B-chromosome origin in the endemic New Zealand frog Leiopelma hochstetteri through sex chromosome devolution.
The endemic New Zealand frog Leiopelma hochstetteri has variable numbers of mitotically stable B chromosomes. To assess whether the B chromosomes were derived from the autosome complement, they were isolated by micromanipulation and their DNA amplified by degenerate oligonucleotide primed PCR. Southern hybridizations of B chromosome DNA probes to genomic DNA from males and females characterized by differing numbers of B chromosomes demonstrated that the B chromosomes were derived from the univalent W sex chromosome characteristic of North Island populations. The presence of homologous B chromosome specific sequences from geographically distinct populations indicates a single origin of the B chromosomes. Furthermore, a primitive homology shared by B chromosomes and the W sex chromosome from an ancestral WZ/ZZ karyotype, which is still present in frogs from Great Barrier Island, shows that the B chromosomes originated soon after the univalent W sex chromosome had originated. Sequence analysis revealed that B chromosome DNA is composed of repeat sequences and has the potential to form stable hairpin structures. The molecular dynamics of these structures may reflect an inherent propensity to undergo rapid change in nucleotide sequence and chromosome structure.


Adult-onset Satoyoshi syndrome with prominent laterality of clinical features.
We herein report the case of a patient with adult-onset Satoyoshi syndrome. Alopecia was detected on the patient's head, left leg and abdomen, with pigmentation on the left thigh and abdomen. Painful muscle spasms were also noted in the abdomen and left upper and lower extremities, and a sensory disturbance was present in the left thigh. A skin biopsy of this field showed lymphocyte infiltration, and the patient was found to be positive for antinuclear antibodies and rheumatoid factor. These clinical findings were atypical, as they were lateralized. This case is the first report of Satoyoshi syndrome associated with a sensory disturbance. The patient's histological findings and positivity for autoantibodies indicated the presence of immunological abnormalities in this case of Satoyoshi syndrome.


The morphogen behind primary congenital glaucoma and the dream of targeting.
Glaucoma is a clinical entity with multifactorial etiology, a severe subtype occurs in infancy called primary congenital glaucoma (PCG). Three distinct levels interact sequentially to produce PCG: (i) genetic mutations mainly affecting the CYP1B1 gene, (ii) absence or dysregulation of a morphogen, and (iii) trabecular meshwork pathological changes either in patterning or remodeling. We will discuss these three levels in detail towards further understanding of the morphological basis of the disease, focusing on the missing points, for instance the exact nature and function of the morphogen along with the putative role of CYP1B1 gene.


[High incidence of work-related disease among asthmatics on sick-leave].
We have previously shown that work-related asthma is substantially underreported and usually not notified to the Labour Inspection Authority until it has become chronic and interferes with future work. The aim of this study was to evaluate whether conditions relating to individuals are important for the susceptibility to work-related asthma and to assess whether there is a correspondence between patients' and physicians' perception of the importance of exposure to work in relation to the disease. Questionnaires were sent to 824 workers (56% women) aged 18-55 years, who had been on sick leave > 16 days in the years 2000-2003. The disease was classified as work-related asthma if the following questions were answered positively: "Have you ever had respiratory symptoms in relation to your work?" and "Did the symptoms improve on absence from work?" The response rate was 72%, 58% of the responders were women. 416 (70%) had work-related asthma. There were fewer smokers in the group with work-related asthma than among those without, atopy was equally prevalent. Occupational titles reflected the gender differences of the Norwegian labour force. Indoor climate at the workplace was stated as the most frequent provoking factor. The physicians suspected a relationship to work for about half of the 416, notification was only sent for 21% of the male and 10% of the female employees. The importance of occupational exposure seems to be underestimated, especially for women with asthma. Neither atopy nor smoking increased the risk for work-related symptoms. Indoors climate at the work place was most often given as the reason for work-related symptoms. A reduction of exposure led to a reduction of symptoms for most individuals.


Effectiveness of Statins as Primary Prevention in People With Gout: A Population-Based Cohort Study.
Cardiovascular guidelines do not give firm recommendations on statin therapy in patients with gout because evidence is lacking. To analyze the effectiveness of statin therapy in primary prevention of coronary heart disease (CHD), ischemic stroke (IS), and all-cause mortality in a population with gout. A retrospective cohort study (July 2006 to December 2017) based on Information System for the Development of Research in Primary Care (SIDIAPQ), a research-quality database of electronic medical records, included primary care patients (aged 35-85 years) without previous cardiovascular disease (CVD). Participants were categorized as nonusers or new users of statins (defined as receiving statins for the first time during the study period). Index date was first statin invoicing for new users and randomly assigned to nonusers. The groups were compared for the incidence of CHD, IS, and all-cause mortality, using Cox proportional hazards modeling adjusted for propensity score. Between July 2006 and December 2008, 8018 individuals were included; 736 (9.1%) were new users of statins. Median follow-up was 9.8 years. Crude incidence of CHD was 8.16 (95% confidence interval [CI]: 6.25-10.65) and 6.56 (95% CI: 5.85-7.36) events per 1000 person-years in new users and nonusers, respectively. Hazard ratios were 0.84 (95% CI: 0.60-1.19) for CHD, 0.68 (0.44-1.05) for IS, and 0.87 (0.67-1.12) for all-cause mortality. Hazard for diabetes was 1.27 (0.99-1.63). Statin therapy was not associated with a clinically significant decrease in CHD. Despite higher risk of CVD in gout populations compared to general population, patients with gout from a primary prevention population with a low-to-intermediate incidence of CHD should be evaluated according to their cardiovascular risk assessment, lifestyle recommendations, and preferences, in line with recent European League Against Rheumatism recommendations.


Low expression of microRNA-30c promotes prostate cancer cells invasion involved in downregulation of KRAS protein.
Aberrant microRNA expression is associated with tumor development. The present study aimed to elucidate the role of miR-30c in the development of prostate cancer. Quantitative polymerase chain reaction was performed to compare miR-30c expression in LNCaP, DU145, PC-3 and RWPE-1 cell lines. Lentivirus expressing miR-30c was used to create stable overexpression cell lines to investigate the effects of miR-30c overexpression on cell proliferation, migration and invasion, which were determined in the prostate cancer cell line PC-3 by MTT, colony formation, wound healing and Transwell assays. Effects of miR-30c on KRAS were examined by western blot analysis. miR-30c expression was significantly lower (P<0.05) in the PC-3 cell line compared with LNCaP, DU145 and RWPE-1 cell lines. miR-30c overexpression in PC-3 inhibited tumor cell proliferation, migration and invasion in vitro. Furthermore, KRAS protein expression was downregulated in miR-30c overexpression cell lines compared with the negative control (NC) group (P<0.05). The present results demonstrated that overexpression of miR-30c inhibits prostate cancer cell line proliferation, migration and invasion, which was possibly caused by downregulation of KRAS protein by miR-30c. The data implicate miR-30c in the prognosis and treatment of prostate cancer.


EBV latent membrane proteins promote hybrid epithelial-mesenchymal and extreme mesenchymal states of nasopharyngeal carcinoma cells for tumorigenicity.
EBV-encoded LMPs are consistently detected in nasopharyngeal carcinoma (NPC). Recent evidence suggests potential roles of LMP1 and LMP2A in Epithelial-to-mesenchymal transition (EMT) process in NPC. EMT engages in the generation and maintenance of cancer stem cells (CSCs) and confers on cancer cells increased tumor-initiating and metastatic potential, and higher resistance to anticancer therapies. However, how LMP1 and LMP2A regulate the EMT process to generate cells with different EMT states and its implications for tumor progression remain unclear. Here we report that LMP1 and LMP2A promote EMT that drives NPC cells from the epithelial-like state (E) (CD104+, CD44low) to epithelial-mesenchymal hybrid (E/M) state (CD104+, CD44high). Furthermore, LMP2A possesses an additional function in stabilizing LMP1 and increasing the level of LMP1 in NPC cells. The elevated LMP1 further forces the EMT to generate extreme-mesenchymal (xM) state cells (CD104-, CD44high). To define the tumorigenic features of cancer stem cells at different states in the EMT spectrum, E, E/M and xM subpopulations were isolated and tested for tumorigenic capability in a tumor xenograft animal model. We found that the cells with E/M phenotypes possess the highest tumor initiating capacity. However, the xM subpopulation exhibits increased vasculogenic mimicry, a hallmark of metastatic cancers. Taken together, coordinated action of LMP1 and LMP2A generates an array of intermediate subpopulations in the EMT spectrum that are responsible for distinct tumorigenic features of NPC such as tumor-initiation, vasculogenesis, and metastasis.


Ferroptosis in Cancer Progression: Role of Noncoding RNAs.
Ferroptosis is a novel form of programmed cell death, and it is characterized by iron-dependent oxidative damage, lipid peroxidation and reactive oxygen species accumulation. Notable studies have revealed that ferroptosis plays vital roles in tumor occurrence and that abundant ferroptosis in cells can inhibit tumor progression. Recently, some noncoding RNAs (ncRNAs), particularly microRNAs, long noncoding RNAs, and circular RNAs, have been shown to be involved in biological processes of ferroptosis, thus affecting cancer growth. However, the definite regulatory mechanism of this phenomenon is still unclear. To clarify this issue, increasing studies have focused on the regulatory roles of ncRNAs in the initiation and development of ferroptosis and the role of ferroptosis in progression of various cancers, such as lung, liver, and breast cancers. In this review, we systematically summarized the relationship between ferroptosis-associated ncRNAs and cancer progression. Moreover, additional evidence is needed to identify the role of ferroptosis-related ncRNAs in cancer progression. This review will help us to understand the roles of ncRNAs in ferroptosis and cancer progression and may provide new ideas for exploring novel diagnostic and therapeutic biomarkers for cancer in the future.


