytology demonstrated an intermodality agreement among 3 observers who had sufficient training in digital pathology at concordance rates between 81% and 90% with kappa values between 0.76 and 0.86, whereas the other 2 observers who did not have sufficient training in digital pathology had lower agreement at a concordance rate of between 56% and 57%, with kappa values between 0.41 and 0.44. Panoptiq appears to be feasible for the interpretation of cervicovaginal cytology specimens but requires adequate training in digital pathology. Cancer Cytopathol 2017;125:918-25. © 2017 American Cancer Society.


[Mechanism of the change in adipocyte sensitivity to ACTH and adrenaline in spontaneous genetic hypertesion in rats].
As compared to fatty tissue cells of animals with normal pressure, those of SHR rats were found to be characterized by a higher lipolytic response and a larger increase in the cAMP content on exposure to the effect of ACTH. As compared to the controls, adrenalectomized SHR rats had an increased basal cAMP content and an increased lipolytic response of the adipocytes following adrenaline administration. In inhibition of phosphodiesterase in the fatty cells of adrenalectomized rats with normal pressure, the cAMP content grew by 20% as compared to that in SHR rats subjected to the operation. It is suggested that the changes in intracellular distribution of calcium, shown in this model of hypertension, may be the direct cause of the altered sensitivity of the "target" cells to the effect of hormones.


'Rapid transit' constipation in children: a possible genesis for irritable bowel syndrome.
Children with chronic idiopathic constipation (CIC) often end up at the surgeon when medical treatments have failed. This opinion piece discusses a recently described pattern of CIC called 'Rapid transit constipation (RTC)' first identified in 2011 as part of surgical workup. RTC was identified using a nuclear medicine gastrointestinal transit study (NMGIT or nuclear transit study) to determine the site of slowing within the bowel and to inform surgical treatment. Unexpectedly, we found that RTC occured in 29% of 1000 transit studies in a retrospective audit. Irritable bowel syndrome (IBS) occurs in 7-21% of the population, with a higher prevalence in young children and with constipation type dominating in the young. While 60% improve with time, 40% continue with symptoms. First-line therapy for IBS in adults is a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols which reduces symptoms in > 70% of patients. In children with functional gastrointestinal disorders, fructose intolerance occurs in 35-55%. Reducing fructose produced significant improvement in 77-82% of intolerant patients. In children with RTC and a positive breath test upon fructose challenge, we found that exclusion of fructose significantly improved constipation, abdominal pain, stool consistency and decreased laxative use. We hypothesise that positive breath tests and improvement of pain and bowel frequency with sugar exclusion diets in RTC suggest these children have IBS-C. These observations raise the possibility that many children with CIC could be treated by reducing fructose early in their diet and this might prevent the development of IBS in later life.


Serum transforming growth factor-beta1 as a risk stratifier of sudden cardiac death.
Sudden cardiac death prematurely claims the lives of some 7 million each year worldwide. It occurs primarily in patients with an underlying structural cardiac abnormality, and regardless of the type of the underlying pathology (heart failure, dilated and hypertrophic cardiomyopathies, myocardial infarction and aging), death is almost always caused by ventricular tachycardia (VT) which rapidly degenerates to ventricular fibrillation (VF). Implantable cardioverter defibrillator is an effective but expensive therapy for preventing SCD, and finding a reasonably specific, sensitive and cost-effective risk stratification tool for patients at high risk of sudden cardiac death will have great clinical utility in preventing premature sudden cardiac death. Increased myocardial fibrosis has been shown to develop in a wide range of cardiac diseases all manifesting increased risk of VT and VF. Clinical and experimental studies attribute a major role for fibrosis in the initiation of VT, VF and sudden cardiac death. Transforming growth factor-beta1 (TGF-beta1) has been shown to promote myocardial tissue fibrosis and perhaps more importantly in cardiac conditions associated with increased myocardial fibrosis are shown to be positively correlated with increased serum levels of TGF-beta1. In the present hypothesis we suggest that monitoring the serum levels of TGF-beta1 may be a cost-effective risk stratifier to identify patients at high risk of sudden cardiac death caused by VT and VF.


[Alpha-fetoprotein synthesis in clonogenic cells of rat hepatoma McA-RH 7777].
Production of alpha-fetoprotein (AFP) was determined in single cells of hepatoma McA-RH7777 and in the clones of their progeny. To elucidate the heritability of this trait in a series of cell generations, a variety of local hemolysis in gel was devised. According to the method the cells and red cells conjugated with protein A were placed on the polylysine covered surface and layered with agarose gel containing antibodies. AFP production by single cells was determined from the formation of plaques--areas of red cell hemolysis. The cells forming the plaques (+AFP) and not forming them (-AFP) were distinguished and their reproduction was followed up. After 7-14 days the cells were fixed and stained by the immunoperoxidase technique with antibodies to AFP. High efficacy of the cloning has been demonstrated for both +AFP- and -AFP-cells (69 and 71%). Negative cells preserved their phenotype more frequently, producing homogenous negative clones, whereas +AFP cells gave "negative" clones in 1/3 of the cases. Both cells gave mixed clones in a small percentage of the cases. At present the AFP trait in these cells is being studied by recloning.


NMR studies of intracellular sodium ions in mammalian cardiac myocytes.
The unambiguous measurement of intracellular sodium ion [Na+]i by the noninvasive NMR technique offers a new opportunity to monitor precisely the maintenance and fluctuations of [Na+]i levels in intact cells and tissues. The anionic frequency shift reagent, dysprosium (III) tripolyphosphate, which does not permeate intact cells, when added to suspensions of intact adult rat cardiac myocytes, alters the NMR frequency of extracellular sodium ions, [Na+]o, leaving that of intracellular ions, [Na+]i, unaffected. Using 23Na NMR in conjunction with this shift reagent, we have determined NMR-visible intracellular Na+ ion concentration in a suspension of isolated cardiac myocytes under standard conditions with insulin and Ca2+ in the extracellular medium to be 8.8 +/- 1.2 mmol/liter of cells (n = 4). This value is comparable to that measured by intracellular ion-selective microelectrodes in heart tissue. Cardiac myocytes incubated for several hours in insulin-deficient, Ca2+-containing medium prior to NMR measurement exhibited a somewhat lower [Na+]i value of 6.9 +/- 0.5 mmol/liter of cells (n = 3). Reversible Na+ loading of the cells by manipulation of extracellular calcium levels is readily measured by the NMR technique. Incubation of myocytes in a Ca2+-free, insulin-containing medium causes a 3-fold increase in [Na+]i to a level of 22.8 +/- 2.6 mmol/liter of cells (n = 10). In contrast to cells with insulin, insulin-deficient myocytes exhibit a markedly lower level of [Na+]i of only 14.6 +/- 2.0 mmol/liter of cells (n = 4) in Ca2+-free medium. These observations suggest that insulin may stimulate a pathway for Na+ influx in heart cells.


