Evaluation of the effects of locally applied rosuvastatin on bone formation in a three-dimensional reconstruction rabbit xenograft model
Guided bone regeneration (GBR) is commonly performed to repair bone defects, and rigid occlusive titanium barriers play a vital role in bone formation in regions with no prior bone tissue. The statin, rosuvastatin (RSV), strongly affects bone apposition when applied locally. Here, we aimed to evaluate the anabolic effects of locally applied RSV with a xenograft placed on rabbit calvaria. Two rigid occlusive titanium caps were used in 16 rabbits after decorticating the calvarial bone. In the control group, the area under the cap was filled with a xenograft, while in the RSV group, a xenograft in combination with RSV (1 mg) was used. In both groups, at 6 and 12 weeks, new bone, residual graft, soft tissue areas, and histological and radiological bone volume were evaluated. At 12 weeks, histologically, the RSV group exhibited superior new bone proportion values, and radiologically, new bone and total bone volume in the RSV group were significantly higher than in the control group (p < 0.05); there were no significant differences at 6 weeks (p > 0.05). According to our results, RSV applied locally under a titanium barrier on an area to be repaired with bone grafts increases new bone and total bone volume.


A new approach for treatment of deep skin infections by an ethosomal antibiotic preparation: an in vivo study.
Dermal and subdermal bacterial infections, caused mainly by Staphylococcus aureus, are currently treated by systemic antibiotics. The aim of the present study was to investigate a new approach to treat deep skin and soft tissue bacterial infections by dermal application of erythromycin in an ethosomal carrier. A model for deep dermal S. aureus infection in mice was developed. The efficiency of ethosomal erythromycin applied to the skin-infected site was compared with intraperitoneal erythromycin administration and with local application of hydroethanolic erythromycin solution. The parameters evaluated were the development of dermal wound, histological sections and bacterial count of the infected tissue. The in vivo experiments demonstrated a very efficient healing of S. aureus-induced deep dermal infections when the mice were treated with ethosomal erythromycin. Bacterial counts and histological evaluation of the skin treated with ethosomal antibiotic revealed no bacterial growth and normal skin structure. On the contrary, no subdermal healing was observed in infected animals treated with topical hydroethanolic erythromycin solution. In this group, animals developed deep dermal abscesses and the dermal structures were destroyed where S. aureus colonies were present. Bacterial counts of the infected tissues were 1.06 x 10(7) and 0.27 x 10(7) cfu/g of tissue, respectively, on days 7 and 10. Therapy with ethosomal erythromycin applied to the skin of S. aureus-infected mice was as effective as systemically administered erythromycin, suggesting a new possibility to treat deep dermal infections by local application of antibiotic in ethosomal carrier.


Learning-based resource optimization in asynchronous transfer mode (ATM) networks.
This paper tackles the issue of bandwidth allocation in asynchronous transfer mode (ATM) networks using recently developed tools of computational intelligence. The efficient bandwidth allocation technique implies effective resources utilization of the network. The fluid flow model has been used effectively among other conventional techniques to estimate the bandwidth for a set of connections. However, such methods have been proven to be inefficient at times in coping with varying and conflicting bandwidth requirements of the different services in ATM networks. This inefficiency is due to the computational complexity of the model. To overcome this difficulty, many approximation-based solutions, such as the fluid flow approximation technique, were introduced. Although such solutions are simple, in terms of computational complexity, they nevertheless suffer from potential inaccuracies in estimating the required bandwidth. Soft computing-based bandwidth controllers, such as neural networks- and neurofuzzy-based controllers, have been shown to effectively solve an indeterminate nonlinear input-output (I-O) relations by learning from examples. Applying these techniques to the bandwidth allocation problem in ATM network yields a flexible control mechanism that offers a fundamental tradeoff for the accuracy-simplicity dilemma.


Cerebral Venous Thrombosis Presenting as Simultaneous Intracerebral Hemorrhage.
A 37-year-old pregnant woman presented to the emergency department with central facial palsy, ipsilateral right hemiparesis, and seizures. Brain Computed Tomogram (CT) showed intracerebral hemorrhage (ICH) and bilateral frontal edema. Magnetic resonance imaging (MRI) revealed multifocal hemorrhages consistent with a diagnosis of multiple simultaneous ICH (MSICH) (Figure 1). We suspected cerebral venous thrombosis (CVT) and performed a MR angiogram confirming this diagnosis (Figure 2). Upon admission, the patient was treated with low-molecular-weight heparin and transitioned to direct oral anticoagulation at discharge. Non traumatic MSICH is a rare imaging finding with high mortality, usually arterial in origin (1). However, since treatment options vary, cerebral venous thrombosis should always be considered in the differential diagnosis, especially in young female patients with known risk factors, such as pregnancy and puerperium (2-4). MRI modalities (Echo-GRE) are valuable tools in identifying ICH when CT is inconclusive (5).


Repetitive transcranial magnetic stimulation in a patient suffering from depression and rheumatoid arthritis: evidence for immunomodulatory effects.
Repetitive transcranial magnetic stimulation (rTMS) has been suggested as antidepressive treatment strategy. The mechanism of action by which the antidepressive effect is brought about remains unclear at present. Here, we report findings in a patient suffering from recurrent major depression and rheumatoid arthritis. Improvement of depressive symptoms during 20 Hz rTMS of the left dorsolateral prefrontal cortex was repeatedly associated with a systemic inflammatory reaction, suggesting that rTMS induced an immunomodulatory effect.


Complexity-enhanced polarization-resolved chaos in a ring network of mutually coupled vertical-cavity surface-emitting lasers with multiple delays.
The complexity properties of polarization-resolved chaotic signals generated in a ring network of vertical-cavity surface-emitting lasers (VCSELs) mutually coupled with multiple delays are investigated quantitatively by using the proposed mean permutation entropy (MPE). For direct comparison, the complexity of polarization-resolved chaos in a ring network of VCSELs coupled with single delay is also considered. The effects of injection current, coupling strength, and frequency detuning on the chaotic complexity for both a single-delay ring network (SDRN) and a multiple-delay ring network (MDRN) are evaluated quantitatively and compared by the MPE. The effects of internal parameters of VCSELs on the complexity are also discussed, and the correlation properties between different polarization-resolved modes are also analyzed. It is shown that the complexity of chaos in two polarization-resolved modes of VCSELs in MDRN is much higher than those in SDRN in a much wider parameter region. Besides, wider range of injection current, coupling strength, and frequency detuning can be tuned to achieve the enhancement of chaotic complexity in MDRN. These results provide an effective quantifier, the proposed MPE, to evaluate quantitatively the complexity of chaos generated in systems with multiple delays, and the multichannel complexity-enhanced polarization-resolved chaos generated in MDRN of mutually coupled VCSELs is extremely meaningful for the chaos-based random number generators.


Genome-Scale Profiling and High-Throughput Analyses Unravel the Genetic Basis of Arsenic Content Variation in Rice.
Ionomics, the study of the composition of mineral nutrients and trace elements in organisms that represent the inorganic component of cells and tissues, has been widely studied to explore to unravel the molecular mechanism regulating the elemental composition of plants. However, the genetic factors of rice subspecies in the interaction between arsenic and functional ions have not yet been explained. Here, the correlation between As and eight essential ions in a rice core collection was analyzed, taking into account growing condition and genetic factors. The results demonstrated that the correlation between As and essential ions was affected by genetic factors and growing condition, but it was confirmed that the genetic factor was slightly larger with the heritability for arsenic content at 53%. In particular, the cluster coefficient of japonica (0.428) was larger than that of indica (0.414) in the co-expression network analysis for 23 arsenic genes, and it was confirmed that the distance between genes involved in As induction and detoxification of japonica was far than that of indica. These findings provide evidence that japonica populations could accumulate more As than indica populations. In addition, the cis-eQTLs of AIR2 (arsenic-induced RING finger protein) were isolated through transcriptome-wide association studies, and it was confirmed that AIR2 expression levels of indica were lower than those of japonica. This was consistent with the functional haplotype results for the genome sequence of AIR2, and finally, eight rice varieties with low AIR2 expression and arsenic content were selected. In addition, As-related QTLs were identified on chromosomes 5 and 6 under flooded and intermittently flooded conditions through genome-scale profiling. Taken together, these results might assist in developing markers and breeding plans to reduce toxic element content and breeding high-quality rice varieties in future.


Bipolar transurethral resection in saline (TURis): outcome and complication rates after the first 1000 cases.
TURis((R)) is an emerging technique that shows the same efficacy of monopolar resection. However, there is currently little available data on the safety of bipolar devices. We assessed outcome and safety of TURis on a large cohort of patients with at least 6 months' follow-up. Between January 2006 and October 2007, 1000 consecutive transurethral resection (TUR), 376 transurethral resection of prostate, 480 transurethral resection of bladder neoplasm, and 144 transurethral incision of prostate were performed. All procedures were carried out with a bipolar device in physiologic saline (TURis). The resectoscope used was an Olympus 26F in continuous flow-type Iglesias with continuous aspiration. The loops were all disposable/single use. The incidence of unwanted stimulation of the obturator reflex, TUR syndrome, thermal skin lesion, blood transfusion, urethral strictures, and bladder neck contractures were recorded. None of the patients operated experienced a TUR syndrome or a thermal skin lesion. The median follow-up of the entire cohort was 12 months (range, 6-24 months); 663 patients had at least 1-year follow-up (66.3%). Urethral stricture occurred in 27 patients (2.7%). Four patients developed a bladder neck contracture after transurethral resection of prostate (1%). Early postoperative clot retention occurred in 21 patients (2.1%), and 11 patients needed one or more transfusion (1.1%). Only six patients (2%) submitted to TUR of a neoplastic lesions at the lateral bladder wall experienced an unwanted trigger of the obturator reflex. TURis offers the patient the same results as monopolar technology guaranteeing maximum safety without increasing the incidence of urethral strictures.


Two bit optical analog-to-digital converter based on photonic crystals.
In this paper, we demonstrate a 2-bit optical analog-to-digital (A/D) converter. This converter consists of three cascaded splitters constructed in a self-guiding photonic crystal through the perturbation of the uniform lattice. The A/D conversion is achieved by adjusting splitting ratios of the splitters through changing the degree of perturbation. In this way, output ports reach a state of '1' at different input power levels to generate unique states desired for an A/D converter. To validate this design concept, we first experimentally characterize the relation between the splitting ratio and the degree of lattice perturbation. Based on this understanding, we then fabricate the 2-bit A/D converter and successfully observe four unique states corresponding to different power levels of input analog signal.