Behavioral and electrophysiological correlates of cognitive control in ex-obese adults.
Impaired cognitive control functions have been documented in obesity. It remains unclear whether these functions normalize after weight reduction. We compared ex-obese individuals, who successfully underwent substantial weight loss after bariatric surgery, to normal-weight participants on measures of resistance to interference, cognitive flexibility and response inhibition, obtained from the completion of two Stroop tasks, a Switching task and a Go/NoGo task, respectively. To elucidate the underlying brain mechanisms, event-related potentials (ERPs) in the latter two tasks were examined. As compared to controls, patients were more susceptible to the predominant but task-irrelevant stimulus dimension (i.e., they showed a larger verbal Stroop effect), and were slower in responding on trials requiring a task-set change rather than a task-set repetition (i.e., they showed a larger switch cost). The ERP correlates revealed altered anticipatory control mechanisms (switch positivity) and an exaggerated conflict monitoring response (N2). The results suggest that cognitive control is critical even in ex-obese individuals and should be monitored to promote weight loss maintenance.


A longitudinal study of electronic cigarette use among a population-based sample of adult smokers: association with smoking cessation and motivation to quit.
Increasingly popular electronic cigarettes (e-cigarettes) may be the most promising development yet to end cigarette smoking. However, there is sparse evidence that their use promotes cessation. We investigated whether e-cigarette use increases smoking cessation and/or has a deleterious effect on quitting smoking and motivation to quit. Representative samples of adults in 2 US metropolitan areas were surveyed in 2011/2012 about their use of novel tobacco products. In 2014, follow-up interviews were conducted with 695 of the 1,374 baseline cigarette smokers who had agreed to be re-contacted (retention rate: 51%). The follow-up interview assessed their smoking status and history of electronic cigarette usage. Respondents were categorized as intensive users (used e-cigarettes daily for at least 1 month), intermittent users (used regularly, but not daily for more than 1 month), and non-users/triers (used e-cigarettes at most once or twice). At follow-up, 23% were intensive users, 29% intermittent users, 18% had used once or twice, and 30% had not tried e-cigarettes. Logistic regression controlling for demographics and tobacco dependence indicated that intensive users of e-cigarettes were 6 times more likely than non-users/triers to report that they quit smoking (OR: 6.07, 95% CI = 1.11, 33.2). No such relationship was seen for intermittent users. There was a negative association between intermittent e-cigarette use and 1 of 2 indicators of motivation to quit at follow-up. Daily use of electronic cigarettes for at least 1 month is strongly associated with quitting smoking at follow-up. Further investigation of the underlying reasons for intensive versus intermittent use will help shed light on the mechanisms underlying the associations between e-cigarette use, motivation to quit, and smoking cessation.


Heterogeneous expression of transketolase in ocular tissues.
Previous studies have shown that transketolase is preferentially expressed in the corneal epithelium and comprises up to 10% of the soluble protein of the mature mouse cornea. The aim of this study is to evaluate the expression and distribution of TKT in the different ocular tissues. We have used in situ hybridization and immunohistochemistry to localize TKT mRNA and protein in the developing and adult mouse eye. TKT were found to be widely distributed throughout the adult mouse eye. Among the ocular tissues examined, the corneal epithelium exhibited the highest levels of TKT mRNA and protein. Within the epithelial layer, TKT mRNA and protein were differentially distributed with the highest expression occurring in basal cells and the lowest in apical cells, suggesting that TKT expression in the corneal epithelium may be differentiation-related. Enriched expression of TKT was also found in the cornea endothelium, lens epithelium, ciliary body, and iris. Low basal levels of expression were observed in the limbus and conjunctiva. In contrast to the adult eye, TKT expression in the one-day-old mouse eye was homogeneous at low, but detectable levels, suggesting that TKT expression is developmentally regulated in the cornea as well as in the other ocular tissues. In the healing corneal epithelium, TKT expression in the single cell layer of the leading edge was completely suppressed until the cells began to stratify, at which point TKT expression increased markedly. The results presented here suggest that TKT is differentially expressed and developmentally regulated in the various tissues that comprise the eye.


Reproductive endocrinology and weight change in relation to reproductive success in the magellanic penguin (Spheniscus magellanicus).
The Magellanic penguin is a colonial monogamous species that lays only a single clutch of two eggs per year. However, failed breeders remain at the colony and engage in nest building, fights, and copulations without relaying. The seasonal changes in reproductive hormones and body weight through the nesting cycle were studied, with respect to the reproductive success or failure of individuals. Body weight changed dramatically in both sexes through the season, in response to fasting during incubation, and high body weight in males at the onset of incubation was a strong predictor of eventual reproductive success. Circulating steroid hormones had a biphasic seasonal pattern, with elevated levels during the sexual phase of breeding (prior to egg laying), declining to low, stable levels during the parental phase after eggs were laid. Luteinizing hormone levels were elevated in females, but not in males, prior to egg laying. Both sexes responded to reproductive failure by increasing the secretion of testosterone, and females also increased the secretion of estradiol, a response that would be expected of a species that can renest following failure. However, renesting is extremely rare, and this hormonal response to failure may instead serve to promote maintenance of pair bonds and also territory ownership across years.


[Study of the surface properties of spinal ganglion neurons in the rat by the microelectrophoresis technic].
Surface charges of isolated neurons of rat dorsal root ganglion were studied by the microelectrophoresis. It was shown that the surface potential of these neurons is produced by anion groups which form complexes with calcium ions and a binding constant ranging from 10 to 50 1/mole; they can be titrated by hydrogen ions according to pK = 3.8. Under trypsin treatment the surface loses most of these groups. Tosylchloride (reagent for aminogroups ) slightly increases the surface charge and N- bromsuccinimide (reagent for carboxylic groups) partially neutralizes it. It is suggested that the surface charge of rat dorsal root ganglion neurons measured by the microelectrophoresis is mainly determined by carboxylic groups of periphery proteins. These groups seem to be located in the glycoprotein sheath which covers the outer surface of the membrane. According to our estimates the average distance between these groups is about 2 nm and the thickness of the sheath is about 10 nm.


Three cases of metaldehyde poisoning in cattle.
Poisoning of dairy cows and of calves by metaldehyde is reported. The clinical signs, post mortem and toxicological findings are described. Confirmations of the diagnoses was obtained by biochemical estimations. It would appear that a dose as low as 0.2 g/kg in adult cattle, and even less in calves, can be lethal.


Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced myelosuppression.
An increase in the dose of chemotherapy enhances the response of many experimental and clinical cancers, but the extent of dose escalation is often limited by myelosuppression. In preliminary trials, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) has augmented leukocyte numbers and function, but the optimal dose is not established. We treated 16 adults who had inoperable or metastatic sarcomas with escalating doses of rhGM-CSF before and immediately after a first cycle of chemotherapy (cycle 1) to assess hematologic response and toxicity. A second cycle of chemotherapy (cycle 2) was given without rhGM-CSF. RhGM-CSF was tolerated well at doses of 4 to 32 micrograms per kilogram of body weight per day. At 64 micrograms per kilogram per day, edema and thrombi around a central venous catheter developed in two of four patients. Leukocyte and granulocyte counts increased significantly during the rhGM-CSF infusion. Neutropenia after cycle 1 was significantly less severe and shorter in duration than after cycle 2 (P less than 0.01). Mean total leukocyte and platelet nadirs were 1.0 and 101 x 10(9) per liter for cycle 1 and 0.45 and 44 x 10(9) per liter for cycle 2 (P less than 0.01), and the median intervals from day 1 of chemotherapy to neutrophil recovery (greater than 0.500 x 10(9) per liter) were 15 and 19 days, respectively (P less than 0.01). The duration of neutropenia was 3.5 days with cycle 1 and 7.4 days with cycle 2 (P less than 0.01). We conclude that rhGM-CSF is tolerated well at doses up to 32 micrograms per kilogram per day and is biologically active in leukopenic patients. It merits further evaluation for the prevention of morbidity from chemotherapy.


Changes in antimicrobial susceptibility profiles of Mycoplasma bovis over time.
Mycoplasma bovis is a major cause of pneumonia, arthritis, and mastitis in cattle and can lead to significant economic losses. Antimicrobial resistance is a concern and further limits the already short list of drugs effective against mycoplasmas. The objective of this study was to examine changes in in vitro minimum inhibitory concentrations (MICs) of antimicrobials of aminoglycoside, fluoroquinolone, lincosamide, macrolide, pleuromutilin, phenicol, and tetracycline classes for 210 M. bovis isolates collected from 1978 to 2009. The MIC50 values of the various antimicrobials were also compared. The MIC50 levels for enrofloxacin and danofloxacin remained low (0.25 μg/mL) across all 3 decades. MIC50 levels for tetracyclines, tilmicosin, and tylosin tartrate were low in the 1980s, then increased in the 1990s and remained high. In the 1980s, MIC50 levels were low for clindamycin, spectinomycin, and tulathromycin, increased in the 1990s to 8 μg/mL (clindamycin) and 32 μg/mL (spectinomycin and tulathromycin), then decreased again in the 2000s. Members of the fluoroquinolone class of antimicrobials had the lowest MIC50 levels across all 3 decades, which suggests in vitro susceptibility of M. bovis to this class of antimicrobials. Statistically significant associations were observed between MIC values for chlortetracycline, oxytetracycline, tylosin tartrate, and tilmicosin; between clindamycin, tulathromycin, spectinomycin, and tiamulin; and between tylosin tartrate and clindamycin. Changes in MIC levels of various antimicrobials over time show the importance of monitoring the susceptibility of mycoplasmas to antimicrobials. The number of antimicrobials that showed elevated MIC50 levels, and therefore possibly reduced in vitro effectiveness against M. bovis, supports initiatives that promote prudent use of antimicrobials in agriculture.


Future of diagnostic microbiology.
Diagnostic Microbiology is the tool that makes it possible to identify the exact etiology of infectious diseases and the most optimal therapy at the level of individual patients as well as communities. Conventional methods require time to grow the microbes in vitro under specific conditions and not all microbes are easily cultivable. This is followed by biochemical methods for identification which also require hours and sometimes days. Transport of the specimens under less than ideal conditions, prior use of antibiotics and small number of organisms are among the factors that render culture-based methods less reliable. Newer methods depend on amplification of nucleic acids followed by use of probes for identification. This mitigates the need for higher microbial load, presence of metabolically active viable organisms and shortens the time to reporting. These methods can be used to detect antibiotic resistance genes directly from the specimen and help direct targeted therapy. Since these methods will not fulfill all the diagnostic needs, a second approach is being used to shorten the time to identification after the organism has already grown. Mass spectrometry and bioinformatics are the tools making this possible. This review gives a historical perspective on diagnostic microbiology, discusses the pitfalls of current methodology and provides an overview of newer and future methods.