Low levels of ionic mercury modulate protein tyrosine phosphorylation in lymphocytes.
The ability of ionic mercury to induce protein tyrosine phosphorylation in mouse spleen cells and in the mouse WEHI-231 B-cell lymphoma was investigated. We have confirmed previous studies which showed that exposure to high levels (several hundred microM) of mercury lead to very large increases in the level of protein tyrosine phosphorylation in these cell systems. However we have also demonstrated that low levels (in the order of 0.1 to 1.0 microM) of mercury also significantly upregulate protein tyrosine phosphorylation. Mercury induced protein tyrosine phosphorylation is inhibited by the mercury chelator penicillamine and by pretreating treating target cells with the sulfhydryl blocking reagent N-hydroxymaleimide. These results suggest that exposure to low levels of mercury could potentially interfere with lymphocyte signal transduction and so offer a possible explanation as to how mercury exposure could lead to immune cellular dysfunction. On a molecular level, the results suggest that the site(s) of action with respect to mercury dependent induction of protein tyrosine phosphorylation is likely a free disulfide group or groups located on the outer leaflet of the plasma membrane.


Functionalized paper--A readily accessible adsorbent for removal of dissolved heavy metal salts and nanoparticles from water.
Paper, a readily available renewable resource, comprises of interwoven cellulosic fibers, which can be functionalized to develop interesting low-cost adsorbent material for water purification. In this study, polyethyleneimine (PEI)-functionalized paper was used for the removal of hazardous pollutants such as Au and Ag nanoparticles, Cr(VI) anions, Ni(2+), Cd(2+), and Cu(2+) cations from spiked water samples. Compared to untreated paper, the PEI-coated paper showed significant improvement in adsorption capacities toward the pollutants investigated in this study. Kinetics, isotherm models, pH, and desorption studies were carried out to study the adsorption mechanism of pollutants on the adsorbent surface. Adsorption of pollutants was better described by pseudo-second order kinetics and Langmuir isotherm model. Maximum adsorption of anionic pollutants was achieved at pH 5 while that of cations was at pH>6. Overall, the PEI-functionalized paper showed interesting Langmuir adsorption capacities for heavy metal ions such as Cr(VI) (68 mg/g), Ni(2+) (208 mg/g), Cd(2+) (370 mg/g), and Cu(2+) (435 mg/g) ions at neutral pH. In addition, the modified paper was also used to remove Ag-citrate (79 mg/g), Ag-PVP (46 mg/g), Au-citrate (30 mg/g), Au-PVP (17 mg/g) nanoparticles from water. Desorption of NPs from the adsorbent was done by washing with 2 M HCl or thiourea solution, while heavy metal ions were desorbed using 1 M NaOH or HNO3 solution. The modified paper retained its extraction efficiencies upon desorption of pollutants.


Polyglutamation of antifolates is not required for induction of extracellular release of adenosine or expression of their anti-inflammatory effects.
Methotrexate (MTX) exerts an anti-inflammatory effect, reportedly by enhancing the release of adenosine, through an accumulation of 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR). To examine the role of polyglutamation in promoting anti-inflammatory effects by antifolates, we tested whether a new antifolate designed to be resistant to intracellular polyglutamation (MX-68) exhibited anti-inflammatory effects and stimulated adenosine release. Both MX-68 and MTX (at concentrations greater than 0.1 microM) increased the release of adenosine from Daudi cells in vitro. Inhibition of AICAR synthesis suppressed adenosine release by MX-68 and MTX. The anti-inflammatory effects of antifolates were estimated using the murine air pouch model, in which a BALB/c mouse was intraperitoneally injected with MX-68 or MTX once a week for 3 weeks. MX-68 (0.5 mg kg(-1) week(-1)), as well as MTX, inhibited infiltration of leukocytes into the air pouch. This inhibitory effect was suppressed in the presence of an adenosine A(2) receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX). These results suggest that MX-68, like MTX, exerts anti-inflammatory effects through the accumulation of AICAR and release of adenosine. These results suggest that polyglutamation of antifolate is not required for expression of anti-inflammatory effects.


Encorafenib in Combination With Cetuximab After Systemic Therapy in Patients With BRAFV600E Mutant Metastatic Colorectal Cancer: German Health Technology Assessment-Driven Analyses From the BEACON CRC Study.
Purpose of this analysis was to report data of the BEACON CRC trial used in the German Health Technology Assessment (HTA) and previously unpublished data focusing on the dual blockade (encorafenib + cetuximab) and appropriate comparative therapy (ACT/control: cetuximab + irinotecan-based chemotherapy) of patients with BRAFV600E-mutant mCRC. Analyses included overall survival (OS) and time-to-event analyses of morbidity and safety. A total of 220 patients received encorafenib + cetuximab and 221 patients ACT/control. Median OS was 9.3 (encorafenib + cetuximab) versus 5.9 months (ACT/control) (stratified hazard ratio (HRstrat): 0.61 [95% confidence interval: 0.48-0.77]). Time-to-response (TTR) showed a statistically significant advantage for encorafenib + cetuximab compared to ACT/control (HRstrat [95% CI]: 10.46 [3.75; 29.15]; P < .0001). Median progression-free survival 2, ie, PFS after initiation of subsequent treatment after completion of study treatment, was 8.3 (dual blockade) versus 5.3 months (ACT/control), representing a statistically significant benefit for the dual blockade (HRstrat [95% CI]: 0.62 [0.48; 0.78]; P < .0001). The statistically significant advantage for diarrhea (EORTC QLQ-C30) reached clinical relevance (LS-mean [95% CI]; P-value / Hedges'g [95% CI]: -12.61 [-17.75; -7.47]; P < .0001 / -0.53 [-0.74; -0.31]). The time-to-event analyses showed a statistically significant benefit for the dual blockade for serious adverse events (AE), severe AEs and AEs leading to discontinuation. In the HTA, the German G-BA granted a "hint for a considerable additional benefit" of encorafenib + cetuximab compared to the ACT in BRAFV600E-mutant mCRC patients. This treatment is considered the new standard of care for these patients.