Intraocular lens power calculation by ray-tracing after myopic excimer laser surgery.
To investigate the refractive outcomes of intraocular lens (IOL) power calculation by ray-tracing after myopic excimer laser surgery. Prospective, interventional case series. setting: Multicenter study. participants: Twenty-one eyes of 21 patients undergoing phacoemulsification and IOL implantation after myopic laser in situ keratomileusis or photorefractive keratectomy were enrolled. intervention: IOL power calculation was performed using internal software of a Scheimpflug camera combined with a Placido disc corneal topographer (Sirius; CSO). Exact ray-tracing was carried out after the axial length (measured either by immersion ultrasound biometry or partial coherence interferometry), target refraction, and pupil size had been entered. main outcome measures: Median absolute error, mean absolute error, and mean arithmetic error in refraction prediction, that is, the difference between the expected refraction (as calculated by the software) and the actual refraction 1 month after surgery. The mean postoperative refraction was -0.43 ± 1.08 diopters (D), with a range between -1.28 and 0.85 D. The mean arithmetic error was -0.13 ± 0.49 D. The median and mean absolute errors were +0.25 D and 0.36 D, respectively. Also, 71.4% of the eyes were within ± 0.50 D of the predicted refraction, 85.7% were within ± 1.00 D, and 100% within ± 1.50 D. Ray-tracing can calculate IOL power accurately in eyes with prior myopic laser in situ keratomileusis and photorefractive keratectomy, with no need for preoperative data.


Campylobacter lanienae sp. nov., a new species isolated from workers in an abattoir.
Campylobacter-like organisms were isolated from the faeces of healthy individuals during a hygiene survey of abattoir workers. The strains, which exhibited characteristics of Campylobacter, being non-glucose-fermenting, oxidase- and catalase-positive, Gram-negative, motile rods, were identified to the genus level by a PCR assay. Nucleotide sequence analysis of the 16S rRNA gene, DNA homology experiments and determination of G + C content demonstrated that they constituted a previously undescribed species, whose nearest phylogenetic neighbours were Campylobacter hyointestinalis subsp. hyointestinalis, Campylobacter fetus and Campylobacter mucosalis. The name Campylobacter lanienae sp. nov. is proposed for this taxon and species-specific PCR primers were evaluated which will find use in the study of its epidemiology, prevalence and pathogenicity.


Dopamine stimulation of cAMP production in cultured opossum kidney cells.
Dopamine receptors have been identified in many tissues including the kidney. To establish an in vitro system as a model for dopamine action, we studied the effect of dopamine (DA) receptor agonists and antagonists on adenosine 3',5'-cyclic monophosphate (cAMP) formation in opossum kidney (OK) cells. The stimulation of cAMP production in these cells by dopamine was dose dependent, and markedly higher levels were observed in the presence of dopamine plus a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine. Half-maximal stimulation was found with 1.15 +/- 0.22 microM dopamine. A DA1-receptor agonist, SKF 82526J, stimulated cAMP production, whereas a DA2-receptor agonist, Ly 171555, did not. The stimulatory effects of dopamine and SKF 82526J were abolished by a specific DA1-receptor antagonist, Sch 23390 with half-maximal inhibition concentrations of 1.24 +/- 0.18 and 4.0 +/- 0.5 nM, respectively. In contrast, the DA2-receptor antagonist, spiperone, had no inhibitory effect on dopamine- and SKF 82526J-stimulated cAMP production. Beta-Adrenergic antagonists failed to attenuate the stimulatory effects of dopamine and SKF 82526J on cAMP production. In addition, the beta-adrenergic receptor agonist, isoproterenol, did not stimulate cAMP production. These results suggest that the action of dopamine was not mediated through beta-adrenergic receptors. Furthermore, our results clearly demonstrated the existence of DA1-receptors linked to adenylate cyclase in OK cells.


Effectiveness of train-the-trainer HIV education: a model from Vietnam.
As HIV prevention and treatment efforts expand around the globe, local capacity-building to update and maintain nurses' HIV competence is essential. The purpose of this project was to develop and sustain a national network of nurse-trainers who could provide ongoing HIV continuing education and training experiences to Vietnamese nurses. Over the course of 6 years, 87 nurses received training to become HIV trainers; their HIV knowledge increased significantly (p = .001), as did teaching self-confidence (p = .001 to .007). The 87 nurses subsequently reported training more than 67,000 health care workers. Recipients of train-the-trainer-led workshops demonstrated increased HIV knowledge (p = .001) and increased willingness to provide nursing care for HIV-infected patients (p = .001). The program demonstrated that including a substantial amount of instruction in pedagogical strategies and experiential learning could enhance knowledge transfer, expand education outreach, and contribute to sustainable HIV competence among nurses.


Aniseikonia and visual functions with optical correction and after refractive surgery in axial anisometropia.
To evaluate differences in the subjective aniseikonia and stereoacuity in patients with axial anisometropia after full correction of the refractive error with spectacles, contact lenses, and refractive surgery. A prospective study was performed in Cairo University Hospitals on 20 patients with axial anisometropia caused by unilateral myopia > 5 D with > 4 D inter-ocular difference in spherical equivalent who were suitable candidates for excimer laser ablation (LASIK) or implantable collamer lens implantation (ICL). All patients had measurement of best-corrected visual acuity (BCVA), fusion, stereoacuity, and magnitude of aniseikonia with spectacles, contact lenses, and after surgery. The mean age at time of surgery was 25.7 ± 3.1 years. There were no statistically significant differences in the BCVA or stereoacuity with spectacles, contact lenses, or after refractive surgery. Microkonia < 5%) was perceived with spectacles in 8 patients (40%) and remained unchanged in 7 of these 8 patients with contact lenses. Following LASIK (n = 11), there was an induced macrokonia < 2% in 4 patients (36%), persistent microkonia of 3% in 1 patient (9%), and no change in image size in 6 (55%) patients. Following ICL implantation (n = 9), there was a perceived macrokonia of 2% in 4 patients (44%), disappearance of microkonia in 1 patient (11%) and no change in 4 patients (44%). Differences in BCVA, stereoacuity, and aniseikonia after correction of anisometropia by glasses, contact lens and surgery are both clinically and statistically insignificant. Retinal or neural adaptation might have a role in correction for differences in image size.


Angular tolerant resonant grating filters under oblique incidence.
Resonant grating filters have been proposed as a promising alternative to multilayer stacks for narrowband free-space filtering. The efficiency of such filters under normal incidence has been demonstrated. Unfortunately, under oblique incidence, the limited angular tolerance of the resonance forbids any filtering applications with use of standard collimated incident beams. Using a multimode planar waveguide and a bi-atom grating, we show how to increase the angular tolerance up to the divergence of standard beams (0.2 deg) without modifying the spectral bandwidth (0.1 nm), under any oblique angle of incidence.


Tyrosine kinase inhibitors, immune checkpoint inhibitors combined with hepatic arterial infusion of oxaliplatin and raltitrexed versus oxaliplatin, 5-fluorouracil and leucovorin for intermediate and advanced hepatocellular carcinoma: A retrospective study.
Hepatic arterial infusion chemotherapy (HAIC) has demonstrated promising benefits in treating advanced hepatocellular carcinoma (HCC). In China, the most frequently used HAIC regimen is oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). However, arterial infusion of fluorouracil over 46 h was not convenient. Raltitrexed, another antimetabolic agent with a long plasma half-life, allows for shorter infusion durations. We aimed to compare the effectiveness and toxicity of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) combined with HAIC with raltitrexed plus oxaliplatin (RALOX) or FOLFOX in patients with intermediate and advanced HCC. This retrospective study enrolled 82 eligible patients from February 2019 to December 2021. Forty patients were treated with FOLFOX HAIC (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 administered on day 1, and 5-fluorouracil 2400 mg/m2 infusion for 46 h, every 3 weeks) combined with TKIs and ICIs. Forty-two patients received RALOX HAIC (oxaliplatin 100 mg/m2 and raltitrexed 3 mg/m2 on day 1, every 3 weeks) combined with TKIs and ICIs. We compared the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profile. ORR was similar between the FOLFOX HAIC and RALOX HAIC groups (42.5% vs 42.5%, P = 0.974). DCR also showed no significant difference between the two groups (87.5% vs 85.7%, P = 0.813). Median PFS was 10.7 months in the FOLFOX HAIC group versus 10.2 months in the RALOX HAIC group (P = 0.41). Median OS was 20.3 months in the FOLFOX HAIC group, compared to 17.7 months in the RALOX HAIC group (P = 0.50). Both groups had similar profiles of grade 3/4 treatment-related adverse events, including thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, and leukocytopenia. The effectiveness and safety of HAIC with RALOX were comparable to HAIC with FOLFOX in intermediate and advanced HCC patients.


Evaluating the performance of electrocoagulation system in the removal of polystyrene microplastics from water.
Emerging pollutants, particularly microplastics, present a significant threat to both the environment and human health. Traditional treatment methods lack targeted strategies for their removal. This study thoroughly investigated the efficacy of electrocoagulation as a method for efficiently extracting microplastics from water. Various critical operational parameters, including electrode combinations, pH levels, electrolyte concentrations, electrode geometries, configurations, current intensities, and reaction times, were systematically examined. The study systematically examined the impact of different combinations of aluminium (Al) and stainless steel (SS) electrodes, including Al-Al, SS-SS, Al-SS, and SS-Al. Among these combinations, it was found that the Al-Al pairing exhibited outstanding efficiency in microplastic removal, while simultaneously minimizing energy consumption. Initial pH emerged as a critical parameter, with a neutral pH of 7 demonstrating the highest removal efficiency. In the pursuit of optimizing parameters like electrolyte concentrations, electrode geometry, and configuration, it's noteworthy that consistently achieving removal efficiencies exceeding 90% has been a significant achievement. However, to ascertain economic efficiency, additional factors such as energy consumption, electrode usage, and post-treatment conductivity must be taken into account. To tackle the complexity posed by various parameters and criteria, using multi-criteria decision-making tools like TOPSIS is essential, as it has a track record of effectiveness in practical applications. The electrolyte concentration of 0.5 g L-1 is identified as optimal by TOPSIS analysis Additionally, the TOPSIS highlighted the superiority of cylindrical hollow wire mesh electrodes and established the monopolar parallel configuration as the most effective electrode connection method. The investigation carefully evaluated the effect of reaction time, determining that a 50-min window provides optimal microplastic removal efficiency. This refined system exhibited remarkable proficiency in eliminating microplastics of varying size ranges (0-75 μm, 75-150 μm, and 150-300 μm), achieving removal efficiencies of 90.67%, 93.6%, and 94.6%, respectively, at input concentration of 0.2 g L-1. The present study offers a comprehensive framework for optimizing electrocoagulation parameters, presenting a practical and highly effective strategy to address the critical issue of microplastic contamination in aquatic environments.