Evaluation of non-Gaussian statistical properties in virtual breast phantoms.
Images derived from a "virtual phantom" can be useful in characterizing the performance of imaging systems. This has driven the development of virtual breast phantoms implemented in simulation environments. In breast imaging, several such phantoms have been proposed. We analyze the non-Gaussian statistical properties from three classes of virtual breast phantoms and compare them to similar statistics from a database of breast images. These include clustered-blob lumpy backgrounds (CBLBs), truncated binary textures, and the UPenn virtual breast phantoms. We use Laplacian fractional entropy (LFE) as a measure of the non-Gaussian statistical properties of each simulation procedure. Our results show that, despite similar power spectra, the simulation approaches differ considerably in LFE with very low scores for the CBLB to high values for the UPenn phantom at certain frequencies. These results suggest that LFE may have value in developing and tuning virtual phantom simulation procedures.


Stress-induced dependence on endogenous opioid peptides--a fundamental process in the pathophysiology of a disturbed adaptation--its influence by substance P.
Using previous findings of stress-induced disturbances in regulation of peripheral and central function within the general adaptation process and hints from the literature to a multiple participation of opioid peptides in adaptive processes, this paper represents experimental data which gives hints to a functional relation in the etiopathophysiology between the development of stress-induced dependence on endogenous opioid peptides and stress-induced disturbances in blood pressure regulation and to the adaptive effect of substance P within the peptidergic interaction with endogenous opioid peptides and its importance for the physiology or pathophysiology of adaptive processes.


Group differences in measures of voice production and revised values of maximum airflow declination rate.
In previous reports, aerodynamic and acoustic measures of voice production were presented for groups of normal male and female speakers [Holmberg et al., J. Acoust. Soc. Am. 84, 511-529 (1988); J. Voice 3, 294-305 (1989)] that were used as norms in studies of voice disorders [Hillman et al., J. Speech Hear. Res. 32, 373-392 (1989); J. Voice 4, 52-63 (1990)]. Several of the measures were extracted from glottal airflow waveforms that were derived by inverse filtering a high-time-resolution oral airflow signal. Recently, the methods have been updated and a new study of additional subjects has been conducted. This report presents previous (1988) and current (1993) group mean values of sound pressure level, fundamental frequency, maximum airflow declination rate, ac flow, peak flow, minimum flow, ac-dc ratio, inferred subglottal air pressure, average flow, and glottal resistance. Statistical tests indicate overall group differences and differences for values of several individual parameters between the 1988 and 1993 studies. Some inter-study differences in parameter values may be due to sampling effects and minor methodological differences; however, a comparative test of 1988 and 1993 inverse filtering algorithms shows that some lower 1988 values of maximum flow declination rate were due at least in part to excessive low-pass filtering in the 1988 algorithm. The observed differences should have had a negligible influence on the conclusions of our studies of voice disorders.


Elevated Serum Retinol and Low Beta-Carotene but not Alpha-Tocopherol Concentrations Are Associated with Dyslipidemia in Brazilian Adolescents.
The purpose of this study was to investigate the status of retinol, beta-carotene, and alpha-tocopherol serum concentrations in adolescents with dyslipidemia. A case series dyslipidemia study was conducted, with an attached control group, including 104 adolescents of public schools in Recife during the months of March/April 2013. Retinol, beta-carotene and alpha-tocopherol serum concentrations were analysed by high efficiency liquid chromatography. Sociodemographic, anthropometric, clinical and biochemical variables were analysed. Dyslipidemic adolescents had high serum concentrations of both retinol (p=0.007) and beta-carotene/apolipoprotein A-I ratio (p=0.034); they also had low concentrations of beta-carotene/total cholesterol (p<0.0001) and beta-carotene/apolipoprotein B ratios (p=0.033) when compared to the controls. The alpha-tocopherol serum status was not associated with dyslipidemia. Overweight, abdominal obesity, lipid profile markers, and systolic and diastolic blood pressures were more prevalent in dyslipidemic adolescents. The findings show an association between vitamin A and dyslipidemia in adolescents. However, additional investigations of this risk group are necessary to clarify the mechanisms of action of this nutrient in the pathogenesis of this syndrome, aiming at reducing cardiometabolic risks as of earlier ages.


Augmentation of random-flap survival by implantation of vascularized fascia allografts and temporary immunosuppression: implications for flap fabrication.
The purpose of this study was to explore the possible use of an allogeneic vascular source for flap fabrication. Epigastric fascia with its superficial epigastric vessel pedicle was harvested from the donor rat and microsurgically revascularized in the recipient rat across a major histocompatibility barrier. ACI rats (Rtl-a) served as donors, and Lewis rats (Rtl-1) served as recipients. The recipient rat was immunosuppressed with a daily dose of 2 mg/kg cyclosporin A plus 5 mg/kg prednisone for 4 weeks. Three experiments were performed for skin, muscle, and bone studies. In experiment 1 (20 Lewis rats), placement of the allotransplanted fascia underneath the epigastric skin significantly improved the survival of a random epigastric skin flap raised 3 weeks later (7.35 +/- 0.65 cm2 versus 6.09 +/- 0.90 cm2, p < 0.05). Immunosuppression was discontinued 10 days after flap elevation with no observable additional skin necrosis. In experiment 2 (13 Lewis rats) and experiment 3 (14 Lewis rats), segments of isogeneic muscle and bone were grafted successfully on the allotransplanted fascia, respectively. The survival of these grafts was confirmed by metabolic bone activity, bone labeling, microangiography, and histologic studies and further confirmed 2 weeks after cessation of immunosuppression. An allotransplanted fascia as a vascular source proved in this model its capability to improve the survival of a random skin flap and to accept a free bone or muscle graft with temporary immunosuppression. These findings hold promise for possible use of an allogeneic vascular source in flap fabrication.


Intention tremor and deficits of sensory feedback control in multiple sclerosis: a pilot study.
Intention tremor and dysmetria are leading causes of upper extremity disability in Multiple Sclerosis (MS). The development of effective therapies to reduce tremor and dysmetria is hampered by insufficient understanding of how the distributed, multi-focal lesions associated with MS impact sensorimotor control in the brain. Here we describe a systems-level approach to characterizing sensorimotor control and use this approach to examine how sensory and motor processes are differentially impacted by MS. Eight subjects with MS and eight age- and gender-matched healthy control subjects performed visually-guided flexion/extension tasks about the elbow to characterize a sensory feedback control model that includes three sensory feedback pathways (one for vision, another for proprioception and a third providing an internal prediction of the sensory consequences of action). The model allows us to characterize impairments in sensory feedback control that contributed to each MS subject's tremor. Models derived from MS subject performance differed from those obtained for control subjects in two ways. First, subjects with MS exhibited markedly increased visual feedback delays, which were uncompensated by internal adaptive mechanisms; stabilization performance in individuals with the longest delays differed most from control subject performance. Second, subjects with MS exhibited misestimates of arm dynamics in a way that was correlated with tremor power. Subject-specific models accurately predicted kinematic performance in a reach and hold task for neurologically-intact control subjects while simulated performance of MS patients had shorter movement intervals and larger endpoint errors than actual subject responses. This difference between simulated and actual performance is consistent with a strategic compensatory trade-off of movement speed for endpoint accuracy. Our results suggest that tremor and dysmetria may be caused by limitations in the brain's ability to adapt sensory feedback mechanisms to compensate for increases in visual information processing time, as well as by errors in compensatory adaptations of internal estimates of arm dynamics.


Mechanisms of complement activation by dextran-coated superparamagnetic iron oxide (SPIO) nanoworms in mouse versus human serum.
The complement system is a key component of innate immunity implicated in the neutralization and clearance of invading pathogens. Dextran coated superparamagnetic iron oxide (SPIO) nanoparticle is a promising magnetic resonance imaging (MRI) contrast agent. However, dextran SPIO has been associated with significant number of complement-related side effects in patients and some agents have been discontinued from clinical use (e.g., Feridex™). In order to improve the safety of these materials, the mechanisms of complement activation by dextran-coated SPIO and the differences between mice and humans need to be fully understood. 20 kDa dextran coated SPIO nanoworms (SPIO NW) were synthesized using Molday precipitation procedure. In vitro measurements of C3 deposition on SPIO NW using sera genetically deficient for various components of the classical pathway (CP), lectin pathway (LP) or alternative pathway (AP) components were used to study mechanisms of mouse complement activation. In vitro measurements of fluid phase markers of complement activation C4d and Bb and the terminal pathway marker SC5b-C9 in normal and genetically deficient sera were used to study the mechanisms of human complement activation. Mouse data were analyzed by non-paired t-test, human data were analyzed by ANOVA followed by multiple comparisons with Student-Newman-Keuls test. In mouse sera, SPIO NW triggered the complement activation via the LP, whereas the AP contributes via the amplification loop. No involvement of the CP was observed. In human sera the LP together with the direct enhancement of the AP turnover was responsible for the complement activation. In two samples out of six healthy donors there was also a binding of anti-dextran antibodies and C1q, suggesting activation via the CP, but that did not affect the total level of C3 deposition on the particles. There were important differences and similarities in the complement activation by SPIO NW in mouse versus human sera. Understanding the mechanisms of immune recognition of nanoparticles in mouse and human systems has important preclinical and clinical implications and could help design more efficient and safe nano-formulations.