[Paroxysmal tachycardia with long QRS (left branch block type) in a female patient with accessory nodo-ventricular pathway. Role of the anomalous pathway in the electrogenesis of the arrhythmia].
The authors report a case of paroxysmal tachycardia with widened QRS (left bundle branch block morphology), where the electrophysiologic investigation shows an accessory nodo-ventricular pathway and suggests its involvement, as descendent (anterograde) pathway in a circular movement, the ascendant (retrograde) limb of which is the nodo-hisian pathway.


Prevalence of sexually transmitted diseases and human immunodeficiency virus among women attending prenatal services in Apia, Samoa.
There is no routine prenatal screening for sexually transmitted diseases (STDs) and human immunodeficiency virus (HIV) in pregnancy in Samoa. Testing for chlamydial infection is not available. To gather information on pregnant women, a prevalence survey was conducted in Apia, Samoa, utilizing two prenatal hospital clinics. Pregnant (n=427) women were tested for Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis using polymerase chain reaction (PCR), and for syphilis (n=441) by rapid plasmid reagin (RPR) and HIV (n=441) by enzyme-linked immunosorbent assay (ELISA). Results were: chlamydia 30.9% (132); trichomoniasis 20.8%; gonorrhoea 3.3%; syphilis 0.5%; and HIV 0%. Overall 42.7% had at least 1 STD. Young women aged <25 years were three times more likely to have a STD than older women (odds ratio=3.0, 95% confidence intervals 2.0, 4.5). The lack of inexpensive, reliable field diagnostics remain a barrier to sustainable STD control programmes for pregnant women living in developing countries.


Electric showers as a control measure for Legionella spp. in a renal transplant unit in São Paulo, Brazil. Legionellosis Study Team.
After an outbreak of legionnaires' disease Legionella pneumophila serogroup 1 in a renal transplant unit in São Paulo, Brazil, periodic hyperchlorination and flushing of pipes were instituted as control measures. These were only partially effective as every two to five months water cultures turned positive or new cases of the disease occurred. In November 1993 the hot water was disconnected from the unit and small, plastic electric showers were installed in each bathroom. Over a period of 12 months water from showers and taps was cultured for Legionella spp. every two weeks. On only one occasion was a water culture positive for L. pneumophila from a sink tap. No water sample obtained from showers was positive during the study period. No cases of legionnaires' disease occurred. We considered the use of electric showers an inexpensive and effective method of controlling the problem of Legionella spp. in the water system of our renal transplant unit.


Redo hepatic resection for metastatic colorectal carcinoma.
Redo hepatic resection for recurrent colorectal metastasis was performed in eight patients. There was no operative mortality; major morbidity occurred in 25% and minor morbidity in 13% of patients. Four patients are alive and disease-free at 9, 23, 39, and 49 months, respectively, after their repeat hepatic resection. Four patients have died of recurrent disease, with a median time to recurrence of 6 months and median survival of 15 months. Patterns of failure include hepatic failure alone in two patients and pulmonary and hepatic failure in two. Repeat liver resection can be performed safely and may be beneficial in some patients with recurrent metastases confined to the liver after previous hepatic metastasectomy.


New calcium channel mutations predict aberrant RNA splicing in episodic ataxia.
Episodic ataxia type 2 (EA2) is an autosomal dominant channelopathy characterized by paroxysmal cerebellar ataxia. Previous studies suggest that most EA2 cases are associated with mutations in the alpha1A subunit of the P/Q-type voltage-gated calcium channel gene CACNA1A. In a UK national study, the authors analyzed 15 index cases with typical EA2 and identified two unreported intronic mutations that predict aberrant splicing.


The disruptive radiologist.
Radiologists interact with many individuals during daily practice, including patients, technologists, and other physicians. Some interactions may potentially negatively affect patient care and are termed "disruptive" behaviors. These actions are not uncommon and may begin during training, long before a radiologist enters clinical practice. The causes of disruptive behavior are multifactorial, and it is important that educators and radiologists in practice alike be able to identify them and respond accordingly. An escalated approach for both trainees and practicing radiologists is recommended, with substantial penalties after each incident that can include termination of employment. Training programs and practices must have clearly defined methods for confronting this potentially time-consuming and difficult issue.


Stability-indicating methods for the determination of sumatriptan succinate.
Four stability-indicating methods were developed for the determination of sumatriptan succinate in the presence of its degradation products. The first method depends on the quantitative densitometric evaluation of thin-layer chromatography of sumatriptan succinate in the presence of its degradation products without any interference. Cyclohexane-dichloromethane-diethylamine (50:40:10 v/v/v) was used as a mobile phase and the chromatogram was scanned at 228 nm. This method determines sumatriptan succinate in the concentration range l-8 microg per spot with mean percentage recovery 100.52+/-1.23%. The second and third methods depend on the use of first-derivative (D(1)) and second-derivative (D(2)) spectrophotometry at 234 and 238 nm, respectively. These methods determine the drug in the concentration range 1.25-10 microg x ml(-1) with mean percentage recovery 99.91+/-1.01% and 99.96+/-1.13% for (D(1)) and (D(2)), respectively. The fourth method depends on the use of ratio derivative spectrophotometric technique. The amplitude in the first derivative of the ratio spectra at 235 nm was selected to determine the cited drug in the presence of its degradation products. Calibration graph is linear in the concentration range 1.25-10 microg x ml(-1) with mean percentage recovery 100.19+/-1.19%. The suggested methods were successfully applied for determining sumatriptan succinate in bulk powder, laboratory-prepared mixtures and pharmaceutical dosage forms (Imigran tablet) with good accuracy and precision. The results obtained by applying the proposed methods were statistically analyzed and compared with those obtained by the reported method.