Genome Analysis and Replication Studies of the African Green Monkey Simian Foamy Virus Serotype 3 Strain FV2014.
African green monkey (AGM) spumaretroviruses have been less well-studied than other simian foamy viruses (SFVs). We report the biological and genomic characterization of SFVcae_FV2014, which was the first foamy virus isolated from an African green monkey (AGM) and was found to be serotype 3. Infectivity studies in various cell lines from different species (mouse, dog, rhesus monkey, AGM, and human) indicated that like other SFVs, SFVcae_FV2014 had broad species and cell tropism, and in vitro cell culture infection resulted in cytopathic effect (CPE). In Mus dunni (a wild mouse fibroblast cell line), MDCK (Madin-Darby canine kidney cell line), FRhK-4 (a fetal rhesus kidney cell line), and MRC-5 (a human fetal lung cell line), SFVcae_FV2014 infection was productive resulting in CPE, and had delayed or similar replication kinetics compared with SFVmcy_FV21 and SFVmcy_FV34[RF], which are two Taiwanese macaque isolates, designated as serotypes 1 and 2, respectively. However, in Vero (AGM kidney cell line) and A549 (a human lung carcinoma cell line), the replication kinetics of SFVcae_FV2014 and the SFVmcy viruses were discordant: In Vero, SFVcae_FV2014 showed rapid replication kinetics and extensive CPE, and a persistent infection was seen in A549, with delayed, low CPE, which did not progress even upon extended culture (day 55). Nucleotide sequence analysis of the assembled SFVcae_FV2014 genome, obtained by high-throughput sequencing, indicated an overall 80-90% nucleotide sequence identity with SFVcae_LK3, the only available full-length genome sequence of an AGM SFV, and was distinct phylogenetically from other AGM spumaretroviruses, corroborating previous results based on analysis of partial env sequences. Our study confirmed that SFVcae_FV2014 and SFVcae_LK3 are genetically distinct AGM foamy virus (FV) isolates. Furthermore, comparative infectivity studies of SFVcae_FV2014 and SFVmcy isolates showed that although SFVs have a wide host range and cell tropism, regulation of virus replication is complex and depends on the virus strain and cell-specific factors.


Coronary heart disease in women: a challenge for the 21st century.
Heart disease is the first killer of women in the modern era, regardless of age, race and of ethnicity, although its prevalence rises after menopause. Modern women have professional and housewife responsibilities, consume excess of fat and carbohydrates, smoke, do not exercise regularly and do not have enough time to rest. This situation leads to overweight, dyslipidemia, arterial hypertension, impaired glucose tolerance and diabetes. Women do not often participate in preventive studies and still undergo less intensive and invasive evaluation and treatment for chest pain when compared to men. However, the rate of coronary death is twice higher in women than in men after myocardial infarction and revascularization procedures. The objective of this review is to analyze the main gender differences regarding symptoms, diagnosis, management and prognosis of coronary heart disease and to discuss the influence of hormonal replacement therapy in the prevention of cardiovascular disease in postmenopausal women.


Gold induced hepatitis and pure red cell aplasia. Complete recovery after corticosteroid and N-acetylcysteine therapy.
A 54-year-old man developed severe cholestatic jaundice and pure red cell aplasia shortly after beginning treatment with gold sodium thiomalate. Although the hepatic toxicity began to spontaneously improve, the pure red cell aplasia was progressive. Treatment with prednisone and N-acetylcysteine (NAC) infusions was followed by prompt and complete hematologic recovery. Gold induced pure red cell aplasia should be added to the list of gold induced hematologic toxicities that can be potentially reversed with NAC infusion therapy.


The dento-gingival junction as seen with light microscopy and scanning electron microscopy.
The purpose of this paper is to review the anatomical relationship of the Dento-Gingival Junction as seen in the human dentition. The junction is described under light microscopy and then reviewed as seen in the SEM with the author's unpublished findings. The authors' material was derived from extracted human teeth with remaining marginal gingival tissue. The specimens were fixed with 2% glutaraldehyde in 0.15M sodium cacodylate buffer (pH 7.2) for 24 h. The specimens were then washed and freeze-fractured in Freon 113 using liquid nitrogen. Afterwards they were processed by freeze-drying or CPD methods, coated with gold, and placed in the scanning electron microscope (SEM) for viewing. These specimens demonstrated the presence of numerous Sharpey's fibers at the cemental surface. A large number of fibrils intermingled with the fibers to produce a dense mass of tissue. Junctional epithelium, with the adjacent homogeneous dental cuticle was demonstrated. Plaque deposits on the tooth surface extended to a cell-free zone. Morphological detail viewed with SEM and light microscopy are compared.


IL-10-secreting human MSCs generated by TALEN gene editing ameliorate liver fibrosis through enhanced anti-fibrotic activity.
Mesenchymal stem cells (MSCs) are known for their ability to repair liver damage. However, their therapeutic potential still needs to be enhanced. In the present study, we produced genome-edited MSCs that secrete interleukin 10 (IL-10) and evaluated their therapeutic potential in a liver fibrosis model. Multiple copies of the IL-10 gene were inserted into a safe harbor genomic locus in amniotic mesenchymal stem cells (AMMs) using transcription activator-like effector nucleases (TALENs). The IL-10 gene-edited AMMs (AMM/I) were characterized by reverse transcription PCR (RT-PCR), quantitative RT-PCR (qRT-PCR), and microarray. The effects of AMM/I-conditioned cell medium (CM) on the activation of hepatic stellate cells (HSC) were analyzed in vitro and in vivo therapeutic assays were performed on a mouse liver fibrosis model. The engineered AMM/I expressed high levels of IL-10. AMM/I-CM inhibited the activation of HSC (in vitro) and TNF-α expression of T cells/macrophage derived from fibrotic liver. In addition, human IL-10 was detected in the serum of the mice transplanted with AMM/I and transplantation of AMM/I significantly inhibited thioacetamide (TAA)-induced liver fibrosis and ameliorated abnormal liver function. Furthermore, a high number of human albumin-expressing AMM/I were successfully engrafted into the liver of recipient mice. Overall, genome-edited AMMs overexpressing anti-fibrotic IL-10 might be a promising alternative therapeutic option for the treatment of liver cirrhosis.


Brush mouse (Peromyscus boylii) population dynamics and hantavirus infection during a warm, drought period in southern Arizona.
We monitored Limestone Canyon hantavirus (LSCV) antibody prevalence, host (brush mouse, Peromyscus boylii) abundance, and environmental variables (temperature and rainfall) in brush mice captured on three trapping webs in southern Arizona for 5 yr. Although seasonal patterns were subtle, we observed large multiyear variation in population abundance and antibody prevalence. Limestone Canyon hantavirus infection in brush mouse populations varied over time with prevalence ranging from 0% to 33%. At all trapping webs, evidence of infection disappeared completely for an extended period (up to 2 yr) and eventually reappeared, suggesting that dispersal may play a role in maintaining infection in brush mouse metapopulations. Weather during the study period was drier and warmer than average and these conditions, especially during spring through fall, may have contributed to low brush mouse population density and the local extinction of LSCV during the second year of the study. Nevertheless, population growth was associated with relatively warm, dry conditions during winter periods and a cool, wet spring and summer period in the fifth year of the study. After prolonged absence, LSCV infection was consistently detected only when brush mouse population abundance reached relatively high levels during that fifth year. Comparison of our results to similar studies suggests that stochastic events resulting in the loss or survival of a few infected mice in low-density host populations may result in local extinction of virus; reestablishment of infection may occur via immigration of infected individuals from adjacent populations, but may be successful only when populations are of sufficient density to support frequent rodent-to-rodent interactions and virus transmission.


Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of Fas and Fas ligand to lipid rafts.
Cholangiocarcinomas are devastating cancers of biliary origin with limited treatment options. Modulation of the endocannabinoid system is being targeted to develop possible therapeutic strategies for a number of cancers; therefore, we evaluated the effects of the two major endocannabinoids, anandamide and 2-arachidonylglycerol, on numerous cholangiocarcinoma cell lines. Although anandamide was antiproliferative and proapoptotic, 2-arachidonylglycerol stimulated cholangiocarcinoma cell growth. Specific inhibitors for each of the cannabinoid receptors did not prevent either of these effects nor did pretreatment with pertussis toxin, a G(i/o) protein inhibitor, suggesting that anandamide and 2-arachidonylglycerol did not exert their diametric effects through any known cannabinoid receptor or through any other G(i/o) protein-coupled receptor. Using the lipid raft disruptors methyl-beta-cyclodextrin and filipin, we demonstrated that anandamide, but not 2-arachidonylglycerol, requires lipid raft-mediated events to inhibit cellular proliferation. Closer inspection of the lipid raft structures within the cell membrane revealed that although anandamide treatment had no observable effect 2-arachidonylglycerol treatment effectively dissipated the lipid raft structures and caused the lipid raft-associated proteins lyn and flotillin-1 to disperse into the surrounding membrane. In addition, anandamide, but not 2-arachidonylglycerol, induced an accumulation of ceramide, which was required for anandamide-induced suppression of cell growth. Finally we demonstrated that anandamide and ceramide treatment of cholangiocarcinoma cells recruited Fas and Fas ligand into the lipid rafts, subsequently activating death receptor pathways. These findings suggest that modulation of the endocannabinoid system may be a target for the development of possible therapeutic strategies for the treatment of this devastating cancer.


Small-cell lung cancer: state of the art.
Thirty years ago, there was a pervasive atmosphere of pessimism concerning the management of small-cell lung cancer (SCLC). Surgery or radiation therapy alone resulted in few cures since these techniques utilize a local therapy for a disseminated disease. Chemotherapy remains the backbone of treatment for all patients with SCLC, regardless of stage. For patients with limited-stage disease (LD), the addition of thoracic radiation to chemotherapy is standard. The optimal timing, dose, and schedule of radiation remains undefined. The majority of studies demonstrate equivalent or superior survival for early radiation when compared to delayed radiation. Approximately 50% of patients with LD will achieve a complete remission with chemoradiation and will be candidates for prophylactic cranial irradiation (PCI). While phase III trials have failed to demonstrate a statistically significant survival for PCI, brain relapse is clearly reduced, and a metaanalysis reports a small long-term survival advantage favoring patients receiving PCI. Unfortunately, unlike LD SCLC, advances in extensive-stage disease have been elusive, despite the testing of numerous strategies. Four courses of cisplatin (or carboplatin) plus etoposide remain standard first-line therapy. Promising results have been seen with irinotecan/cisplatin, but confirmatory trials are still needed. A plateau has been reached with chemotherapy regimens, and novel strategies are greatly needed to improve survival for patients with SCLC.