Adsorption protein layers above erythrocytes and an electrophoretic method for studying their properties under pathogenesis of infection and malignant tumors.
The use of thickness of protein layers adjacent to the surface of each erythrocyte is discussed as a diagnostic test. The given method of studying such layers is based on electrophoretic measurements which make it possible to evaluate the structure, composition and thickness of these layers. It has been shown that the normalization of erythrocyte electrophoretic mobility of stored or pathologic blood flowing through an active-carbon column may be explained by a full or partial removal of adsorption protein layers and intermicellar liquid contained it.


Prior exposure to lamivudine increases entecavir resistance risk in chronic hepatitis B Patients without detectable lamivudine resistance.
The efficacy of entecavir (ETV) treatment in chronic hepatitis B (CHB) patients who were exposed to lamivudine (LAM) but had no detectable LAM resistance (LAM-R) is not well evaluated. In this study, we aimed to evaluate whether the probability of developing genotypic resistance to ETV in LAM-exposed patients with or without LAM-R is comparable to that in antiviral-naive patients. This retrospective cohort study included 500 consecutive patients with CHB who started ETV monotherapy at a single tertiary hospital in Korea. The patients were divided into three groups: nucleos(t)ide analogue (NA)-naive patients (group 1, n=142), patients who were previously exposed to LAM and had no currently or previously detected LAM-R (group 2, n=233), and patients with LAM-R when starting ETV (group 3, n=125). The overall median ETV treatment duration was 48.7 months. The probabilities of virologic breakthrough were significantly increased not only in group 3 (hazard ratio [HR]=14.4, P<0.001) but also in group 2 (HR=5.0, P<0.001) compared to group 1. Genotypic ETV resistance (ETV-R) developed more frequently in group 2 (HR=13.0, P=0.013) as well as group 3 (HR=43.9, P<0.001) than in group 1: the probabilities of developing ETV-R in groups 1, 2, and 3 were <1.0%, 8.0%, and 28.2%, respectively, at month 48. The results of this study indicate that ETV-R occurred more frequently in LAM-exposed patients, even though they had no detectable LAM-R, than in NA-naive patients. Therefore, LAM-exposed CHB patients, regardless of the presence or absence of LAM-R, should be monitored more cautiously for the development of ETV-R during ETV monotherapy.


Effects of shoe heel height on biologic rollover characteristics during walking.
This study investigated the effects of shoe heel height on the rollover characteristics of the biologic ankle-foot system. Ten nondisabled adult female volunteers walked using three pairs of shoes with varying heel heights and at three walking speeds with each pair of shoes. Kinematic and kinetic data needed to calculate the rollover shapes of the ankle-foot systems of the participants were collected. Rollover shapes are the effective rocker geometries that ankle-foot systems conform to between heel contact and opposite heel contact. Parameters of the best-fit circular arcs to the rollover shapes were used in an examination of the effects of shoe heel height on the ankle-foot system. The results support the notion that nondisabled humans automatically adapt their ankle-foot systems to accommodate a range of shoe heel heights, resulting in rollover shapes that do not change appreciably. Given physiologic constraints, this adaptation may not be possible for very high heels.


Estrogen attenuates expression of calcitonin-like immunoreactivity in the anterior pituitary gland.
Estrogens increase prolactin (PRL) synthesis and release in rats and humans, whereas pituitary-derived calcitonin-like immunoreactive peptide (pit-CT) inhibits PRL gene expression and release. To test the hypothesis that estrogens stimulate lactotrophs by diminishing pit-CT expression, the present studies examined effects of ovariectomy (ovx) and estradiol (E2) administration on (1) pit-CT IR cell population; (2) pit-CT IR content and (3) release of pit-CT IR by cultured anterior pituitary (AP) cells. Ability of anti-calcitonin immunoglobulins (anti-CT IgG) to stimulate PRL release from cultured AP cells was also examined. The results suggest that ovariectomy induced a large increase in pit-CT IR cell population in the AP gland and E2-treatment dramatically reversed this increase. Similar changes were observed in pit-CT IR content of AP extracts. Cultured AP cells from ovx rats released significantly higher amounts of pit-CT IR, and anti-CT IgG induced a significant increase in basal PRL release. AP cells from E2-treated rats secreted lower amounts of pit-CT IR and this was associated with significantly higher PRL release. These results suggest that estrogens may stimulate lactotrophs, at least in part, by removing inhibitory influence of endogenous pit-CT.


Anti-apoptotic activity of Bak Foong Pills and its ingredients on 6-hydroxydopamine-induced neurotoxicity in PC12 cells.
Bak Foong Pills (BFP), a traditional Chinese medicine used for centuries for the enhancement of women's health, was shown to display neuro-protective activity in the 1-methyl-4-phenyl-1,2,4,6,-tetrahydro-pyridine (MPTP)-induced mouse model in a previous study. In order to elucidate its mechanism of action, we investigated the anti-apoptotic properties of Bak Foong Pills and its main ingredients, including Panax ginseng, Angelica sinensis, Glycyrrhiza uralensis, and Ligusticum chuanxiong, in the 6-hydroxydopamine (6-OHDA)-treated PC12 cell model. The addition of the neurotoxin could cause significant cell death and reduction of cell proliferation, as shown in the results determined by MTT assay, nitric oxide (NO) measurement and flow cytometric propidium iodine (PI) staining analysis, while pre-treatment of PC12 cell with either BFP or its main ingredients prevented the toxicity to some degree. In addition, the neurotoxin caused an elevated activation of caspase-3, the key enzyme for activation of the cellular apoptotic cascade, whereas BFP or its main ingredients inhibited the activation of caspase-3. These results strongly indicate that BFP and its main ingredients may provide a useful therapeutic strategy for the treatment of neurodegenerative diseases, such as Parkinson's disease.


Electrical coupling between cells and graphene transistors.
In this work, both experimental data and a model are presented on the coupling between living cells and graphene solution-gated field-effect transistors. Modified HEK 293 cells are successfully cultured on graphene transistor arrays and electrically accessed by the patch clamp method. Transistor recordings are presented, showing the opening and closing of voltage-gated potassium ion channels in the cell membrane. The experimental data is compared with the broadly used standard point-contact model. The ion dynamics in the cell-transistor cleft are analyzed to account for the differences between the model and the experimental data revealing a significant increase in the total ionic strength in the cleft. In order to describe the influence of the ion concentration resulting from the cell activity, the ion-sensitivity of graphene solution-gated field-effect transistors is investigated experimentally and modelled by considering the screening effect of the ions on the surface potential at the graphene/electrolyte interface. Finally, the model of the cell-transistor coupling is extended to include the effect of ion accumulation and ion sensitivity. The experimental data shows a very good agreement with this extended model, emphasizing the importance of considering the ion concentration in the cleft to properly understand the cell-transistor coupling.


Effectiveness of the smart care service for diabetes management.
The aim of this study was to assess the effectiveness of the Smart Care service for the diabetes management. Fifty-six patients with diabetes mellitus were recruited in Daegu, Korea. All participants completed a diabetes management education course (diet, exercise, and complications) for their self-care and received access to a care management website through a netbook and smartphone. The website accepts uploads of glucose level, body weight, HbA1c, low-density lipoprotein cholesterol level, and blood pressure. Participants communicated with the care manager through the internal management system of the website. The intervention was applied for 6 months. Participants receiving the Smart Care service had lower blood glucose and HbA1c during 6 months follow-up when 1-month values (p < 0.001) were compared. There was no significant difference in body weight and body mass index between 1 month and 6 months. The average number of remote consultation with the Smart Care service per person was 10.4 by nurses, 3.0 by nutritionists, and 1.6 by sports curers. Regression analysis indicated that the number of times counseling was offered by nurses influences body weight and that the number of minutes of telephone counseling influences both body weight and body mass index. We have confirmed that the Smart Care service might be an effective system for reduction in blood glucose and HbA1c. We expect that the Smart Care service will contribute to delaying diabetes complications and improving the quality of life of patients with diabetes.


Drug-Drug Interaction of Ergotamine with a Combination of Darunavir, Abacavir, and Lamivudine Causing a Fatal Vasospastic Ischemia.
Ergotamine toxicity has become a rare condition which can be caused by, among others, drug-drug interaction. In this work we report a case with vasospastic ischemia induced by the wrongful combination of ergotamine with recently started Antiretroviral Therapy. Clinicians were not aware that patient was self-medicating for years with medication containing ergotamine and caffeine for migraines. This diagnosis was established after evaluating the evolving 'and spreading' ischemia and CT scans and thoroughly interviewing patient's family. Treatment was started with intravenous nimodipine and intra-arterial sodium nitroprusside on the affected limbs. The patient developed severe limb ischemia, cerebral ischemia, and metabolic encephalopathy. Unfortunately no improvements were noticeable and due to evolving cerebral edema as a result of the ischemia, the patient developed brain herniation and died shortly after.


The Heparan Sulfate Binding Peptide in Tumor Progression of Triple-Negative Breast Cancer.
Angiogenesis is the formation of new vessels from pre-existing vasculature. The heparan sulfate chains from endothelial cell proteoglycans interact with the major angiogenic factors, regulating blood vessels´ formation. Since the FDA´s first approval, anti-angiogenic therapy has shown tumor progression inhibition and increased patient survival. Previous work in our group has selected an HS-binding peptide using a phage display system. Therefore, we investigated the effect of the selected peptide in angiogenesis and tumor progression. The HS-binding peptide showed a higher affinity for heparin N-sulfated. The HS-binding peptide was able to inhibit the proliferation of human endothelial umbilical cord cells (HUVEC) by modulation of FGF-2. It was verified a significant decrease in the tube formation of human endothelial cells and capillary formation of mice aorta treated with HS-binding peptide. HS-binding peptide also inhibited the formation of sub-intestinal blood vessels in zebrafish embryos. Additionally, in zebrafish embryos, the tumor size decreased after treatment with HS-binding peptide.