Switching and amplification in disordered lasing resonators.
Controlling the flow of energy in a random medium is a research frontier with a wide range of applications. As recently demonstrated, the effect of disorder on the transmission of optical beams may be partially compensated by wavefront shaping, but losing control over individual light paths. Here we demonstrate a novel physical effect whereby energy is spatially and spectrally transferred inside a disordered active medium by the coupling between individual lasing modes. We show that it is possible to transmit an optical resonance to a remote point by employing specific control over optical excitations, obtaining a random lasing system, which acts both as a switch and as an amplifier.


Organization of radial glial cells during the development of the rat dentate gyrus.
The temporal and spatial patterns of development of radial glial processes in the rat dentate gyrus have been studied in immunohistochemical preparations stained for the presence of either the glial fibrillary acidic protein (GFAP) or the vimentin-associated antigen R4. Additional electron microscopic (EM) observations were made from material prepared either immunohistochemically or by the Golgi method. R4 immunoreactive radial fibers were observed in the incipient dentate gyrus as early as E13 and by E14 the density of stained fibers was clearly higher in the anlage of the dentate gyrus than in the adjacent hippocampus. By E15 it was possible to identify in the EM the endfeet of radial glial cells that contained numerous glycogen particles. GFAP-positive radial processes were first observed on E17; these processes tended to be of larger diameter than those stained with the R4 antibody, suggesting that they were among the more mature processes. The orientation of both the R4- and GFAP-positive glial processes changed throughout the last week of embryonic life and by the end of the first postnatal week they formed a complex meshwork of intertwined processes. The distribution of their cell bodies also changed with time; initially their perikarya were located in the neuroepithelium at the lateral margin of the hippocampal primordium; later they were found mainly beneath the granule cell layer. Dividing cells that contained GFAP were observed along the trajectory of the migrating granule cell precursors and in the hilus of the dentate gyrus; at later stages some GFAP-positive mitotic figures were seen within and immediately below the granule cell layer. On the basis of these observations, we have attempted to reconstruct the role that radial glial processes play in the morphogenesis of the dentate gyrus. First, radial processes extend from the neuroepithelium to the pial surface prior to the migration of neurons that will form the dentate gyrus. These early generated glia appear to form the boundaries of the developing dentate gyrus and provide an internal lattice that may guide the initial wave of migrating progenitor cells. As the dentate gyrus enlarges, these early formed processes maintain their contacts along the hippocampal fissure and along the pial surface of the dentate anlage. Thus, with time they become increasingly distorted and are ultimately compressed into two bundles; one lies deep to the hippocampal fissure parallel to the granule cell layer and the other is located at the fimbriodentate juncture.(ABSTRACT TRUNCATED AT 400 WORDS)


Cortical excitability in neuroleptic-naive first-episode schizophrenic patients.
Transcranial magnetic stimulation (TMS) provides an intriguing in vivo method to investigate motor cortex excitability in men. This offers new insights into the neurophysiological basis of neuropsychiatric diseases. Earlier TMS studies in patients with schizophrenia revealed inconsistent results, probably due to major confounding variables like state of medication and stage of illness. To control for these effects, we studied two TMS paradigms in 21 drug-naive first-episode schizophrenic patients and 21 age- and sex-matched healthy controls. The patient group demonstrated a significant lower resting motor threshold as compared with healthy controls, whereas TMS paradigms of intracortical inhibition and intracortical facilitation failed to show significant differences between patients and controls. This pattern of TMS parameters is similar to that obtained in healthy volunteers investigated under increasing doses of ketamine, a central acting drug known to produce psychosis-like effects. In agreement with recent results of functional imaging, our neurophysiological findings suggest that drug-induced and naturally occurring psychosis may share a common pathway, which may base on dysfunctional glutamatergic mechanisms.


The Impact of Multiple Prostate Needle Biopsies on Long-Term Erectile Dysfunction.
The impact of transrectal ultrasound guided prostate needle biopsy on erectile dysfunction remains uncertain. We examined whether transrectal ultrasound guided prostate needle biopsy contributes to the development or worsening of erectile dysfunction as assessed by IIEF-5 scores in patients who underwent multiple prostate needle biopsies. The study population consisted of 826 men who underwent transrectal ultrasound guided 10 to 12-core prostate needle biopsy for suspicion or surveillance of prostate cancer. Men were evaluated for erectile dysfunction using the IIEF-5 questionnaire. Erectile dysfunction was modeled as a categorical variable, defined as any (0 to 20), mild (16 to 20), mild to moderate (11 to 15), moderate (6 to 10) or severe (0 to 5). The impact of multiple prostate needle biopsies was also evaluated. Of 826 men who underwent prostate needle biopsy 240 (29%) had undergone 1 or more and 168 (20%) had undergone 2 or more biopsies. Mean patient age was 63 years and mean IIEF-5 score was 16. On univariate analysis age (OR 1.11, 95% CI 1.09-1.14, p <0.001), and 1 (OR 1.79, 95% CI 1.06-3.03, p=0.03) or 2 (OR 1.80, 95% CI 1.02-3.17, p=0.04) prior prostate needle biopsies were associated with erectile dysfunction. On multivariate analysis age alone was predictive of severe erectile dysfunction (OR 1.09, 95% CI 1.05-1.12, p=0.002). A repeat prostate needle biopsy within 12 months was associated with worse erectile dysfunction (OR 1.55, 95% CI 1.08-2.93, p=0.02). When long-term erectile function was evaluated, prostate needle biopsy was not significant after adjustment for covariates. In the short term prostate needle biopsy may be important in predicting transient (less than 1 year) erectile dysfunction. However, in the long term prostate needle biopsy does not predict erectile dysfunction in aging men.


Separate presentation of additional accelerating motion does not enhance visually induced self-motion perception.
It has been repeatedly reported that visual stimuli containing ajittering/oscillating motion component can induce self-motion perception more strongly than a pure radial expansion pattern. A psychophysical experiment with 11 observers revealed that the additional accelerating components of the visual motion have to be convoluted with the motion of the main-axis to facilitate self-motion perception; additional motion presented in an isolated fashion impairs the perception of self-motion. These results are inconsistent with a simple hypothesis about the perceptual mechanism underlying the advantage of jitter/oscillation, which assumes that the accelerating component induces an additional self-motion independently of the main motion at the first stage, and then the two self-motions induced by the main motion and the additional component become integrated.