Scalable spin squeezing in a dipolar Rydberg atom array.
The standard quantum limit bounds the precision of measurements that can be achieved by ensembles of uncorrelated particles. Fundamentally, this limit arises from the non-commuting nature of quantum mechanics, leading to the presence of fluctuations often referred to as quantum projection noise. Quantum metrology relies on the use of non-classical states of many-body systems to enhance the precision of measurements beyond the standard quantum limit1,2. To do so, one can reshape the quantum projection noise-a strategy known as squeezing3,4. In the context of many-body spin systems, one typically uses all-to-all interactions (for example, the one-axis twisting model4) between the constituents to generate the structured entanglement characteristic of spin squeezing5. Here we explore the prediction, motivated by recent theoretical work6-10, that short-range interactions-and in particular, the two-dimensional dipolar XY model-can also enable the realization of scalable spin squeezing. Working with a dipolar Rydberg quantum simulator of up to N = 100 atoms, we demonstrate that quench dynamics from a polarized initial state lead to spin squeezing that improves with increasing system size up to a maximum of -3.5 ± 0.3 dB (before correcting for detection errors, or roughly -5 ± 0.3 dB after correction). Finally, we present two independent refinements: first, using a multistep spin-squeezing protocol allows us to further enhance the squeezing by roughly 1 dB, and second, leveraging Floquet engineering to realize Heisenberg interactions, we demonstrate the ability to extend the lifetime of the squeezed state by freezing its dynamics.


Distrontium trimanganese(II) bis-(hydro-gen-phosphate) bis-(ortho-phosphate).
The title compound, Sr2Mn3(HPO4)2(PO4)2, was synthesized under hydro-thermal conditions. In the structure, one of two Mn atoms is located on an inversion centre, whereas all others atoms are located in general positions. The framework structure is built up from two types of MnO6 octa-hedra (one almost undistorted, one considerably distorted), one PO3OH and one PO4 tetra-hedron. The centrosymmetric MnO6 octa-hedron is linked to two other MnO6 octa-hedra by edge-sharing, forming infinite zigzag chains parallel to [010]. The PO3OH and PO4 tetra-hedra connect these chains through common vertices or edges, resulting in the formation of sheets parallel to (100). The Sr(2+) cation is located in the inter-layer space and is bonded to nine O atoms in form of a distorted polyhedron and enhances the cohesion of the layers. Additional stabilization is achieved by a strong inter-layer O-H⋯O hydrogen bond between the PO3OH and PO4 units. The structure of the title phosphate is isotypic to that of Pb2Mn3(HPO4)2(PO4)2.


Inbreeding depression and genetic load in laboratory metapopulations of the butterfly Bicyclus anynana.
We investigated the effects of inbreeding on various fitness components and their genetic load in laboratory metapopulations of the butterfly Bicyclus anynana. Six metapopulations each consisted of four subpopulations with breeding population sizes of N = 6 or N = 12 and migration rate of m = 0 or m = 0.33. Metapopulations were maintained for seven generations during which coancestries and pedigrees were established. Individual inbreeding coefficients at the F7 were calculated and ranged between 0.01 and 0.51. Even though considerable purging had occurred during inbreeding, the genetic load remained higher than that of many outbreeding species: approximately two lethal equivalents were detected for egg sterility, one for zygote survival, one for juvenile survival, and one for longevity. Severe inbreeding depression occurred after seven generations of inbreeding, which jeopardized the metapopulation survival. This finding suggests that the purging of genetic load by intentional inbreeding cannot be recommended for the genetic conservation of species with a high number of lethal equivalents.


The Death of Confidants and Changes in Older Adults' Social Lives.
This study examines the consequences of confidant death for the social lives of older adults, testing hypotheses from socio-emotional selectivity theory and the hierarchical compensatory model. We draw upon longitudinal data from the National Social Life Health and Aging Project-a nationally representative survey of older adults (N = 2,261). We employ ordinary least squares (OLS) and ordinal logistic regressions in the context of multiple imputation with chained equations, checking our findings with doubly robust estimation. We find that the death of a spouse, but not the death of a family member or friend, was associated with increased support from friends and family, spending more time with family, and more frequent participation in religious services, but not volunteering. Death of other confidants also had little impact on older adults' social lives, suggesting the robustness of their networks to nonspousal loss.


Efficacy and toxicity of chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer.
To evaluate the efficacy and toxicity of primary chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer and to identify predictors of treatment failure and toxicity. Retrospective analysis of 155 stage IB-IVA cervical cancer patients treated from 2008 to 2016 with chemoradiation and image-guided adaptive brachytherapy. Treatment consisted of external beam radiotherapy (45 - 48.6 Gy in 1.8 - 2 Gy fractions) with concurrent weekly cisplatin (40 mg/m2, 5 - 6 cycles) and image-guided adaptive brachytherapy (3-4 × 7 Gy high dose rate) using intracavitary or combined intracavitary-interstitial techniques according to GEC-ESTRO (Group Européen de Curiethérapie and the European Society for Radiotherapy and Oncology) recommendations. Incidences of all outcomes were calculated using Kaplan-Meier's methodology. Risk factors for treatment failure and toxicity were identified using Cox's proportional hazards model and the Kruskal-Wallis H-test respectively. Median follow-up was 57 months. Five-year local control was 90.4 %. Five-year para-aortic lymph node metastasis-free and distant metastasis-free survival were 85.3 % and 70.2 % respectively. Tumor size and lymph node metastasis were independent risk factors for treatment failure. Cumulative incidences of severe late bladder, rectal, bowel, and vaginal toxicity were 0.8%, 3.3%, 3.6%, and 1.4% respectively at 5 years of follow-up. Combined intracavitary-interstitial brachytherapy techniques were associated with less vaginal morbidity. Primary chemoradiation with image-guided adaptive brachytherapy for locally advanced cervical cancer is a highly effective local and loco-regional treatment. However, survival is compromised by the occurrence of distant metastasis. Patients with large tumors and nodal involvement at diagnosis are at increased risk and may benefit from intensified treatment. Severe late gastrointestinal and urogenital toxicity is limited and may be further reduced by increasing conformity, using combined intracavitary-interstitial techniques and lowering doses to organs at risk.


A Physiologically Based Pharmacokinetic Model to Predict the Impact of Metabolic Changes Associated with Metabolic Associated Fatty Liver Disease on Drug Exposure.
Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease, with an estimated prevalence of between 20 and 30% worldwide. Observational data supported by in vitro and pre-clinical animal models of MAFLD suggest meaningful differences in drug disposition in MAFLD patients. This study aimed to build a physiologically based pharmacokinetic (PBPK) model reflecting observed changes in physiological and molecular parameters relevant to drug disposition that are associated with MAFLD. A comprehensive literature review and meta-analysis was conducted to identify all studies describing in vivo physiological changes along with in vitro and pre-clinical model changes in CYP 1A2, 2C9, 2C19, 2D6 and 3A4 protein abundance associated with MAFLD. A MAFLD population profile was constructed in Simcyp (version 19.1) by adapting demographic and physiological covariates from the Sim-Healthy population profile based on a meta-analysis of observed data from the published literature. Simulations demonstrated that single dose and steady state area under the plasma concentration time curve (AUC) for caffeine, clozapine, omeprazole, metoprolol, dextromethorphan and midazolam, but not s-warfarin or rosiglitazone, were increased by >20% in the MAFLD population compared to the healthy control population. These findings indicate that MAFLD patients are likely to be experience meaningfully higher exposure to drugs that are primarily metabolized by CYP 1A2, 2C19, 2D6 and 3A4, but not CYP2C9. Closer monitoring of MAFLD patients using drugs primarily cleared by CYP 1A2, 2C19 and 3A4 is warranted as reduced metabolic activity and increased drug exposure are likely to result in an increased incidence of toxicity in this population.


Complementation of class II A alleles in the immune response to (GluLysTyr) polymers.
The proliferative T cell responses to poly(GluLysTyr) (GLT) and poly(GLULysPhe) (GLPhe) are restricted by the E alpha E beta class II MHC molecule (E) in most responded strains. Some nonresponder strains that carry responder E beta, but cannot express cell surface E molecules, can complement with other nonresponder strains that provide the missing E alpha chain needed for the expression of E molecules and for responsiveness to GLT and GLPhe. Here another type of complementation is described between two E-nonexpressor haplotypes, H-2f and H-2s, which result in E-nonexpressor F1 hybrids, which are responders to GLT. The restriction element involved in this response is an Af/As hybrid molecule. The data support the hypothesis that conformational determinants resulting from the free association of alpha and beta chains in heterozygotes can increase the immune potential of the individual.


Possible anticancer activity of rosuvastatine, doxazosin, repaglinide and oxcarbazepin.
Rosuvastatine, doxazosin, repaglinide and oxcarbazepin are therapeutic drugs available in the market for the treatment of different diseases. Potential to display antitumor activities has also been suggested. The aim of the current study was to evaluate their in vitro effects on some human transformed cell lines. Cytotoxicity of the four drugs was tested in MCF-7, HeLa and HepG2 cells by the neutral red assay method and also the effect of rosuvastatine and doxazosin against Ehrlich Ascities Carcinoma Cells (EACC) by trypan blue assay. Rosuvastatine exerted the greatest cytotoxic effect against HepG2 cells with an IC50 value of 58.7±69.3; in contrast doxazosin showed least activity with IC50=104.4 ±115.7. Repaglinide inhibited the growth of both HepG2 and HeLa cells with IC50 values of 87.6±117.5 and 89.3±119.5, respectively. Oxcarbazepine showed a potent cytotoxicity against both HeLa (IC50=19.4±43.9) and MCF7 cancer cells ((IC50=22±35.7).On the other hand the growth of EACC was completely inhibited by doxazosine (100% inhibition) while rosuvastatine had weak inhibitory activity (11.6%) . The four tested drugs may have cytotoxic effects against hepatic, breast and cervical carcinoma cells; also doxazosine may inhibit the growth of endometrial cancer cells. Further investigations in animals are needed to confirm these results.


Development of a RP-LC method for a diastereomeric drug valganciclovir hydrochloride by enhanced approach.
Two methods, prescribed in USP, for the analysis of related substances of valganciclovir hydrochloride drug substance, were evaluated in terms of selectivity and ease of use. A new, simple, selective, stability indicating and user friendly RP-LC method was developed for related substances analysis. The developed single method is capable of separating all known impurities, which are quantified by two methods of USP. A central composite design was applied to optimize the critical chromatographic parameters. A multi step gradient program was strategically designed and a part of the program was optimized through Design of Experiments. Separation was achieved with a Zorbax SB C18 column with 0.1% trifluoro acetic acid and methanol in gradient elution. Design space is proposed graphically for the robust operation of the method. The method is linear, precise and accurate from LOQ level to 150% level of specification limit of impurities. Simple modification in the gradient program with reduced run time is also proposed for assay and diastereomer ratio.