Effect of plantar local anesthetic injection on dorsal horn neuron activity and pain behaviors caused by incision.
Hypersensitivity after tissue injury is an expression of neuronal plasticity in the central nervous system. This has been explored most extensively using in vitro preparations and animal models of inflammatory pain and chemical irritation. For pain after surgery, a similar process has been proposed. In the present study, we examined dorsal horn neuron (DHN) sensitization using the plantar incision model for post-operative pain. In behavioral experiments, the effect of a local anesthetic injection (or saline vehicle) 15 min before plantar incision on pain behaviors several days after incision was studied. Bupivacaine injection before incision prevented pain behaviors until 4 h afterwards; injection after incision produced the same effect. One day after incision, pain behaviors were not different between rats injected with saline or bupivacaine. In neurophysiologic experiments, however, bupivacaine injection blocked activation of DHNs during incision. One hour after incision, expansion of receptive fields (RFs) to pinch and increased background activity occurred in 14 of 16 neurons in the saline group but only in two of 22 neurons in the bupivacaine group. The difference was not due to a systemic effect of bupivacaine. Ten sensitized neurons were studied using the injection of bupivacaine 90 min after incision. Increased background activity (n=7) and expanded RFs (n=7) were reversed by bupivacaine. Sensitization was re-established in seven of eight neurons 2 h after injection as the local anesthetic dissipated. These results indicate that activation of DHNs during plantar incision and sensitization 1 h later are not necessary for subsequent pain behaviors. Because sensitization was reversed 90 min after plantar incision and then re-established as the local anesthetic effect diminished, enhanced responsiveness of DHN requires ongoing afferent input during the first day after incision.


Resistance of the suckling guinea pig to lithocholic acid-induced cholestasis.
Although immaturity of the liver and synthesis of monohydroxy bile acids have been implicated as pathogenic factors in neonatal cholestasis, there is no direct evidence to show that these bile acids induce cholestasis in the newborn. In the present investigation, we compared the effects of lithocholic acid (LCA) injection on bile flow in suckling (2-week-old) and adult (12-week-old) guinea pigs. Bile flow was not modified by LCA in 2-week-old animals, but it was reduced by 50 to 80% in the adults, the decrease being dose-dependent. In the newborn, the injected LCA was mainly secreted in bile (greater than 90%), while in the adults it was distributed between the liver and bile. The percentage of biliary bile acids (as determined by gas-liquid chromatography) in the two groups was similar before and after LCA injection. Morphologic lesions characteristic of LCA-induced cholestasis were observed only in the adult guinea pigs. This study demonstrates that the newborn guinea pig is less susceptible to cholestasis induced by 90 to 180 mumoles per kg body weight of lithocholate and that, in the neonatal liver, there is no defect in the transport of this bile acid from blood to bile.


Proteomics of reproductive systems: Towards a molecular understanding of postmating, prezygotic reproductive barriers.
Following mating and insemination, fertility is dependent on the successful execution of a complex array of morphological, physiological and molecular interactions between male and female proteins, cells and tissues. Many of these interacting components bear hallmarks of co-evolving systems and are suspected to contribute to postmating, prezygotic (PMPZ) reproductive barriers involved in the formation of new species. Although PMPZ reproductive isolation has historically been more difficult to study than precopulatory and postzygotic barriers, recent research has highlighted its potential role in speciation and revealed the impact of molecular investigation utilizing proteomic approaches. Proteomics, in conjunction with transcriptomic and evolutionary genomic studies, has been widely used to identify rapidly evolving male and female reproductive proteins. Increased access to high-throughput and quantitative proteomic techniques, as well as the ease of generating genomic and transcriptomic resources necessary for protein identification, can facilitate the extension of proteomics from traditional model species to systems of relevance to PMPZ phenotypes and hence greatly expand our understanding of how rapidly diverging molecular systems may contribute to PMPZ barriers. Here we review the influence proteomic analyses can have on our understanding of the function and evolution of the complex cellular and molecular processes governing postcopulatory male-female interactions and the study of PMPZ reproductive isolation, with the goal of expanding our understanding of the contribution of PMPZ processes to speciation.


Modulation of macrophage phenotype via phagocytosis of drug-loaded microparticles.
Monocyte-derived macrophages play a critical role in directing wound pathology following injury. Depending on their phenotype, macrophages also promote tissue regeneration. However, the therapeutic administration of macrophages with a controlled phenotype is challenging because macrophages are highly plastic and quickly revert to a detrimental, inflammatory phenotype in response to the environment of a damaged tissue. To address this issue, we developed a novel strategy to modulate macrophage phenotype intracellularly through phagocytosis of drug-loaded microparticles. Poly(lactic-co-glycolic acid) microparticles loaded with the anti-inflammatory drug dexamethasone (Dex) were phagocytosed by monocytes and stored intracellularly for at least 5 days. After differentiation into macrophages, cell phenotype was characterized over time with high-throughput gene expression analysis via NanoString. We found that the microparticles modulated macrophage phenotype for up to 7 days after microparticle uptake, with decreases in inflammation-related genes at early timepoints and upregulation of homing- and phagocytosis-related genes at multiple timepoints in a manner similar to cells treated with continuous free Dex. These data suggest that intracellularly loading macrophages with Dex microparticles via phagocytosis could be a unique methodology to selectively modulate macrophage phenotype over time. This strategy would allow therapeutic administration of macrophages for the treatment of a number of inflammatory disease and disorders. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1213-1224, 2019.


Community invasion resistance is influenced by interactions between plant traits and site productivity.
Plant communities are predicted to be more resistant to invasion if they are highly productive, harbor species with similar functional traits to invaders, or support species with high competitive potential. However, the strength of competition may decrease with increasing abiotic stress if species more heavily invest in traits that confer stress tolerance over competitive ability, potentially influencing community trait-resistance relationships. Recent research examining how community traits influence invasion resistance has been predominantly focused on single vegetation types, and results between studies are often conflicting. Few studies have evaluated the extent to which abiotic factors and community traits interact to influence invasion along vegetation gradients. Here, we use an in situ seed addition experiment to examine how above- and below-ground plant traits and vegetation type interact to influence community resistance to invasion by a recently introduced annual grass, Ventenata dubia, along a productivity gradient in eastern Oregon, USA. To measure invasion resistance, we evaluated V. dubia biomass in seeded subplots with varying trait compositions across three vegetation types situated along a productivity gradient: scab-flats (sparsely vegetated dwarf-shrublands), low sage-steppe, and ephemeral wet meadows. Trait-resistance relationships were highly context dependent. In wet meadows (the most productive sites), resistance to invasion increased with increasing resident biomass and as community weighted mean trait values for specific leaf area, fine-to-total root volume, and height become more similar to V. dubia's trait values, although these relationships were relatively weak. We did not find evidence that neighboring species influenced invasion resistance in less productive vegetation types, in contrast to our expectations that facilitative interactions may increase with decreasing productivity as posited by the stress-gradient hypothesis. Unlike V. dubia, which heavily invaded all three vegetation types, introduced species with similar trait values, including Bromus tectorum, were not abundant throughout the study area demonstrating V. dubia's unique ability to take advantage of available resources. Our results illustrate how community traits and site productivity interact to influence community resistance to invasion and highlight that communities with lower overall biomass and few functionally similar species to V. dubia may be at the greatest risk for invasion.


Field evidence for density-dependent effects in the trematode Microphallus papillorobustus in its manipulated host, Gammarus insensibilis.
Numerous studies have demonstrated that parasites with complex life cycles frequently manipulate the phenotype of their hosts to increase their transmission rate. Little is known, however, concerning density-dependent processes within infrapopulations of manipulative parasites--whether parasites cooperate to manipulate the host, whether competition counteracts with these potential cooperative benefits, or both. Here we explored these ideas, focusing on the association between the manipulative trematode Microphallus papillorobustus and its second intermediate host, the gammarid Gammarus insensibilis. From the data collected in the field, we found no evidence that co-occurring M. papillorobustus individuals benefit from the presence of conspecifics; instead, individuals in larger infrapopulations suffered reduced size and fecundity. Thus, the net effect of increasing density suggests that competition rather than cooperation is the dominant force in infrapopulations of M. papillorobustus.


Psychometric Properties in Forensic Application of the Screening Version of the Psychopathy Checklist.
The Psychopathy Checklist: Screening Version (PCL: SV) is a short form of the Psychopathy Checklist-Revised (PCL-R), an expert-rated assessment that measures psychopathic personality traits in research, clinical, and community settings. The PCL-R is an extensively relied upon tool in psycho-legal contexts. The screening version is also widely used; however, it has received far less empirical attention than the PCL-R. This review examines the psychometric properties of the PCL: SV, specifically in relation to forensic samples, and evaluates its comparability with the full PCL-R. Previously reported similarity in the reliability and validity of the PCL: SV as established for the PCL-R was supported through further testing in forensic samples. However, limitations in terms of available normative data are highlighted, and the review engages with wider debate concerning the measurement of psychopathy.


[Hidradenitis suppurativa - symptoms, diagnostics, and therapy].
Hidradenitis suppurativa is a chronic skin disorder characterized by recurrent inflammatory nodules, fistulas, abscesses, and scarring mainly in the intertriginous areas with terminal hair and apocrine glands. Hidradenitis suppurativa manifests usually after puberty, in the third life decade and persists for many years. The prevalence of the disease is estimated to be 0,5 % in the Czech Republic. Women are most often affected in the axillary and inguinal parts, while men in the perianal and gluteal areas. The exact pathogenesis is still unknown. It is assumed that hyperkeratosis of the hair follicle leads to its occlusion, dilatation and further rupture when keratin and bacteria are spilled into the dermis causing a massive inflammatory reaction. Smoking and obesity belong to the main triggering factors. Without therapy, the disease is chronic and progressive. The standard therapy depends on the extension of the disorder. For not extensive lesions, treatment consists of topical antiseptics, antibiotics or long- term therapy with systemic antibiotics. In more advanced stages, systemic therapy with TNF-α antagonists is needed. Further therapeutic modality is surgical intervention and wide excision of the affected area. Nevertheless, recurrences in the adjacent tissue cannot be avoided.