The optimal therapy strategy for epidermal growth factor receptor-mutated non-small cell lung cancer patients with brain metastasis: A real-world study from Taiwan.
The treatment options for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases (BMs) include EGFR-tyrosine kinase inhibitors (TKIs), stereotactic radiosurgery (SRS), whole-brain radiotherapy, brain surgery, and antiangiogenesis therapy. As treatment options evolve, redefining optimal treatment strategies to improve survival are crucial. A total of 150 EGFR-mutant NSCLC patients with BMs who received first- or second-generation EGFR-TKIs as first-line treatment between January 2012 and October 2019 were included in this analysis. After multivariate analysis, patients with the graded prognostic assessment for lung cancer using molecular markers (Lung-mol GPA) ≥3 (hazard ratio [HR]: 0.538, 95% confidence interval [CI]: 0.35-0.83), who received afatinib or erlotinib as first-line treatment (HR: 0.521, 95% CI: 0.33-0.82), underwent SRS therapy (HR: 0.531, 95% CI: 0.32-0.87), or were sequentially treated with osimertinib (HR: 0.400, 95% CI: 0.23-0.71) were associated with improved overall survival (OS). Furthermore, SRS plus EGFR-TKI provided more OS benefits in patients with Lung-mol GPA ≥3 compared with EGFR-TKI alone in our patient cohort (44.9 vs. 26.7 months, p = 0.005). The OS in patients who received sequential osimertinib therapy was significantly longer than those without osimertinib treatment (43.5 vs. 24.3 months, p < 0.001), regardless of T790 mutation status (positive vs. negative vs. unknown: 40.4 vs. 54.6 vs.43.4 months, p = 0.227). The study demonstrated that EGFR-mutant NSCLC patients with BMs could be precisely treated with SRS according to Lung-mol GPA ≥3. Sequential osimertinib was associated with prolonged survival, regardless of T790M status.


Recovery of intellectual ability after closed head-injury.
Seven children with intellectual and personality changes after closed head-injury were followed-up with neuropsychological and psycho-educational evaluations. Two cases are presented in detail. Persistent intellectual changes documented on standardized tests were not always apparent to parents or physicians, and recovery of intellectual abilities lagged behind the disappearance of neurological abnormalities. Some of the children required special class placement for several years after the injury. Personality changes were thought to be secondary to stress on impaired perceptual and cognitive abilities, and the desirability of limiting such stress is emphasized.


Transformations of prostaglandin H2 in the cat brain.
Transformations of prostaglandin H2 were studied in the whole homogenate and subcellular fractions (microsomes, high-speed supernatant) of the cat brain. Prostaglandin H2 was converted enzymatically to prostaglandin E2, 6-ketoprostaglandin F 1 alpha, and thromboxane B2. While prostaglandin E2 and thromboxane B2 predominated, respectively, in the whole homogenate and the microsomes, 6-ketoprostaglandin F1 alpha was formed in both tissue preparations. Pretreatment of the microsomes with reduced glutathione stimulated the formation of prostaglandin E2 at the expense of 6-ketoprostaglandin F1 alpha and thromboxane B2. Imidazole and 15-hydroperoxyarachidonic acid interfered with the microsome-induced transformations of prostaglandin H2 to thromboxane B2 and 6-ketoprostaglandin F1 alpha, respectively. No prostaglandin D2 was detected even after treatment of the tissue with reduced glutathione. Prostaglandin H2, on the other hand, was converted to prostaglandin F2 alpha, but the yield of this compound in native tissue was equal to, or lower than, that in boiled tissue. We conclude that the feline brain is endowed with several enzymes (prostaglandin E2 isomerase, thromboxane A2 and prostaglandin I2 synthetases) competing for the added endoperoxide. All enzymes were located in the microsomes. No evidence was obtained indicating enzymic reduction of prostaglandin H2 to prostaglandin F2 alpha.


Sister chromatid exchanges in human lymphocytes exposed to 8-methoxypsoralen and long wave UV radiation prior to incorporation of bromodeoxyuridine.
Human lymphocytes exposed to the effects of long wave UV radiation in the presence of 8-methoxypsoralen prior to stimulation by PHA show dose related sister chromatid exchanges after 2 replication cycles in vitro. This has implications for interpreting the processes involved and for monitoring DNA damaging agents in vivo.


Multistage Chemical Heating for Instrument-Free Biosensing.
Improving the portability of diagnostic medicine is crucial for alleviating global access-to-care deficiencies. This requires not only designing devices that are small and lightweight, but also autonomous and independent of electricity. Here, we present a strategy for conducting automated multistep diagnostic assays using chemically generated, passively regulated heat. Ligation and polymerization reagents for rolling circle amplification of nucleic acids are separated by meltable phase-change partitions, thus replacing precise manual reagent additions with automated partition melting. To actuate these barriers and individually initiate the various steps of the reaction, field ration heaters exothermically generate heat in a thermos, whereas fatty acids embedded in a carbonaceous matrix passively buffer the temperature around their melting points. Achieving multistage temperature profiles extend the capability of instrument-free diagnostic devices and improve the portability of reaction automation systems built around phase-change partitions.


Detection of a natural antibody targeting the shed ectodomain of BP180 in mice.
Pemphigoid diseases are characterized by subepidermal blister formation accompanied by autoantibodies targeting skin component molecules, such as BP180. It is suggested that an epitope-phenotype correlation exists among autoantibodies recognizing BP180. However, it is unclear which regions of BP180 are likely targets for autoantibodies. To elucidate the portions of BP180 where antibodies tend to react under the breakdown of immune tolerance. We immunized mice with full-length mouse BP180 (mBP180) to produce anti-mBP180 antibodies. Using the immunized mice, hybridoma cells were established to produce anti-mBP180 antibodies. We analyzed the characteristics of the anti-mBP180 antibodies that were produced in terms of epitopes, immunoglobulin subclasses, and somatic hypermutations. Hybridoma cells derived from immunized mice with full-length mBP180 produced antibodies targeting the intracellular domain (IC) and the shed ectodomain (EC) of mBP180. Using the domain-deleted mBP180 recombinant protein, we revealed that monoclonal anti-mBP180 EC antibodies react to neoepitopes on the 13th collagenous region of cleaved mBP180, which corresponds to the epitopes of linear IgA bullous dermatosis antibodies in human BP180. Furthermore, the subclasses of these antibodies could be distinguished by epitope: The subclass of the anti-mBP180 IC monoclonal antibodies was IgG, whereas that of the anti-mBP180 EC antibodies was IgM. Of note, a clone of these IgM mBP180 EC antibodies was a germline antibody without somatic hypermutation, which is also known as a natural antibody. These data suggest that mice potentially have natural antibodies targeting the neoepitopes of cleaved mBP180 EC.