Comparative Analyses of Gibbon Centromeres Reveal Dynamic Genus-Specific Shifts in Repeat Composition.
Centromeres are functionally conserved chromosomal loci essential for proper chromosome segregation during cell division, yet they show high sequence diversity across species. Despite their variation, a near universal feature of centromeres is the presence of repetitive sequences, such as DNA satellites and transposable elements (TEs). Because of their rapidly evolving karyotypes, gibbons represent a compelling model to investigate divergence of functional centromere sequences across short evolutionary timescales. In this study, we use ChIP-seq, RNA-seq, and fluorescence in situ hybridization to comprehensively investigate the centromeric repeat content of the four extant gibbon genera (Hoolock, Hylobates, Nomascus, and Siamang). In all gibbon genera, we find that CENP-A nucleosomes and the DNA-proteins that interface with the inner kinetochore preferentially bind retroelements of broad classes rather than satellite DNA. A previously identified gibbon-specific composite retrotransposon, LAVA, known to be expanded within the centromere regions of one gibbon genus (Hoolock), displays centromere- and species-specific sequence differences, potentially as a result of its co-option to a centromeric function. When dissecting centromere satellite composition, we discovered the presence of the retroelement-derived macrosatellite SST1 in multiple centromeres of Hoolock, whereas alpha-satellites represent the predominate satellite in the other genera, further suggesting an independent evolutionary trajectory for Hoolock centromeres. Finally, using de novo assembly of centromere sequences, we determined that transcripts originating from gibbon centromeres recapitulate the species-specific TE composition. Combined, our data reveal dynamic shifts in the repeat content that define gibbon centromeres and coincide with the extensive karyotypic diversity within this lineage.


[Experimental bioplasty of tuberculous caverns of the lung].
A possibility of using allontransplants of the "Alloplant" series for pulmonary cavernoplasty has been developed and substantiated experimentally. Histological studies of an experimental pulmonary cavern under conditions of allotransplantation revealed the dynamics of the morphological transformation typical of human pulmonary cavern healing. A reparative process results in the liquidation of the specific changes in the cavern wall followed by the formation of a regenerate in the form of a stellate cicatrix.


Is there added value in obtaining cervical spine MRI in the assessment of nontraumatic angiographically negative subarachnoid hemorrhage? A retrospective study and meta-analysis of the literature.
OBJECTIVE Diagnostic algorithms for nontraumatic angiographically negative subarachnoid hemorrhage (AN-SAH) vary, and the optimal method remains subject to debate. This study assessed the added value of cervical spine MRI in identifying a cause for nontraumatic AN-SAH. METHODS Consecutive patients 18 years of age or older who presented with nontraumatic SAH between February 1, 2009, and October 31, 2014, with negative cerebrovascular catheter angiography and subsequent cervical MRI were studied. Patients with intraparenchymal, subdural, or epidural hemorrhage; recent trauma; or known vascular malformations were excluded. All cervical MR images were reviewed by two blinded neuroradiologists. The diagnostic yield of cervical MRI was calculated. A literature review was conducted to identify studies reporting the diagnostic yield of cervical MRI in patients with AN-SAH. The weighted pooled estimate of diagnostic yield of cervical MRI was calculated. RESULTS For all 240 patients (mean age 53 years, 48% male), catheter angiography was performed within 4 days after admission (median 12 hours, interquartile range [IQR] 10 hours). Cervical MRI was performed within 19 days of admission (median 24 hours, IQR 10 hours). In a single patient, cervical MRI identified a source for SAH (cervical vascular malformation). Meta-analysis of 7 studies comprising 538 patients with AN-SAH produced a pooled estimate of 1.3% (95% confidence interval 0.5%-2.5%) for diagnostic yield of cervical MRI. No statistically significant between-study heterogeneity or publication bias was identified. CONCLUSIONS Cervical MRI following AN-SAH, in the absence of findings to suggest spinal etiology, has a very low diagnostic yield and is not routinely necessary.


Influence of morphine on the distal oesophagus and the lower oesophageal sphincter--a manometric study.
Basal pressure and relaxation of the lower oesophageal sphincter (LOS) as well as amplitude, duration and propagation velocity of peristaltic waves in the distal third of oesophagus were measured in 15 healthy adults (nine men and six women). A highly standardised technique was used employing manometric equipment including a low-compliance pneumohydraulic infusion system and a triple lumen recording catheter. After establishment of baseline manometry values the catheter was positioned with its distal orifice in the lower oesophageal sphincter. In 10 subjects 0.2 mg/kg body weight of morphine sulphate was then injected subcutaneously. In five others equal volume of saline was given. The manometric data were analysed blindly. Repeated manometric evaluations were carried out 15, 30, 45, 60, and 75 minutes after the injection. Morphine increased slightly LOS-pressure and significantly (p less than 0.001) decreased LOS-relaxation, the maximal effect occurring 30 minutes after the injection. Amplitude of peristaltic waves increased slightly but insignificantly, whereas propagation velocity and duration were uninfluenced. The results of this study suggest that pharmacologic doses of morphine influence normal function of the LOS and possibly the distal oesophagus. The role of endogenous opiates in this respect, however, awaits further studies. It is suggested that abnormalities in opioid neurotransmission may explain some of the non-specific oesophageal motility disorders.


Prospective association between emotional health and clinical evidence of Parkinson's disease.
Whilst disorders of emotion are commonly comorbid with Parkinson's disease (PD), evidence concerning their association with PD risk is limited. We investigate the prospective association between selected measures of emotional health and incident suspected PD. 20,855 men and women, considered PD-free at baseline, completed a postal assessment of major depressive disorder (MDD), generalized anxiety disorder (GAD), psychological distress [defined by the five-item Mental Health Inventory (MHI-5)], and neuroticism. PD case ascertainment was based upon PD medication use, self-report questionnaires, hospital record discharge codes, and death certification, subsequently checked against general practitioner, hospital records and neurological service records. 175 suspected cases of incident PD were identified in 160,725 (median 7.9) person-years of follow-up (with 43 recorded in neurological service records). MDD lifetime history, GAD lifetime history, MHI-5 and neuroticism were all significantly associated with suspected PD following adjustment for age, sex, cigarette smoking, alcohol consumption, social class and education. This study supports an association between measures of emotional health, assessed prior to evidence of motor symptoms, and subsequent suspected PD diagnosis. However, we were unable to determine whether our measures of personality and emotional health represent genuine premorbid risk factors or early stages of PD. Long-term prospective healthy cohort studies are required to investigate the relationship between emotional health history and the evolution of the premotor and motor phases of PD.


Protein-mediated viral latency is a novel mechanism for Merkel cell polyomavirus persistence.
Viral latency, in which a virus genome does not replicate independently of the host cell genome and produces no infectious particles, is required for long-term virus persistence. There is no known latency mechanism for chronic small DNA virus infections. Merkel cell polyomavirus (MCV) causes an aggressive skin cancer after prolonged infection and requires an active large T (LT) phosphoprotein helicase to replicate. We show that evolutionarily conserved MCV LT phosphorylation sites are constitutively recognized by cellular Fbw7, βTrCP, and Skp2 Skp-F-box-cullin (SCF) E3 ubiquitin ligases, which degrade and suppress steady-state LT protein levels. Knockdown of each of these E3 ligases enhances LT stability and promotes MCV genome replication. Mutations at two of these phosphoreceptor sites [serine (S)220 and S239] in the full viral genome increase LT levels and promote MCV virion production and transmission, which can be neutralized with anti-capsid antibody. Virus activation is not mediated by viral gene transactivation, given that these mutations do not increase late gene transcription in the absence of genome replication. Mechanistic target of rapamycin inhibition by either nutrient starvation or use of an active site inhibitor reduces Skp2 levels and stabilizes LT, leading to enhanced MCV replication and transmission. MCV can sense stresses in its intracellular environment, such as nutrient loss, through SCF E3 ligase activities, and responds by initiating active viral transmission. Protein-mediated viral latency through cellular SCF E3 ligase targeting of viral replication proteins is a unique form of latency that may promote chronic viral persistence for some small DNA and RNA viruses.


Alpine infrastructure in Central Europe: integral evaluation of wastewater treatment systems at mountain refuges.
Planning, construction and operation of onsite wastewater treatment systems at mountain refuges is a challenge. Energy supply, costly transport, limited water resources, unfavourable climate and load variations are only some of the problems that have to be faced. Additionally, legal regulations are different between and even within countries of the Alps. To ensure sustainability, integrated management of the alpine infrastructure management is needed. The energy and water supply and the wastewater and waste disposal systems and the cross-relations between them were analysed for 100 mountain refuges. Wastewater treatment is a main part of the overall 'mountain refuge' system. The data survey and first analyses showed the complex interaction of the wastewater treatment with the other infrastructure. Main criteria for reliable and efficient operation are training, technical support, user friendly control and a relatively simple system set up. Wastewater temperature, alkalinity consumption and high peak loads have to be considered in the planning process. The availability of power in terms of duration and connexion is decisive for the choice of the system. Further, frequency fluctuations may lead to damages to the installed aerators. The type of water source and the type of sanitary equipment influence the wastewater quantity and quality. Biosolids are treated and disposed separately or together with primary or secondary sludge from wastewater treatment dependent on the legal requirements.


Effect of hypernatremia on injury caused by energy deficiency: role of T-type Ca2+ channel.
Hypernatremia exerts multiple cellular effects, many of which could influence the outcome of an ischemic event. To further evaluate these effects of hypernatremia, isolated neonatal cardiomyocytes were chronically incubated with medium containing either normal (142 mM) or elevated sodium (167 mM) and then transferred to medium containing deoxyglucose and the electron transport chain inhibitor amobarbital. Chronic hypernatremia diminished the degree of calcium accumulation and reactive oxygen species generation during the period of metabolic inhibition. The improvement in calcium homeostasis was traced in part to the downregulation of the Ca(V)3.1 T-type calcium channel, as deficiency in the Ca(V)3.1 subtype using short hairpin RNA or treatment with an inhibitor of the Ca(V)3.1 variant of the T-type calcium channel (i.e., diphenylhydantoin) attenuated energy deficiency-mediated calcium accumulation and cell death. Although hyperosmotically stressed cells (exposed to 50 mM mannitol) had no effect on T-type calcium channel activity, they were also resistant to death during metabolic inhibition. Both hyperosmotic stress and hypernatremia activated Akt, suggesting that they initiate the phosphatidylinositol 3-kinase/Akt cytoprotective pathway, which protects the cell against calcium overload and oxidative stress. Thus hypernatremia appears to protect the cell against metabolic inhibition by promoting the downregulation of the T-type calcium channel and stimulating cytoprotective protein kinase pathways.