Skeletal Muscle Pump Drives Control of Cardiovascular and Postural Systems.
The causal interaction between cardio-postural-musculoskeletal systems is critical in maintaining postural stability under orthostatic challenge. The absence or reduction of such interactions could lead to fainting and falls often experienced by elderly individuals. The causal relationship between systolic blood pressure (SBP), calf electromyography (EMG), and resultant center of pressure (COPr) can quantify the behavior of cardio-postural control loop. Convergent cross mapping (CCM) is a non-linear approach to establish causality, thus, expected to decipher nonlinear causal cardio-postural-musculoskeletal interactions. Data were acquired simultaneously from young participants (25 ± 2 years, n = 18) during a 10-minute sit-to-stand test. In the young population, skeletal muscle pump was found to drive blood pressure control (EMG → SBP) as well as control the postural sway (EMG → COPr) through the significantly higher causal drive in the direction towards SBP and COPr. Furthermore, the effect of aging on muscle pump activation associated with blood pressure regulation was explored. Simultaneous EMG and SBP were acquired from elderly group (69 ± 4 years, n = 14). A significant (p = 0.002) decline in EMG → SBP causality was observed in the elderly group, compared to the young group. The results highlight the potential of causality to detect alteration in blood pressure regulation with age, thus, a potential clinical utility towards detection of fall proneness.


C1s and O1s photoelectron satellite spectra of CO with symmetry-dependent vibrational excitations.
The photoelectron shake-up satellite spectra that accompany the C1s and O1s main lines of carbon monoxide have been studied by a combination of high-resolution x-ray photoelectron spectroscopy and accurate ab initio calculations. The symmetry-adapted cluster-expansion configuration-interaction general-R method satisfactorily reproduces the satellite spectra over a wide energy region, and the quantitative assignments are proposed for the 16 and 12 satellite bands for C1s and O1s spectra, respectively. Satellite peaks above the pi(-1)pi(*) transitions are mainly assigned to the Rydberg excitations accompanying the inner-shell ionization. Many shake-up states, which interact strongly with three-electron processes such as pi(-2)pi(*2) and n(-2)pi(*2), are calculated in the low-energy region, while the continuous Rydberg excitations are obtained with small intensities in the higher-energy region. The vibrational structures of low-lying shake-up states have been examined for both C1s and O1s ionizations. The vibrational structures appear in the low-lying C1s satellite states, and the symmetry-dependent angular distributions for the satellite emission have enabled the Sigma and Pi symmetries to be resolved. On the other hand, the potential curves of the low-lying O1s shake-up states are predicted to be weakly bound or repulsive.


Fungal Keratitis in a Critically Ill Post-trauma Patient.
Keratitis is the leading cause of corneal blindness in the world. Nearly half the cases are due to a fungal infection known as fungal keratitis (FK). There is much variability in the clinical presentation of FK, so diagnosis can be difficult. With the risks of blindness in disease progression being so high, it is vital to diagnose and treat FK quickly. We present a case of FK due to Candida albicans and Staphylococcus lugdunensis-oxa ss after a motor vehicle accident, its treatment, and the general outcome. A 71-year-old man with a history of hypertension, hyperlipidemia, arthritis, and previous tobacco use presented after a helmeted motorcycle accident with back pain and bilateral lower extremity sensory and motor function loss. He suffered many fractures and was in neurogenic shock. He had nearly daily reduction and fixation of multiple axial spinal fractures while in the surgical intensive care unit and was ultimately unable to be successfully extubated. Between two intubations, he complained to his family of blurry vision, and there was notable purulence and corneal haziness in bilateral eyes. The healthcare team initially suspected the eye infection was due to a bacterial etiology, and he was subsequently diagnosed with Pseudomonas pneumonia on respiratory cultures. However, several days of antibiotics did not improve the ocular exam. A corneal culture was positive for C. albicans and S. lugdunensis-oxa ss, and anti-fungal treatment was initiated with ocular improvement. Unfortunately, the patient succumbed to his injuries and further sepsis at another site. With a progressively poor prognosis and machine dependence, he was made do-not-resuscitate per family wishes and died within two hours after cessation of hemodialysis. One of the greatest barriers to diagnosing FK in the United States is the absence of information regarding the disease. Though novel diagnoses and treatment strategies are in development, the fungal etiology of keratitis should be included in the curricula for not just medical students but also for providers and specialists, as the incidence of FK continues to grow with globalization. We also aim to emphasize the importance of a multidisciplinary team in these cases, as ophthalmology and infectious disease specialists should be involved immediately in order to improve patient outcomes.


The online disinhibition effect.
While online, some people self-disclose or act out more frequently or intensely than they would in person. This article explores six factors that interact with each other in creating this online disinhibition effect: dissociative anonymity, invisibility, asynchronicity, solipsistic introjection, dissociative imagination, and minimization of authority. Personality variables also will influence the extent of this disinhibition. Rather than thinking of disinhibition as the revealing of an underlying "true self," we can conceptualize it as a shift to a constellation within self-structure, involving clusters of affect and cognition that differ from the in-person constellation.


Suppression of synchronous spiking in two interacting populations of excitatory and inhibitory quadratic integrate-and-fire neurons.
Collective oscillations and their suppression by external stimulation are analyzed in a large-scale neural network consisting of two interacting populations of excitatory and inhibitory quadratic integrate-and-fire neurons. In the limit of an infinite number of neurons, the microscopic model of this network can be reduced to an exact low-dimensional system of mean-field equations. Bifurcation analysis of these equations reveals three different dynamic modes in a free network: a stable resting state, a stable limit cycle, and bistability with a coexisting resting state and a limit cycle. We show that in the limit cycle mode, high-frequency stimulation of an inhibitory population can stabilize an unstable resting state and effectively suppress collective oscillations. We also show that in the bistable mode, the dynamics of the network can be switched from a stable limit cycle to a stable resting state by applying an inhibitory pulse to the excitatory population. The results obtained from the mean-field equations are confirmed by numerical simulation of the microscopic model.


Unlocking Exosome-Based Theragnostic Signatures: Deciphering Secrets of Ovarian Cancer Metastasis.
Ovarian cancer (OC) is a common gynecological cancer worldwide. Unfortunately, the lack of early detection methods translates into a substantial cohort of women grappling with the pressing health crisis. The discovery of extracellular vesicles (EVs) (their major subpopulation exosomes, microvesicles, and apoptotic bodies) has provided new insights into the understanding of cancer. Exosomes, a subpopulation of EVs, play a crucial role in cellular communication and reflect the cellular status under both healthy and pathological conditions. Tumor-derived exosomes (TEXs) dynamically influence ovarian cancer progression by regulating uncontrolled cell growth, immune suppression, angiogenesis, metastasis, and the development of drug and therapeutic resistance. In the field of OC diagnostics, TEXs offer potential biomarkers in various body fluids. On the other hand, exosomes have also shown promising abilities to cure ovarian cancer. In this review, we address the interlink between exosomes and ovarian cancer and explore their theragnostic signature. Finally, we highlight future directions of exosome-based ovarian cancer research.


Studies on the frequency and associations of equine leucocyte antigens in sarcoid and summer dermatitis.
The equine leucocyte antigen (ELA) types and the clinical diagnosis for equine sarcoid and summer dermatitis were evaluated in 2026 horses representing five breeds. Data were analysed in unrelated animals and in family material. In the case of equine sarcoid, a strong association was observed between the ELA class II DW13 antigen and its effect on Swiss (cP < 0.001), French (cP < 0.0001) and Irish (cP < 0.01) Warmblood horses. The class I antigen A3 occurred more frequently in sarcoid-affected French horses (cP < 0.001). These results confirm our earlier findings (Gerber et al. 1988). Among Freiberger horses, which lack the ELA DW13 and A3 specificities, a breed-specific class I antigen, ABe108, displayed an increased frequency (cP < 0.05) in the affected group. Among Arabian horses, a tendency for increased frequency of the A1 antigen was observed in the affected animals, but the number of affected horses is too small for statistical significance. The Mendelian segregation in diseased half-siblings by ELA DW13 heterozygous stallions showed a strong association (P < 0.0001) between the inherited DW13 antigen and susceptibility to the sarcoid effect. In the case of summer dermatitis, previously published data (Marti et al. 1992) have been extended. The ELA types in four multiple-case families, founded by the same stallion, were analysed for an association with the effect of sarcoid. Eight out of nine ELA-typed affected offspring inherited the paternal haplotype A15, DW23 in contrast to nonaffected offspring where three out of 12 displayed these antigens (P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)


Anti-tumor effects of everolimus and metformin are complementary and glucose-dependent in breast cancer cells.
Clinical efficacy of the mTOR inhibitor everolimus is limited in breast cancer and regularly leads to side-effects including hyperglycemia. The AMPK inhibitor and anti-diabetic drug metformin may counteract everolimus-induced hyperglycemia, as well as enhancing anti-cancer efficacy. We investigated the glucose-dependent growth-inhibitory properties of everolimus, metformin and the combination in breast cancer cell lines. The breast cancer cell lines MCF-7, MDA-MB-231 and T47D were cultured in media containing 11 mM or 2.75 mM glucose with 21% or 1% oxygen. Everolimus and metformin treated cells were subjected to cytotoxicity and clonogenic assays, western blotting, FACS and metabolic measurements. Everolimus was less effective in MCF7 cells under low glucose conditions compared to high glucose conditions (IC50 of >50 nM vs 29.1 ± 1.4 nM) in a short-term survival assay, while sensitivity of MDA-MB-231 and T47D cells to everolimus was lost under low glucose conditions. In contrast, metformin was more effective in low than in high glucose conditions in MCF7 (IC50 of 1.8 ± 1.2 mM vs >5 mM) and MDA-MB231 cells (1.5 ± 1.3 mM vs 2.6 ± 1.2 mM). Metformin sensitivity of T47D cells was independent of glucose concentrations. Everolimus combined with metformin additively inhibited cell survival, clonogenicity, mTOR signaling activity and mitochondrial respiration. These effects were not the result of enhanced autophagy or apoptosis induction. Similar results were observed under hypoxic conditions. Metformin-induced effects are additive to the anti-proliferative and colony inhibitory properties of everolimus through inhibition of mitochondrial respiration and mTOR signaling. These results warrant further in vivo investigation of everolimus combined with metformin as a putative anti-cancer therapy.