Gas cooking and respiratory outcomes in children: A systematic review.
The most recent meta-analysis of gas cooking and respiratory outcomes in children was conducted by Lin et al. [93] in 2013. Since then, a number of epidemiology studies have been published on this topic. We conducted the first systematic review of this epidemiology literature that includes an in-depth evaluation of study heterogeneity and study quality, neither of which was systematically evaluated in earlier reviews. We reviewed a total of 66 relevant studies, including those in the Lin et al. [93] meta-analysis. Most of the studies are cross-sectional by design, precluding causal inference. Only a few are cohort studies that could establish temporality and they have largely reported null results. There is large variability across studies in terms of study region, age of children, gas cooking exposure definition, and asthma or wheeze outcome definition, precluding clear interpretations of meta-analysis estimates such as those reported in Lin et al. [93]. Further, our systematic study quality evaluation reveals that a large proportion of the studies to date are subject to multiple sources of bias and inaccuracy, primarily due to self-reported gas cooking exposure or respiratory outcomes, insufficient adjustment for key confounders (e.g., environmental tobacco smoke, family history of asthma or allergies, socioeconomic status or home environment), and unestablished temporality. We conclude that the epidemiology literature is limited by high heterogeneity and low study quality and, therefore, it does not provide sufficient evidence regarding causal relationships between gas cooking or indoor NO2 and asthma or wheeze. We caution against over-interpreting the quantitative evidence synthesis estimates from meta-analyses of these studies.


Correction: Updated cost-effectiveness of MDMA-assisted therapy for the treatment of posttraumatic stress disorder in the United States: Findings from a phase 3 trial.
[This corrects the article DOI: 10.1371/journal.pone.0263252.].


Evolution of the viral hemorrhagic septicemia virus: divergence, selection and origin.
Viral hemorrhagic septicemia virus (VHSV) is an economically significant rhabdovirus that affects an increasing number of freshwater and marine fish species. Extensive studies have been conducted on the molecular epizootiology, genetic diversity, and phylogeny of VHSV. However, there are discrepancies between the reported estimates of the nucleotide substitution rate for the G gene and the divergence times for the genotypes. Herein, Bayesian coalescent analyses were conducted to the time-stamped entire coding sequences of the six VHSV genes. Rate estimates based on the G gene indicated that the marine genotypes/subtypes might not all evolve slower than their major European freshwater counterpart. Age calculations on the six genes revealed that the first bifurcation event of the analyzed isolates might have taken place within the last 300 years, which was much younger than previously thought. Selection analyses suggested that two codons of the G gene might be positively selected. Surveys of codon usage bias showed that the P, M and NV genes exhibited genotype-specific variations. Furthermore, we proposed that VHSV originated from the Pacific Northwest of North America.


Making Maternal Child Health a Population Health Priority in Maryland.
This case study illustrates state legislative advocacy in action in Maryland. Success in strengthening maternal and child health is described using the Academic Pediatric Association's 4-step approach to advocacy: (1) Identify the Issue and Target Audience; (2) Craft the Message; (3) Develop Relationships and Coalitions, and (4) Communicate the Message. Starting with state legislation and formation of a Maryland Maternal Child Health Task Force led to maternal child health named as 1 of 3 state population health priorities. This guided subsequent programmatic investment and attention. Further dissemination of task force recommendations has led to additional supportive legislation.


Role of interleukin-6 in antigen-specific mucosal immunoglobulin A induction by cationic liposomes.
The COVID-19 pandemic, caused by a highly virulent and transmissible pathogen, has proven to be devastating to society. Mucosal vaccines that can induce antigen-specific immune responses in both the systemic and mucosal compartments are considered an effective measure to overcome infectious diseases caused by pathogenic microbes. We have recently developed a nasal vaccine system using cationic liposomes composed of 1,2-dioleoyl-3-trimethylammonium-propane and cholesteryl 3β-N-(dimethylaminoethyl)carbamate in mice. However, the comprehensive molecular mechanism(s), especially the host soluble mediator involved in this process, by which cationic liposomes promote antigen-specific mucosal immune responses, remain to be elucidated. Herein, we show that intranasal administration of cationic liposomes elicited interleukin-6 (IL-6) expression at the site of administration. Additionally, both nasal passages and splenocytes from mice nasally immunized with cationic liposomes plus ovalbumin (OVA) were polarized to produce IL-6 when re-stimulated with OVA in vitro. Furthermore, pretreatment with anti-IL-6R antibody, which blocks the biological activities of IL-6, attenuated the production of OVA-specific nasal immunoglobulin A (IgA) but not OVA-specific serum immunoglobulin G (IgG) responses. In this study, we demonstrated that IL-6, exerted by nasally administered cationic liposomes, plays a crucial role in antigen-specific IgA induction.


A Framework for Predicting Intraspecific Variation in Plant Defense.
One of the most well-supported theories regarding the evolution of plant defenses is the resource availability hypothesis (RAH). RAH posits that species from high-resource environments grow fast and allocate little to herbivore-resistance traits, whereas those species in low-resource environments grow slow and are highly resistant to herbivores. However, within species, how resources influence defense is unclear and existing theories make opposing predictions. Here, we review studies documenting intraspecific variation in plant defense across resource gradients and find little support for RAH. We outline why RAH does not apply intraspecifically and present a predictive framework for understanding how resources influence intraspecific variation in plant defense. Our framework provides an important step towards reconciling inter- versus intraspecific strategies of defense.