Making things happen: reciprocal relationships between work characteristics and personal initiative in a four-wave longitudinal structural equation model.
The authors used the frameworks of reciprocal determinism and occupational socialization to study the effects of work characteristics (consisting of control and complexity of work) on personal initiative (PI)--mediated by control orientation (a 2nd-order factor consisting of control aspiration, perceived opportunity for control, and self-efficacy) and the reciprocal effects of PI on changes in work characteristics. They applied structural equation modeling to a longitudinal study with 4 measurement waves (N = 268) in a transitional economy: East Germany. Results confirm the model plus 1 additional, nonhypothesized effect. Work characteristics had a synchronous effect on PI via control orientation (full mediation). There were also effects of control orientation and of PI on later changes in work characteristics: As predicted, PI functioned as partial mediator, changing work characteristics in the long term (reciprocal effect); unexpectedly, there was a 2nd reciprocal effect of an additional lagged partial mediation of control orientation on later work characteristics.


Alcohol induces hepatocytes necroptosis through the LC3/RIPK1/RIPK3 pathway.
Excessive alcohol consumption leads to serious liver injury. Necroptosis is a programmed cell death form, which has been confirmed to be involved in alcoholic liver injury. However, the exact mechanism remains still unclear. In this study, we found that ethanol caused hepatocytes necroptosis by activating receptor-interacting serine/threonine-protein kinase 1 and 3 (RIPK1 and RIPK3). Meanwhile, autophagy was activated in ethanol-treated hepatocytes. Accumulative studies have demonstrated a possible link between autophagy and necroptosis. Microtubule-associated protein 1 light chain 3 (LC3), an autophagy marker protein, is essential for autophagosome biogenesis/maturation. But little attention has been paid to its functional role. In this study, we explored whether LC3 was involved in ethanol-induced necroptosis. The data showed that LC3 interacted with RIPK1 and RIPK3 in ethanol-treated AML12 cells and mice liver by co-immunoprecipitation (co-IP) and colocalization assay. Ethanol-induced necrosome formation and subsequent necroptosis were alleviated in hepatocytes by knockdown of LC3 or autophagy inhibitor 3-methyladenine (3-MA). These results demonstrated that LC3 accumulation facilitated the formation of necrosome by LC3-RIPK1 and LC3-RIPK3 interactions, eventually caused hepatocytes necroptosis after acute ethanol exposure. Our current research could potentially offer a new understanding of the intricate mechanisms involved in the development of acute alcoholic liver injury.


Moving from the terminology debate to a transdisciplinary understanding of the problem.
This commentary considers a recent debate paper which presents and counters 10 work addiction myths. I reflect upon the proposal to move the field forward by distinguishing between, work addiction, which denotes a clinical phenomenon; and workaholism, a term used by the occupational psychology literature with little agreement about its defining dimensions beyond working compulsively. Rather than choosing between these two terms, I argue that addiction experts should lead a transdisciplinary integration of findings from studies where participants report both working compulsively and experiencing significant conflict. I also stress the importance of understanding the macro factors underlying this particular addiction.


Refocusing of backscattered microwaves in target detection by using LHM flat lens.
When microwave emitted from a point source is focused on a target by using a left-handed metamaterial (LHM) flat lens, microwave backscattered from the target will be refocused by the LHM lens in the vicinity of the point source. Numerical simulations with two-dimensional (2D) finite-difference time-domain (FDTD) method demonstrate that, even for flat LHM lens of material losses to the order as that reported in some LHM microwave experiments and simulations, the refocusing of backscattered microwave will yield a sub-wavelength lateral resolution and remarkable enhancement of the backscattered microwave, which will benefit the detection and imaging of small target.


Influenza A virus NS1 protein does not suppress RNA interference in mammalian cells.
Influenza A virus NS1 protein has been shown to suppress RNA interference (RNAi) in plants and Drosophila. Although it has not been demonstrated experimentally, NS1 has also been thought to inhibit RNAi in mammals as well as being an antagonist of interferon. In this study, the influence of NS1 protein from influenza virus strain A/WSN/33 on RNAi in mammalian cells was investigated. While transiently or stably expressed NS1 was fully competent to inhibit the interferon pathway in cultured cells, it did not suppress RNAi-mediated silencing of different reporter genes. These findings imply a significant difference in RNAi mechanism between mammals and plants.


Experience of Engagement in a Somatosensory Discrimination Intervention for Children with Hemiplegic Cerebral Palsy: A Qualitative Investigation.
Background: To successfully modify an intervention from an adult population for use with children with cerebral palsy, it is important to understand the components that support a child's motivation and engagement. Method: Ten children who had participated in the Sense© intervention (mean age = 11 years 2 m [SD = 2 years]; four males; Manual Ability Classification System level I = 1, II = 9) and their primary caregivers (N = 11, 10 females) were interviewed. Transcripts were analyzed using framework analysis. Results: Key themes were identified in the core domains of the Synthesis of Child, Occupational Performance and Environment in Time model. Child: children's somatosensory discrimination ability improved; Motivation: incorporating child's goals was essential, as were real-world gains; Environmental: parents were interested in having more involvement in the intervention. Conclusion: The most engaging elements of the intervention for children were the attainment of their self-selected goals. Opportunities to modify the intervention for improved partnership with parents were identified.


Food Addiction Is Associated with Binge Eating and Psychiatric Distress among Post-Operative Bariatric Surgery Patients and May Improve in Response to Cognitive Behavioural Therapy.
The current study examined clinical correlates of food addiction among post-operative bariatric surgery patients, compared the clinical characteristics of patients with versus without food addiction, and examined whether a brief telephone-based cognitive behavioural therapy (Tele-CBT) intervention improves food addiction symptomatology among those with food addiction. Participants (N = 100) completed measures of food addiction, binge eating, depression, and anxiety 1 year following bariatric surgery, were randomized to receive either Tele-CBT or standard bariatric post-operative care, and then, repeated the measure of food addiction at 1.25 and 1.5 years following surgery. Thirteen percent of patients exceeded the cut-off for food addiction at 1 year post-surgery, and this subgroup of patients reported greater binge eating characteristics and psychiatric distress compared to patients without food addiction. Among those with food addiction, Tele-CBT was found to improve food addiction symptomatology immediately following the intervention. These preliminary findings suggest that Tele-CBT may be helpful, at least in the short term, in improving food addiction symptomatology among some patients who do not experience remission of food addiction following bariatric surgery; however, these findings require replication in a larger sample.


[Successful Conversion Therapy for Gastric Cancer with Paraaortic Lymph Node Metastasis after SP Therapy-A Case Report].
A 69-year-old woman, who complained of loss of appetite, was admitted to our hospital and diagnosed with clinical Stage Ⅳgastric cancer and paraaortic lymph node metastases(cT4aN3M1[#16b1LYM], cStage Ⅳ). She underwent 2 cycles of SP therapy(combination of S-1 and CDDP). A partial response of the primary tumor was noted, with no distant metastases, except for the paraaortic lymph nodes. She underwent robotic total gastrectomy with D2 plus paraaortic lymph node dissection. Histopathology showed no residual tumor cells in the stomach or lymph nodes. Postoperatively, the patient underwent 3 cycles of SOX therapy(combination of S-1 and oxaliplatin)and survived for over 6 postoperative months, with no recurrences. For advanced gastric cancers with paraaortic lymph node dissection with no evidences of other distant metastases, gastrectomy with paraaortic lymph node dissection combined with chemotherapy could be a therapeutic option to achieve R0 resection.


Reach and impact of a mass media event among vulnerable patients: the Terri Schiavo story.
It is unknown whether health-related media stories reach diverse older adults and influence advance care planning (ACP). To determine exposure to media coverage of Terri Schiavo (TS) and its impact on ACP. Descriptive study of 117 English/Spanish-speakers, aged >or=50 years (mean 61 years) from a county hospital, interviewed six months after enrollment into an advance directive study. We assessed whether participants had heard of TS and subject characteristics associated with exposure. We also asked whether, because of TS, subjects engaged in ACP. Ninety-two percent reported hearing of TS. Participants with adequate literacy were more likely than those with limited literacy to report hearing of TS (100% vs. 79%, P < .001), as were participants with >or= a high school vs. < high school education (97% vs. 82%, P = .004), and English vs. Spanish-speakers (96% vs. 85%, P = .04). Because of TS, many reported clarifying their own goals of care (61%), talking to their family/friends about ACP (66%), and wanting to complete an advance directive (37%). Most diverse older adults had heard of TS and reported that her story activated them to engage in ACP. Media stories may provide a powerful opportunity to engage patients in ACP and develop public health campaigns.


[Effects of Chinese herbal medicine Yiqi Huoxue Formula on TGF-β/smad signal transduction pathway and connective tissue growth factor in rats with renal interstitial fibrosis].
To observe the effects of Yiqi Huoxue Formula (YQHXF), a compound Chinese herbal medicine, on transforming growth factor-β (TGF-β)/smad signal transduction pathway and connective tissue growth factor (CTGF) in rats with renal interstitial fibrosis Unilateral ureteral obstruction (UUO) rat model was established and the rats were randomly divided into 5 groups: untreated group, high-, medium-, and low-dose YQHXF groups and fosinopril sodium group. Another group with sham operation was set as control. All rats were administered with corresponding drugs for 3 weeks. After the last administration, each rat was sacrificed and weighed and the serum was separated for creatinine (Cr) and blood urea nitrogen (BUN) detection. Kidneys of the rats were taken out, and mRNA and protein expressions of TGF-β, smad2, smad7 and CTGF were measured with real-time fluorescent quantitative reverse transcription-polymerase chain reaction and Western blotting respectively; fibrosis of the kidney tissue was observed with hematoxylin-eosin (HE) staining and Masson trichrome staining. Compared with sham-operation group, Cr and BUN in serum of UUO groups were increased, while high-dose YQHXF treatment decreased the UUO-induced increase of Cr and BUN levels. HE staining and Masson staining results showed that the renal tubular epithelial cells in untreated group got atrophied; lumens of renal tubules expanded; fibroplastic proliferation and inflammatory cell infiltration were observed in renal interstitium; the number of glomerulus decreased and collagen increased significantly compared with sham-operation group. In the high- and medium-dose YQHXF groups and fosinopril sodium group, the histopathological changes of inflammatory cell infiltration, fibroplastic proliferation, expansion of lumens of renal tubules was improved as compared with the untreated group. The mRNA and protein expressions of TGF-β, smad2 and CTGF in untreated group were higher than those in sham-operation group (P<0.05), and the mRNA and protein expressions of smad7 in untreated group were lower than those in the sham-operation group (P<0.05). Compared with untreated group, high- and medium-dose of YQHXF significantly down-regulated the mRNA and protein expressions of TGF-β, smad2 and CTGF (P<0.01, P<0.05), and up-regulated the mRNA and protein expressions of smad7 (P<0.01, P<0.05). The mRNA expression of CTGF in UUO rats may be regulated by TGF-β/smad signaling transduction pathway. YQHXF might inhibit the expression of CTGF through down-regulation of TGF-β and smad2 and up-regulation of smad7, thus inhibiting the progression of renal interstitial fibrosis.