Acyclic germylones: congeners of allenes with a central germanium atom.
The cyclic alkyl(amino) carbene (cAAC:)-stabilized acyclic germylones (Me2-cAAC:)2Ge (1) and (Cy2-cAAC:)2Ge (2) were prepared utilizing a one-pot synthesis of GeCl2(dioxane), cAAC:, and KC8 in a 1:2:2.1 molar ratio. Dark green crystals of compounds 1 and 2 were produced in 75 and 70% yields, respectively. The reported methods for the preparation of the corresponding silicon compounds turned out to be not applicable in the case of germanium. The single-crystal X-ray structures of 1 and 2 feature the C-Ge-C bent backbone, which possesses a three-center two-electron π-bond system. Compounds 1 and 2 are the first acyclic germylones containing each one germanium atom and two cAAC: molecules. EPR measurements on compounds 1 and 2 confirmed the singlet spin ground state. DFT calculations on 1/2 revealed that the singlet ground state is more stable by ~16 to 18 kcal mol(-1) than that of the triplet state. First and second proton affinity values were theoretically calculated to be of 265.8 (1)/267.1 (2) and 180.4 (1)/183.8 (2) kcal mol(-1), respectively. Further calculations, which were performed at different levels suggest a singlet diradicaloid character of 1 and 2. The TD-DFT calculations exhibit an absorption band at ~655 nm in n-hexane solution that originates from the diradicaloid character of germylones 1 and 2.


Osteolipoma in the retromolar trigone: A case report and review of literature.
Osteolipoma is the distinct histological variant of lipoma. Until now, a total of 17 cases have been documented in English literature. It is most commonly seen in buccal mucosa, floor of the mouth, tongue, palate, and parapharyngeal spaces of the oropharyngeal region. The aim of the present communication is to report an unusual presentation of osteolipoma in the retromolar trigone. Conventional radiographs have revealed "whorled pattern" of radiographic appearance in our case that might be due to uniform distribution of bony trabeculae within tumor; such type of finding has not been reported till now. Hence, here, we add these new features to existing literature.


[Adrenal protein expressions after Pinggan Qianyang Formula treatment in hypertensive rats with liver-yang hyperactivity: a comparative proteomic analysis].
To explore the pathogenic mechanism of liver-yang hyperactivity type of hypertension and to observe the effects of Pinggan Qianyang Formula (PGQYF), a compound of traditional Chinese herbals for calming the liver and suppressing yang, so as to provide experimental evidence for new marker proteins of drug therapy. A rat model of liver-yang hyperactivity was prepared with spontaneous hypertensive rats (SHRs) by administration of Aconiti Praeparatae Decoction. Adrenal proteins were separated by 2D gel electrophoresis (2-DE). The differentially expressed proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and database analysis. The rat model of liver-yang hyperactivity was successfully reproduced, and the PGQYF could decrease the grades of irritability, conjunctival congestion and systolic blood pressure of the rats (P<0.05, P<0.01). After analysis, twelve obviously differentially expressed proteins were found, eight of which were identified. The expression levels of isocitrate dehydrogenase and steroidogenic acute regulatory protein in the untreated group were up-regulated as compared with those in the normal control group, and down-regulated in the treatment group. The expression levels of ferritin light chain, elongation factor Tu, Rho GDP disassociation inhibitor 1, flavin reductase and basic transcription factor 3 in the untreated group were down-regulated as compared with those in the normal control group, and up-regulated in the treatment group. Differentially expressed adrenal proteins in SHRs with live-yang hyperactivity are successfully identified. This approach may lay a foundation for the further investigation of pathogenic mechanisms in hypertension with liver-yang hyperactivity and the mechanisms of PGQYF treatment.


[Kinetics of protein synthesis in the human granulosa lutein cell during pregnancy as revealed by electron microscopic autoradiography of 3H-leucine].
Kinetics of protein synthesis in the human granulosa lutein cell during pregnancy were investigated using the electron microscopic autoradiography of 3H-leucine. The corpus luteum of early pregnancy was chased at 10 and 30 min, 1, 3, 6, 12, 24 and 48 h after pulse labelling (10 min) with 100 microCi of 3H-leucine. Although the whole silver grains were very few at 10 min postpulse, silver grains were localized mainly over the rough endoplasmic reticulum (r-ER, 34.3%) and there were no silver grains over the smooth endoplasmic reticulum (s-ER). At 30 min postpulse, the ratio of the grain number to r-ER is decreased (18.7%) and silver grains begin to appear over the s-ER (5.4%). The total number of silver grains over the cell increases with the lapse of time, the ratio of the grain number over the r-ER slightly increases and then decreases afterwards, while that over the s-ER continues to increase gradually. From these facts, it is felt that some protein synthesized on the r-ER might be transported to the s-ER in the human granulosa lutein cell during pregnancy showing steroidogenic activity.


Effect of Different Processing Methods on the Accumulation of the Phenolic Compounds and Antioxidant Profile of Broomcorn Millet (Panicum miliaceum L.) Flour.
Broomcorn millet (Panicum miliaceum L.) is an important nutritious ancient minor-cereal food crop. However, this crop is little explored in the food processing arena to improve its functionality. In this context, different processing methods were applied to enhance the secondary compounds of broomcorn millet. Four different individual methods such as roasting, steaming, puffing, and extrusion were applied at 110 °C to enhance the functional attributes of millet flour. It was observed that the significantly highest content of total phenolic (TP) (670 mg/100 g of ferulic acid equivalent) and total flavonoid (TF) (391 mg/100 g of rutin equivalent ) was attained in the roasted whole millet followed by steaming (315 mg/100 g, 282 mg/100 g), puffing (645 mg/100 g, 304 mg/100 g), extrusion (455 mg/100 g, 219 mg/100 g), and control (295 mg/100 g, 183 mg/100 g). The chromatographic analysis showed a greater content of single phenolic acids such as syringic acid, gallic acid, 4-hydroxy benzoic acid, ferulic acid, sinapic acid, and catechin in roasted millet compared to control, and the content of each acid was higher in whole millet than dehulled. Results also indicated that the content of ferulic acid was relatively higher among the quantified single phenolic acid from broomcorn millet. Likewise, in comparison with dehulled millet, the roasted whole millet showed higher total antioxidant capacity, measured by the 2,2-diphenyl-1 picryl hydrazyl (DPPH), the ferric reducing antioxidant power assay (FRAP), the phosphomolybdenum method (PPMD), and the hydroxyl radical scavenging capacity (HRSC) method. Lastly, it is concluded that the roasting method should be taken into consideration in the processing of broomcorn millet to enhance the content of nutraceutical compounds and improve its functionality.


Malting and fermentation effects on antinutritional components and functional characteristics of sorghum flour.
The research was aimed to observe the effect of malting and fermentation on antinutritional component and functional characteristics of sorghum flour. For whole sorghum flour, cleaned sorghum grain was milled to pass through 40 mesh sieve. For malting, cleaned sorghum grain was steeped in 0.2% calcium hydroxide solution for 24 hr and then germinated for 48 hr at 90% RH and 27 ± 2°C. Sprout was removed, dried in hot air oven at 50 ± 2°C for 24 hr and milled to pass through 40 mesh sieve. For fermented sorghum flour, 13.3 mg% diastase and 2 mg % pepsin (on the basis of whole sorghum flour weight) was added to cooked (88 ± 2°C) sorghum flour and left for 1 hr. Lactobacillus plantarum (107 cfu/g) was inoculated and incubated at temperature 30 ± 2°C for 48 hr. The fermented slurry was dried at 50 ± 2°C in hot air oven for 24 hr and milled to pass through 40 mesh sieve. The lower yield of sorghum flour was obtained compared to whole and malted sorghum flour. Germination of sorghum reduced phytate, tannin, and oxalate by 40%, 16.12% and 49.1%, respectively, whereas fermentation of sorghum flour reduced above by 77%, 96.7% and 67.85%, respectively. There was no significant change in hydrogen cyanide in malted sorghum flour compared to whole sorghum flour, but fermentation of sorghum flour reduced hydrogen cyanide by 52.3%. Bulk density and viscosity was significantly reduced by the malting and fermentation, whereas water absorption capacity and oil absorption capacity was markedly increased by the malting and fermentation. Fermented flour was good due to reduced ANF and improved functional property despite of lower yield.


The Rapunzel syndrome. Report of a case and review of the literature.
The Rapunzel Syndrome, a rare manifestation of trichobezoar, occurs when bolus gastrointestinal obstruction is produced by an unusual trichobezoar with a long tail that extends to or beyond the ileocaecal valve. A five-year-old Jamaican girl presented with this abnormality and was found at laparotomy also to have an ileo-ileal intussusception. For the Rapunzel Syndrome, we recommend bezoar extraction at laparotomy via multiple enterotomies. In addition, psychiatric evaluation and therapy is essential due to the commonly associated finding of underlying emotional stress.


Quality of life in patients and partners after aneurysmal subarachnoid hemorrhage.
Outcome after subarachnoid hemorrhage (SAH) is often graded as "poor," "fair," or "good." Such categories are usually based on physicians' assessments of physical abilities of patients rather than on how patients themselves perceive their physical, psychological, and social well-being. We assessed functional outcome and quality of life (QoL) in patients with SAH and their partners. In a consecutive series of 64 patients and 51 partners studied 4 months after the SAH, we assessed functional outcome by means of the Rankin Scale, and QoL by means of the SF-36, the Sickness Impact Profile (SIP), and a visual analogue scale. Additionally, we asked two "simple questions" about dependency and recovery. All questionnaires were completed in an interview setting. The scores on the QoL instruments from patients and partners were stratified according to the Rankin grades of the patients and were compared with data from a Dutch reference population. Only patients who had no symptoms at all (Rankin grade 0) had no reduction in QoL compared with the reference population; some of these patients even indicated an improvement in QoL from before the SAH according to the visual analogue scale. Patients who had symptoms but were independent (Rankin grades 1 to 3) and therefore usually designated as having "good outcome" often had reductions in QoL, on both the physical and psychosocial subscores of the SIP and SF-36. The QoL of partners was considerably reduced in several psychosocial domains. SAH has a considerable impact on the QoL of patients and their partners. Only patients without residual symptoms (Rankin grade 0) have a good outcome in terms of physical performance and QoL.