The telochore: a telomeric differentiation of the chromosome axis.
We have analysed by means of silver staining the structure of the chromosome axis at the telomeres of meiotic chromosomes in three different grasshopper species. At metaphase I the chromatid axes run the length of the chromatids although they do not reach the chromosome ends. The axes of sister chromatids are associated and show a round differentiation at their distal ends that we have named the 'telochore'. Telochores never contact the chromosome ends: there is always some chromatin beyond them. In late metaphase I bivalents with a distal chiasma, anaphase I and metaphase II half-bivalents and anaphase II chromatids, the axes clearly possess one telochore in each chromosome end. These results seem to indicate that telochores are differentiations of the distal ends of chromatids. We discuss the possible structural significance of telochores according to the current scaffold/radial loop model of chromatin organization of eukaryotic metaphase chromosomes. Additionally, we suggest the possible functional role of the telochore as a nucleoprotein domain forming a protective cap for telomeric DNA.


Construction of an Indonesian herbal constituents database and its use in Random Forest modelling in a search for inhibitors of aldose reductase.
Data on phytochemical constituents of plants commonly used in traditional Indonesian medicine have been compiled as a computer database. This database (the Indonesian Herbal constituents database, IHD) currently contains details on ∼1,000 compounds found in 33 different plants. For each entry, the IHD gives details of chemical structure, trivial and systematic name, CAS registry number, pharmacology (where known), toxicology (LD(50)), botanical species, the part(s) of the plant(s) where the compounds are found, typical dosage(s) and reference(s). A second database has been also been compiled for plant-derived compounds with known activity against the enzyme, aldose reductase (AR). This database (the aldose reductase inhibitors database, ARID) contains the same details as the IHD, and currently comprises information on 120 different AR inhibitors. Virtual screening of all compounds in the IHD has been performed using Random Forest (RF) modelling, in a search for novel leads active against AR-to provide for new forms of symptomatic relief in diabetic patients. For the RF modelling, a set of simple 2D chemical descriptors were employed to classify all compounds in the combined ARID and IHD databases as either active or inactive as AR inhibitors. The resulting RF models (which gave misclassification rates of 21%) were used to identify putative new AR inhibitors in the IHD, with such compounds being identified as those giving RF scores >0.5 (in each of the three different RF models developed). In vitro assays were subsequently performed for four of the compounds obtained as hits in this in silico screening, to determine their inhibitory activity against human recombinant AR. The two compounds having the highest RF scores (prunetin and ononin) were shown to have the highest activities experimentally (giving ∼58% and ∼52% inhibition at a concentration of 15μM, respectively), while the compounds with lowest RF scores (vanillic acid and cinnamic acid) showed the lowest activities experimentally (giving ∼29% and ∼44% inhibition at a concentration of 15μM, respectively). These simple virtual screening studies were thus helpful in identifying novel inhibitors of AR, but yielded compounds with only very modest (micromolar) potency.


Characteristics of collagenolytic enzymes secreted by deuteromycete fungi Aspergillus flavus.
Collagen induced the synthesis of collagenolytic enzymes in the culture of Aspergillus flavus. Enzyme activity of the culture increased during storage and passage on a medium with this inductor. We developed a method for isolation and purification of collagenolytic enzymes and obtained two electrophoretically homogenous enzyme preparations belonging to neutral thermolabile collagenolytic metalloproteinases.


Mortality rate of chronically ill geriatric patients with subnormal serum thyrotropin concentration: a 2-yr follow-up study.
We investigated the natural course of subclinical thyroid dysfunctions in geriatric patients, especially regarding their association with mortality rate. Ninety-three randomly selected chronically ill geriatric patients 64- 87 (median: 77) yr of age participated in the screening study with a 2-yr follow-up. Serum thyrotropin (thyroid- stimulating hormone [TSH]), free thyroxine, triiodothyronine, and antibodies against thyroid peroxidase were measured. During the follow-up, patients with suppressed TSH levels who were otherwise euthyroid (untreated) had a higher mortality rate than patients with normal TSH (5/8 vs 18/64; p < 0.05). The initial clinical state of these two subgroups did not differ significantly. Two-thirds of patients with treated hyperthyroidism died. The mortality rate of patients with initially subnormal but not suppressed TSH level was average and did not differ statistically from either the euthyroid or the hyperthyroid groups. Only 1 of 13 euthyroid patients with positive thyroid antibody titers developed a subsequent subclinical hypothyroidism. Subclinical hyperthyroidism was found to be associated with a higher mortality rate in chronically ill geriatric patients, which justifies screening for thyroid dysfunction and treatment of subclinical hyperthyroidism. In addition, a subnormal but measurable TSH was not indicative regarding the future development of hyperthyroidism. Finally, during the 2-yr follow-up, antibody positivity in the euthyroid cases did not prove to be predictive for the subsequent development of hypothyroidism.


Structure-Based Optimization of Antibody-Based Biotherapeutics for Improved Developability: A Practical Guide for Molecular Modelers.
A great effort to avoid known developability risks is now more often being made earlier during the lead candidate discovery and optimization phase of biotherapeutic drug development. Predictive computational strategies, used in the early stages of antibody discovery and development, to mitigate the risk of late-stage failure of antibody candidates, are highly valuable. Various structure-based methods exist for accurately predicting properties critical to developability, and, in this chapter, we discuss the history of their development and demonstrate how they can be used to filter large sets of candidates arising from target affinity screening and to optimize lead candidates for developability. Methods for modeling antibody structures from sequence and detecting post-translational modifications and chemical degradation liabilities are also discussed.


Sudden death in cases with anomalous origin of the left coronary artery.
Ectopic origin of the left coronary artery from the right sinus of valsalva with anterior and posterior courses are thought to be benign anomalies. a 58-year-old woman died suddenly after a car accident without having sustained any injuries. The only abnormal finding was an ectopic origin of the left coronary artery from the right sinus with anterior free wall course. The anomaly was complicated by the absence of a left descending branch and a hypoplastic circumflex artery. A 38-year-old male died suddenly during work. Beside the ostium of the right coronary artery originated the normal calibered circumflex branch of the left coronary artery which passed behind the aorta. The left anterior descending branch had a normal origin. There was a 2 cm in diameter transmural infarct observed microscopically.