Time-series forecasting of Bitcoin prices using high-dimensional features: a machine learning approach.
Bitcoin is a decentralized cryptocurrency, which is a type of digital asset that provides the basis for peer-to-peer financial transactions based on blockchain technology. One of the main problems with decentralized cryptocurrencies is price volatility, which indicates the need for studying the underlying price model. Moreover, Bitcoin prices exhibit non-stationary behavior, where the statistical distribution of data changes over time. This paper demonstrates high-performance machine learning-based classification and regression models for predicting Bitcoin price movements and prices in short and medium terms. In previous works, machine learning-based classification has been studied for an only one-day time frame, while this work goes beyond that by using machine learning-based models for one, seven, thirty and ninety days. The developed models are feasible and have high performance, with the classification models scoring up to 65% accuracy for next-day forecast and scoring from 62 to 64% accuracy for seventh-ninetieth-day forecast. For daily price forecast, the error percentage is as low as 1.44%, while it varies from 2.88 to 4.10% for horizons of seven to ninety days. These results indicate that the presented models outperform the existing models in the literature.


CRISPR/Cas9-mediated targeted T-DNA integration in rice.
Combining with a CRISPR/Cas9 system, Agrobacterium-mediated transformation can lead to precise targeted T-DNA integration in the rice genome. Agrobacterium-mediated T-DNA integration into the plant genomes is random, which often causes variable transgene expression and insertional mutagenesis. Because T-DNA preferentially integrates into double-strand DNA breaks, we adapted a CRISPR/Cas9 system to demonstrate that targeted T-DNA integration can be achieved in the rice genome. Using a standard Agrobacterium binary vector, we constructed a T-DNA that contains a CRISPR/Cas9 system using SpCas9 and a gRNA targeting the exon of the rice AP2 domain-containing protein gene Os01g04020. The T-DNA also carried a red fluorescent protein and a hygromycin resistance (hptII) gene. One version of the vector had hptII expression driven by an OsAct2 promoter. In an effort to detect targeted T-DNA insertion events, we built another T-DNA with a promoterless hptII gene adjacent to the T-DNA right border such that integration of T-DNA into the targeted exon sequence in-frame with the hptII gene would allow hptII expression. Our results showed that these constructs could produce targeted T-DNA insertions with frequencies ranging between 4 and 5.3% of transgenic callus events, in addition to generating a high frequency (50-80%) of targeted indel mutations. Sequencing analyses showed that four out of five sequenced T-DNA/gDNA junctions carry a single copy of full-length T-DNA at the target site. Our results indicate that Agrobacterium-mediated transformation combined with a CRISPR/Cas9 system can efficiently generate targeted T-DNA insertions.


Xylo-oligosaccharide-based prebiotics upregulate the proteins of the Sus-like system in caecal Bacteroidetes of the chicken: evidence of stimbiotic mechanism.
The present study was conducted to investigate the stimbiotic mechanism of xylo-oligosaccharide (XOS) in degrading the complex polysaccharides by the caecal bacteria of the chicken, by applying a proteomic approach. A total of 800 as-hatched Ross 308 broiler chicks were equally divided into 4 experimental pens (200 chicks per pen) at a commercial poultry barn, allocating 2 pens per treatment. Birds were fed ad libitum with 2 dietary treatments; CON (without XOS) and XOS (with 0.1g XOS/kg diet) from d 0 to 35. From each pen, 60 Individual birds were weighed weekly whereas caecal content was obtained from 5 birds cervically dislocated on d 35. The caecal bacteria were lysed and their proteins were quantified using label-free quantitative proteomic mass spectrometry. The results showed that XOS significantly increased (P < 0.05) bird weight on d 7, 14, 21, and 28, and body weight gain on d 7, 14, 21, and 35 compared to CON. However, no difference (P > 0.05) in body weight gain was observed from d 0 to 35 between CON and XOS. The proteomic analysis of caecal bacteria revealed that 29 proteins were expressed differently between the CON and the XOS group. Out of 29, 20 proteins were significantly increased in the XOS group compared to CON and 9 of those proteins belonged to the starch-utilizing system (Sus)-like system of the gram-negative Bacteroidetes. Bacteroides thetaiotaomicron (Bt) is a significant constituent of the human gut microbiota, known for its remarkable ability to hydrolyze most glycosidic bonds of polysaccharides. This microorganism possesses a 5-protein complex in its outer membrane, named the starch utilization system (Sus), responsible for adhering to, breaking down, and transporting starch into the cell. Sus serves as an exemplar system for numerous polysaccharide utilization loci that target glycans found in Bt and other members of the Bacteroidetes phylum. The proteins of the Sus-like system are involved in the degradation of complex polysaccharides and transportation of the oligosaccharides into the periplasm of the caecal bacteria where they are further broken down into smaller units. These smaller units are then transported into the cytoplasm of the cell where they are utilized in metabolic pathways leading to potential generation of short-chain fatty acids, thus improving the nutritive value of residual feed. In conclusion, XOS supplementation upregulates the expression of the proteins of the Sus-like system indicating its role as a stimbiotic.


1H Nuclear Magnetic Resonance Spectroscopy-Based Methods for the Quantification of Proteins in Urine.
We described several postprocessing methods to measure protein concentrations in human urine from existing 1H nuclear magnetic resonance (NMR) metabolomic spectra: (1) direct spectral integration, (2) integration of NCD spectra (NCD = 1D NOESY-CPMG), (3) integration of SMolESY-filtered 1D NOESY spectra (SMolESY = Small Molecule Enhancement SpectroscopY), (4) matching protein patterns, and (5) TSP line integral and TSP linewidth. Postprocessing consists of (a) removal of the metabolite signals (demetabolization) and (b) extraction of the protein integral from the demetabolized spectra. For demetabolization, we tested subtraction of the spin-echo 1D spectrum (CPMG) from the regular 1D spectrum and low-pass filtering of 1D NOESY by its derivatives (c-SMolESY). Because of imperfections in the demetabolization, in addition to direct integration, we extracted protein integrals by the piecewise comparison of demetabolized spectra with the reference spectrum of albumin. We analyzed 42 urine samples with protein content known from the bicinchoninic acid (BCA) assay. We found excellent correlation between the BCA assay and the demetabolized NMR integrals. We have provided conversion factors for calculating protein concentrations in mg/mL from spectral integrals in mM. Additionally, we found the trimethylsilyl propionate (TSP, NMR standard) spectral linewidth and the TSP integral to be good indicators of protein concentration. The described methods increase the information content of urine NMR metabolomics spectra by informing clinical studies of protein concentration.


On the etiology of tropical spastic paraparesis and human T-cell lymphotropic virus-I-associated myelopathy.
The purpose of this review is to present some concepts on the etiology of tropical spastic paraparesis or human T-cell lymphotropic virus-I (HTLV-I)-associated myelopathy (TSP/HAM). The large number of syndromes that have been associated with HTLV-I (60 to date), the existence of TSP/HAM cases associated with other retroviruses (human immunodeficiency virus-2 [HIV-2], HTLV-II), the existence of many TSPs without HTLV-I, and the evidence of clear epidemiologic contradictions in TSP/HAM indicate that the etiopathogenesis of TSP/HAM is not yet clear. Tropical spastic paraparesis/HAM affects patients of all human ethnic groups, but usually in well localized and relatively isolated geographic regions where HTLV-I has been endemic for a long time. Environmental factors and geographic locations appear to be critical factors. Because the neuropathology of TSP/HAM suggests a toxometabolic, rather than a viral cause, it is proposed that an intoxication similar to neurolathyrism could account for some of TSP/HAM cases, mainly in tropical and subtropical countries. If this were the case, HTLV-I could be a cofactor or act as a bystander. it is possible that co-infection with another agent is necessary to produce TSP/HAM and most of the syndromes associated with HTLV-I.


Role of Cl- currents in rat aortic smooth muscle activation by prostaglandin F2 alpha.
The aim of this study was to determine the role of Cl(-) channel activation in prostaglandin F(2 alpha)-stimulated aortic contraction and in membrane depolarization during stimulation with prostaglandin F(2 alpha) in an aortic smooth muscle cell line (A7r5). The Cl(-) channel antagonists 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), indanyloxyacetic acid-94 (IAA-94) and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) were found to decrease (P<0.05) the maximum tension generated by rat thoracic aortic segments during stimulation with prostaglandin F(2 alpha) and to shift the concentration-response relationship to the right. In the presence of Nifedipine and Cesium, rat aorta-derived A7r5 smooth muscle cells demonstrated outwardly rectifying voltage-dependent currents that were inhibited by NPPB, IAA-94 and DIDS. Both inward and outward currents were enhanced (P<0.05) following addition of prostaglandin F(2 alpha) (4 micromol/l, final concentration) to the bath solution and this increase was completely inhibited by NPPB. In the absence of Cesium, the addition of prostaglandin F(2 alpha) (4 micromol/l) to the extracellular bath solution either depolarized or hyperpolarized the cell membrane depending on the equilibrium potential for Cl(-) ions. Our results indicate that altered Cl(-) conductance is an important mechanism mediating membrane depolarization and contraction of aortic smooth muscle cells during stimulation with prostaglandin F(2 alpha). Given the significant role that prostaglandin F(2 alpha) and its biologically active isomers, the F(2) isoprostanes, play in the control of vascular tone during hypoxic and oxidative stress in the systemic circulation, alterations in Cl(-) channel function and expression may represent an important mechanism in the pathogenesis of abnormal blood flow regulation in disease states.


Mechanism-based inactivation of gastric peroxidase by mercaptomethylimidazole.
The mechanism of inhibition of gastric peroxidase (GPO) activity by mercaptomethylimidazole (MMI), an inducer of gastric acid secretion, has been investigated. Incubation of purified GPO with MMI in the presence of H2O2 results in irreversible inactivation of the enzyme. No significant inactivation occurs in the absence of H2O2 or MMI, suggesting the involvement of peroxidase-catalysed oxidized MMI (MMIOX.) in the inactivation process. The inactivation follows pseudo-first-order kinetics consistent with a mechanism-based (suicide) mode. The pseudo-first-order kinetic constants at pH 8 are ki = 111 microM, k(inact.) = 0.55 min-1 and t1/2 = 1.25 min, and the second-order rate constant is 0.53 x 10(4) M-1 x min-1. Propylthiouracil also inactivates GPO activity in the same manner but its efficiency (k(inact./ki = 0.46 mM-1 x min-1) is about 10 times lower than that of MMI (k(inact./ki = 5 mM-1 x min-1). The rate of inactivation with MMI shows pH-dependence with an inflection point at 7.3, indicating the involvement in the inactivation process of an ionizable group on the enzyme with a pKa of 7.3. The enzyme is remarkably protected against inactivation by micromolar concentrations of electron donors such as iodide and bromide but not by chloride. Although GPO oxidizes MMI slowly, iodide stimulates it through enzymic generation of I+ which is reduced back to I- by MMI. Although MMIOX. is formed at a much higher rate in the presence of I-, a constant concentration of I- maintained via the reduction of I+ by MMI, protects the active site of the enzyme against inactivation. We suggest that MMI inactivates catalytically active GPO by acting as a suicidal substrate.


Yersiniosis in captive exotic mammals.
Within a 2 1/2-month period, Yersinia pseudotuberculosis infection occurred in 3 blesbok (Damaliscus dorcas), 1 dik-dik (Madoqua kirkii), and 1 giant anteater (Myrmecophaga tridactyla) at the National Zoological Park, Washington, DC. Lesions consisted of fibrinonecrotic enteritis and peritonitis, mesenteric lymphadenitis, and embolic pyogranulomatous lesions in the liver, spleen, and lungs. Feed contaminated with the feces of wild rats and pigeons was thought to be the source of infection.


Integrin-matrix interactions affect the form of the structures developing from human mammary epithelial cells in collagen or fibrin gels.
The HB2 cell line, developed from luminal epithelial cells cultured from milk, forms ball-like structures in collagen gels which show a uniform branching response to hepatocyte growth factor. The alpha2beta1 integrin is the major integrin expressed by luminal epithelial cells, and the role of this integrin in mammary morphogenesis has been analysed using HB2 cells cultured in collagen gels and antibodies which affect integrin function. Selectivity of response was followed by comparing effects on morphogenesis in fibrin, where the alphavbeta1 integrin interacts with the matrix. In the presence of hepatocyte growth factor, using alpha2 and beta1 antibodies in collagen and alphav and beta1 antibodies in fibrin, complete blocking of the cell-matrix interaction inhibits cell survival. With partial blocking of the integrin-ligand interaction, the cells proliferate but form dissociated colonies. Activating antibodies to the beta1 integrin subunit which enhance the matrix interaction dramatically inhibit the branching and motility responses to hepatocyte growth factor. A series of non-blocking alpha2 reactive antibodies also inhibit these responses specifically in or on collagen. Studies with ras-transfected HB2 cells emphasise the importance of the alpha2beta1 collagen interaction in the development of form since HB2ras cells, which express reduced levels of the alpha2beta1 integrin, form dissociated colonies in collagen but not in fibrin. Treatment of HB2ras cells with a beta1 activating antibody, however, induces the formation of compact colonies. Even though the ras-transformants form colonies in agar, complete blocking of the alpha2beta1/collagen interaction does not allow survival in collagen. The results indicate that in mammary morphogenesis, the strength of the interaction of integrins with the extracellular matrix modulates the response to motogenic factors and contributes to the definition of form.


MODEL-BASED LAMOTRIGINE CLEARANCE CHANGES DURING PREGNANCY: CLINICAL IMPLICATION.
The objective of the study was to characterize changes in the oral clearance (CL/F) of lamotrigine (LTG) over the course of pregnancy and the postpartum period through a model-based approach incorporating clinical characteristics that may influence CL/F, in support of developing clinical management guidelines. Women receiving LTG therapy who were pregnant or planning pregnancy were enrolled. Maternal blood samples were collected at each visit. A pharmacokinetic analysis was performed using a population-based, nonlinear, mixed-effects model. A total of 600 LTG concentrations from 60 women (64 pregnancies) were included. The baseline LTG CL/F was 2.16 L/h with a between-subject variability of 40.6%. The influence of pregnancy on CL/F was described by gestational week. Two subpopulations of women emerged based on the rate of increase of LTG CL/F during pregnancy. The gestational age-associated increase in CL/F displayed a ten-fold higher rate in 77% of the women (0.118 L/h/week) compared to 23% (0.0115 L/h/week). The between-subject variability in these slopes was 43.0%. The increased CL/F at delivery declined to baseline values with a half-life of 0.55 weeks. The majority of women had a substantial increase in CL/F from 2.16 to 6.88 L/h by the end of pregnancy, whereas 23% of women had a minimal increase. An increase in CL/F may correspond to decreases in LTG blood concentrations necessitating the need for more frequent dosage adjustments and closer monitoring in some pregnant women with epilepsy. Postpartum doses should be tapered to preconception dose ranges within 3 weeks of delivery.


Effect of exercise training on RSNA, baroreflex control, and blood pressure responsiveness.
The effect of exercise training (ET) on renal sympathetic nerve activity (RSNA), baroreflex control of RSNA and heart rate (HR), and arterial pressure (AP) responsiveness to phenylephrine and angiotensin II (ANG II) was studied in six trained (T) and six sedentary (S) male Wistar rats. ET was performed on a motor treadmill for 13 wk. The RSNA signals of unanesthetized rats were processed by an analog-to-digital converter to quantify the nerve discharges associated with changes in AP and HR. The reflex control of RSNA and HR were evaluated during progressive injections of phenylephrine and sodium nitroprusside. Mean arterial pressure (MAP) was similar in both groups. RSNA was significantly lower in T rats (28 +/- 2 vs. 36 +/- 3%). T rats had an impairment of baroreflex control of RSNA in response to nitroprusside (4.9 +/- 0.89 vs. 12.3 +/- 1.2 bars.cycle-1.mmHg-1). ET decreased AP responsiveness for phenylephrine and ANG II. Therefore ET produces 1) no change in resting MAP but a significant decrease in RSNA and AP responsiveness and 2) partial impairment of baroreflexes, i.e., bradycardic responses and RSNA during MAP decrease.


Bacterial recovery from breast skin of genetically feathered and featherless broiler carcasses immediately following scalding and picking.
Genetically feathered and featherless sibling broilers selected for matched BW were killed, scalded, and defeathered to determine the consequences of feathers and empty feather follicles on the recovery of bacteria from carcass breast skin. In trial 1, the vents of all carcasses were plugged and sutured before scalding to prevent the expulsion of cloacal contents during picking. In trial 2, half of the carcasses had their vents plugged and sutured. Immediately after defeathering, breast skin was aseptically removed, and bacteria associated with it were enumerated. In trial 1, the levels of bacteria recovered did not differ between feathered and featherless carcasses: Campylobacter log10 1.4 cfu/mL of rinse, coliform log10 1.8, Escherichia coli log10 1.6, and total aerobic bacteria log10 3.1. In trial 2, the carcasses that had vents plugged and sutured had lower levels of all four types of bacteria (differences of Campylobacter log10 0.7 cfu/mL, coliform log10 1.8, E. coli log10 1.7, and total aerobic bacteria log10 0.5) than those carcasses with open vents. The lower levels of bacteria recovered from carcasses with the vents plugged and sutured during picking enabled detection of small but significant differences between feathered and featherless carcasses. The level of coliform and E. coli recovered was slightly higher by log10 0.7 cfu for feathered carcasses, but featherless carcasses had marginally higher levels of total aerobic bacteria by log10 0.4 cfu. Feathered and featherless carcasses with open vents during picking did not differ in the levels of recovery of coliform, E. coli, and total aerobic bacteria from breast skin.


Relationship between retinopathy severity, visual impairment and depression in persons with long-term type 1 diabetes.
Our aim was to investigate the proportion of individuals with depression and its association with diabetic retinopathy and visual impairment in a cohort with 25 or more years of type 1 diabetes. This was a cross-sectional analysis at the 25-year follow-up of the population-based cohort of the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Examinations followed standardized protocols and included clinical and ophthalmic evaluations and questionnaires to assess current and past medical history, use of medications, and cigarette smoking. The Center for Epidemiologic Studies Depression Scale (CES-D) was administered to all participants. Depression was defined as use of antidepressant or CES-D score ≥16. A total of 484 individuals were included in the analysis. The proportion of depression was 37.8% (95% confidence interval 33.4-42.3%). A higher proportion of individuals with depression was observed among those with more severe diabetic retinopathy and visual impairment. However these associations were not statistically significant while controlling for other factors in the multivariable analyses. Diabetic retinopathy severity and visual acuity in persons with long duration of type 1 diabetes were not cross-sectionally associated with depression in this cohort.


Use of the Motor Optimality Score-Revised (MOS-R) to predict neurodevelopmental outcomes in infants with congenital anomalies.
To describe the Motor Optimality Score-Revised (MOS-R) in infants with congenital anomalies requiring major surgery in the neonatal period; and to determine the predictive validity of the MOS-R, including specific movement and postural patterns, for neurodevelopmental outcomes at 3 years of age. A retrospective cohort study of 201 infants born with congenital anomalies requiring surgery in the neonatal period (mean gestational age 38.2 weeks, SD 2.2). MOS-R completed using the pre-recorded General Movements Assessment (GMA) videos taken at 12 to 14 weeks post-term age (mean 12.45, SD 1.54). Developmental outcomes were assessed at 3 years of age (38.13 months, SD 1.76) using the Bayley Scales of Infant and Toddler Development (3rd ed). The mean score for the MOS-R was 21.85 (SD 5.16), with scores ranging from 6 to 28. Fifty-six infants (27.9 %) scored within the optimal range (25-28) with only 12 % demonstrating a normal movement character. A MOS-R total score of <21 was identified as the best performing cut-off to predict a mild, moderate or severe delay or CP diagnosis with sensitivity 0.39 (95 % CI: 0.25, 0.54) and specificity 0.86 (95 % CI: 0.80, 0.91), and an area under the ROC curve of 0.63. Outcome at 3 years was significantly associated with the MOS-R total (p < 0.01) and the subscales for observed movement patterns (p < 0.01) and age adequate repertoire (p = 0.02). The MOS-R may be an effective tool to use in addition to existing assessments to identify infants who are at risk of adverse developmental outcomes. Our study found that a MOS-R of <21 identified infants who would benefit from referral to early intervention.