Electrospun PA6 multi-stage structured nanofiber membrane with high filtration performance for oily particles.
Oily particles pollution poses a tremendous threat to people's health, so it is urgent to develop air filtration materials with the ability of removing fine oily particles effectively. In this study, a nylon 6 multi-stage structured nanofiber membrane (PA6 MSNM) for effective air filtration of fine oily particles was designed and fabricated by adding a certain amount of tetrabutylammonium hexafluorophosphate (TBAHP) via one-step electrospinning. The PA6 MSNMs were composed of coarse trunk fibres and fine branching fibres. Benefiting from the properties of small pore size and high porosity, the resulting PA6 MSNMs exhibited high average filtration efficiency of 99.80% for oily aerosol particles of 0.20-4.59 μm, a low pressure drop of 251 Pa, and the high quality factor of 0.0248 Pa-1. More importantly, its filtration efficiencies for oily aerosol particles of 0.25 and 0.30 μm were up to 99.99% and 100.00%, respectively. It is expected that the multi-stage electrospun nanofiber membranes would have wide application prospects in air filtration, particularly for filtering oily particles.


Comparative study of diagnostic efficacy of sputum and bronchoalveolar lavage fluid specimens in community-acquired pneumonia children treated with fiberoptic bronchoscopy.
Community-acquired pneumonia (CAP) is usually diagnosed in children, and the type of respiratory specimen is critical. Differences in pathogens detection between induced sputum (IS) and bronchoalveolar lavage fluid (BALF) have not been evaluated. In 2018, paired sputum and BALF samples from CAP hospitalised children with indications for bronchoalveolar lavage (BAL) were subjected to multiplex PCR for the detection of 11 common respiratory pathogens. A total of 142 children with paired sputum and BALF were tested. The overall positivity rate was 85.9% (122/142) for sputum and 80.3% (114/142) for BALF. The two specimens presented almost perfect agreement between the detection on M. pneumoniae, influenza A, influenza B, bocavirus and RSV. In contrast, adenovirus had the lowest kappa value of 0.156, and a false negative rate (FNR) of 66.7%. Rhinovirus had the highest false positive rate (FPR) as 18.5%. The consistent rate was significantly higher in school-age children than those under 1 year old (p = .005). Bacterial co-infection in BALF specimens were observed in 14.8% (21/142). Of the 11 discordant pairs of specimens, 9 cases were sputum(+)/BALF(-) with adenovirus predominating. Our findings suggest that the consistency of results between sputum and BALF is pathogen specific. Careful consideration needs to be given to whether sputum can be used as a substitute for BALF when children are young or co-infections with bacteria are suspected.


Species differences in the activity of a serum triglyceride transferring factor.
Low density lipoproteins (LDL), endogenously labelled with 3H in the triglyceride moiety, were isolated from rabbit serum and subsequently incubated in vitro at 37 degrees C with unlabelled preparations of rabbit high density lipoproteins (HDL) or very low density lipoproteins (VLDL). In incubations performed in the presence of phosphate buffer, there was no significant transfer of [3H]triglyceride from LDL to either HDL or VLDL; but when rabbit lipoprotein-free serum (the dialysed 1.21 g/ml infranatant) was added, transfer was apparent to both HDL and VLDL. The triglyceride transferring activity of the lipoprotein-free serum was abolished by heating at 85 degrees C for 10 min; all the transferring activity was found in the fraction which precipitated with ammonium sulphate at a concentration of less than 50% saturation. In direct contrast to the rabbit studies, rat serum failed to show a comparable process of triglyceride transfer. In subsequent experiments, mixtures of labelled LDL and unlabelled VLDL isolated either from rabbits or from rats were incubated with lipoprotein-free rabbit, rat or human serum. The lipoprotein-free serum of both the rabbit and man was effective in promoting transfer of 30--50% of LDL [3H]triglyceride into VLDL, regardless of the species origin of the lipoproteins. By contrast the lipoprotein-free serum of rats was only slightly more effective than buffer alone in promoting such transfers. It has been concluded that rabbit and human serum contains a triglyceride transferring factor of far greater activity than that in rat serum.


Modulated expression and enzymatic activities of Darkbarbel catfish, Pelteobagrus vachelli for oxidative stress induced by acute hypoxia and reoxygenation.
Large changes in oxygen availability in aquatic environments, ranging from anoxia through to hyperoxia, can lead to corresponding wide variation in the production of reactive oxygen species (ROS) by fish with aquatic respiration. In order to evaluate the effects of hypoxia and reoxygenation on oxidative stress in fish, the mRNA and protein expression of SODs (Cu/Zn-SOD and Mn-SOD) as well as indices (CP, LPO and MDA) and enzymatic activities (SOD, CAT, GPx, GR and GST) were analyzed in liver and brain tissues of Pelteobagrus vachelli. Predominant expression of PvSOD2 was detected in heart, brain, and liver. In contrast, PvSOD1 was highly expressed in liver. Based on the expression patterns of above parameters, we inferred that brain tissue of P. vachelli under 0.7 mg/L degree of acute hypoxia condition could experience hypometabolic states or no suffering stress, but brain tissue has effective mechanisms to minimize or prevent oxidative stress during the transition from hypoxia to reoxygenation. Our results also demonstrated an increased expression of SODs and enzymatic activities for oxidative stress in liver under hypoxic conditions, which supports the hypothesis that anticipatory preparation takes place in order to deal with the encountered oxidative stress during the recovery from hypoxia as proposed by M. Hermes-Lima. Therefore, this study will provide a clue to better understand the action mode of antioxidant genes and enzymes under oxidative stress in fish.


Analysis of human abnormal walking using a multi-body model: joint models for abnormal walking and walking aids to reduce compensatory action.
This paper proposes new models of diseased joints and evaluates the effectiveness of walking aids such as a cane and a brace for compensating for lost functions due to joint disorders. The ZMJ concept described in the previous work (Yamashita and Tagawa, 1988. In: Radharaman (Ed.), Robotics and Factories of the Future'87. Springer, New York, pp. 670-677) is modified into three joint models as follows: a passive element joint (PEJ) which has a spring at the diseased joint; a constrained range joint (CRJ), the motion of which stays within some constrained relative angle; a partial moment joint (PMJ) which can produce a partial amount of the moment produced about the joint in normal walking. A cane can enlarge a supporting area and adjust the posture of the upper torso to be upright. An ischial weight-bearing brace is effective for conservative management of hip disorders by reducing a load to the joint (Shiba et al., 1998. Clinical Orthopaedics and Related Research 351, 149-157). Walking aids like a cane or brace have been conveniently used by the handicapped. Abnormal walking was simulated for each joint model. Dynamic effects of a cane and a brace on abnormal walking were examined by the multi-body walking model.