Molecular and electronic structures of mononuclear iron complexes using strongly electron-donating ligands and their oxidized forms.
The ligand L (2-) (H 2L = N, N'-dimethyl- N, N'-bis(3,5-di- t-butyl-2-hydroxybenzyl)-1,2-diaminoethane) has been employed for the synthesis of two mononuclear Fe (III) complexes, namely, [LFe(eta (2)-NO 3)] and [LFeCl]. L (2-) is comprised of four strongly electron-donating groups (two tert-amines and two phenolates) that increase the electron density at the coordinated ferric ions. This property should facilitate oxidation of the complexes, that is, stabilization of the oxidized species. The molecular structures in the solid state have been established by X-ray diffraction studies. [LFeCl] is five-coordinate in a square-pyramidal coordination environment with the ligand adopting a trans-conformation, while [LFe(eta (2)-NO 3)] is six-coordinate in a distorted octahedral environment with the ligand in a beta-cis conformation. The electronic structures have been studied using magnetization, EPR, Mossbauer (with and without applied field), UV-vis-NIR, and X-ray absorption spectroscopies, which demonstrate highly anisotropic covalency from the strong sigma- and pi-donating phenolates. This analysis is supported by DFT calculations on [LFeCl]. The variations of the well-understood spectroscopic data in the solid state to the spectroscopic data in solution have been used to obtain insight in the molecular structure of the two complexes in solution. While the molecular structures of the solid states are retained in solutions of nonpolar aprotic solvents, there is, however, one common molecular structure in all protic polar solvents. The analysis of the LMCT transitions and the rhombicity E/ D clearly establish that both compounds exhibit a beta-cis conformation in these protic polar solvents. These two open coordination sites, cis to each other, allow access for two potential ligands in close proximity. Electrochemical analysis establishes two reversible oxidation waves for [LFeCl] at +0.55 V and +0.93 V vs Fc (+)/Fc and one reversible oxidation wave at +0.59 V with an irreversible oxidation at +1.07 V vs Fc (+)/Fc for [LFe(eta (2)-NO 3)]. The one- and the two-electron oxidations of [LFeCl] by chronoamperometry have been followed spectroscopically. The increase of a strong band centered at 420 nm indicates the formulation of [LFeCl] (+) as a Fe (III) monophenoxyl radical complex and of [LFeCl] (2+) as a Fe (III) bisphenoxyl radical complex. These studies imply that the ligand L (2-) is capable of providing a flexible coordination geometry with two binding sites for substrates and the allocation of two oxidation equivalents on the ligand.


Research and literature on sex offenders with intellectual and developmental disabilities.
The present paper sets out to review the literature on several aspects of sex offenders with intellectual and developmental disabilities, including the relationship between sex offending and developmental disabilities, the prevalence and characteristics of sex offenders in this client group, assessment, treatment, and outcome of intervention. Several important variables were identified as influencing the disparate results found in different prevalence studies. These include variations in inclusion criteria, differences in the source of the sample, differences in determination of IQ, the impact of deinstitutionalization, and the effect of changing social and penal policies in the area where studies have been conducted. Although some studies have suggested an increasing incidence, there is no clear evidence for the over- or under-representation of people with developmental disabilities amongst sex offenders. One of the main methodological flaws in several reports listing the characteristics of sex offenders is that considerations are based on clinical samples. Therefore, there is no control group to show that these characteristics do not exist in other samples of individuals with intellectual disability (ID). It does appear that sex offenders with ID are more likely to commit offences across categories and to be less discriminating in their victims. There may also be an association with sexual abuse in childhood. The primary issue considered has been assessment of competency, in that people with ID are considered to be disadvantaged by the criminal justice process. While several authors have delineated the important areas for assessment, there are few assessment measures with robust psychometric properties. Pharmacological, behavioural, educational and cognitive treatments are reviewed. Several comprehensive treatments which include all of the aforementioned methods are also considered. Although most studies do not report particularly positive outcomes, several authors have found better outcomes with treatment lasting at least 2 years.


Goodpasture syndrome: recovery after severe renal insufficiency.
A 22-year-old woman developed the sudden onset of cough, dyspnea, blood-tinged sputum, and bilateral fluffy infiltrates on her chest x-ray film, together with severe iron deficiency anemia. Urinalysis initially revealed normal values, but gross hematuria developed on the 12th day. Linear deposits of IgG and C3 were present in the GBM; circulating anti-GBM antibodies were also observed initially but had disappeared 13 months later. Hemodialysis was performed because of oliguria and a rising serum creatinine value. She subsequently had a diuresis; 18 months later, the creatinine clearance was 63 ml/min. The anti-GBM antibody response appears to be transient, lasting only a few months, so that if the patient survives the initial insult, stabilization and even some recovery may ensue. Had this patient undergone immediate nephrectomy as part of her initial therapy, the observed favorable outcome would have been denied.


Suppression of spontaneous activity before visual response in the primate V1 neurons during a visually guided saccade task.
Visually guided saccadic eye movements are thought to involve multiple stages of processing in diverse brain structures including the primary visual cortex (V1). The variability of neural activity in each of these structures may present ambiguities for downstream stages in identifying sensory and motor signals among spontaneous discharges. The response time of saccadic eye movements made toward a visual target is correlated with the time of the first spikes in V1 that are evoked by the target (Lee et al., 2010). This suggests that downstream neurons receiving the output of V1 are faced with a challenging task of discriminating first spikes of visual response against spontaneous discharge. Here we report a novel response property of the macaque V1 neurons. Immediately before neurons discharge a burst of activity to a visual saccade target, spontaneous discharges were transiently suppressed. This suppression was maximal ∼18 ms after target onset. Based on simulations of artificial spike trains, we propose that the transient suppression enhances temporal contrast for identifying the onset of visual response by increasing the reliability of detection of response onset by downstream neurons, thereby facilitating visually guided behavioral responses.


Serum adipokine profiles in patients with microscopic polyangiitis and granulomatosis with polyangiitis: An exploratory analysis.
Previous studies have shown that adipokines may serve as potential biomarkers reflecting disease activity in various autoimmune diseases. Here, we investigated the relationship between four adipokines and clinical/laboratory findings in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Sera from 63 patients with MPA and GPA who were registered in a prospective cohort were used to detect serum levels of adiponectin, chemerin, resistin, and vaspin using commercial enzyme-linked immunosorbent assay kits. Associations between adipokines and clinical and laboratory data was assessed using Pearson's correlation analysis. The median age was 65.0 years, 24 patients were male, and 42 patients were diagnosed with MPA. The median levels of adiponectin, chemerin, resistin, and vaspin in patient sera were 13.9 ng/mL, 9.2 ng/mL, 23.7 ng/mL, and 0.1 ng/mL, respectively. A significant correlation between chemerin level and five-factor score (FFS) was found (r = 0.320, p = 0.011), and resistin was correlated with both Birmingham vasculitis activity score and FFS (r = 0.256, p = 0.043 and r = 0.320, p = 0.011). Regarding laboratory data, adiponectin level was associated with creatinine, and chemerin level was associated with creatinine, albumin, and erythrocyte sedimentation rate (ESR). On the other hand, resistin was found to be associated with white blood cell count, creatinine, ESR, and C-reactive protein. Age did not have a significant impact on the levels of adipokines. The expression of adipokines in the sera of patients with MPA and GPA differs depending on clinical and laboratory features, and serum resistin may be suggested as a potential biomarker reflecting disease activity.


A Chemoproteomics Approach to Investigate Phosphopantetheine Transferase Activity at the Cellular Level.
Phosphopantetheinylation is an essential post-translational protein modification to primary and secondary metabolic pathways that ensures bacterial cell viability and virulence, and it is used in the production of many pharmaceuticals. Traditional methods have not provided a comprehensive understanding of these modifications. By using chemical proteomic probes for adenylation and thiolation domains in nonribosomal peptide synthetases (NRPSs), chemoproteomics has been applied to survey and validate the cellular activity of 4-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267), which is a potent and selective small-molecule 4'-phosphopantetheinyl transferase (PPTase) inhibitor that attenuates secondary metabolism and viability of bacterial cells. ML267 inhibited Sfp-type PPTase and antagonized phosphopantetheinylation in cells, which resulted in a decrease in phosphopantetheinylated NRPSs and the attenuation of Sfp-PPTase-dependent metabolite production. These results indicate that this chemoproteomics platform should enable a precise interpretation of the cellular activities of Sfp-type PPTase inhibitors.


Neurodegeneration and -protection in autoimmune CNS inflammation.
Neurodegeneration in multiple sclerosis (MS) is the structural correlate of permanent neurological disability in patients. The histopathological features of neurodegeneration include destruction of axons as well as apoptotic cell death of neuronal cell bodies. Therapeutic efforts to control these clinically important aspects of MS pathology showed limited success so far. In this review article, we give an overview about the current knowledge concerning the molecular mechanisms of neurodegeneration in autoimmune inflammation that is mainly derived from animal models. Further, we critically discuss experimental neuroprotective strategies with respect to their functional relevance and differentiate between anti-apoptotic and axon protective treatment approaches.


Ceftriaxone/metronidazole is more effective than ampicillin/netilmicin/metronidazole in the treatment of bacterial peritonitis.
In a prospective, open, controlled clinical study, 190 consecutive patients who were thought to have bacterial peritonitis before operation, were randomised to antibiotic treatment during and after operation with either ceftriaxone 1 g plus metronidazole 1.5 g once daily (n = 94) or ampicillin 2 g plus netilmicin 150 mg twice daily plus metronidazole 1.5 g once daily (n = 96). Incisional and deep surgical wound infections, postoperative pneumonia and urinary tract infection as well as deaths caused by infection were recorded. Ceftriaxone-metronidazole was significantly more effective than ampicillin-netilmicin-metronidazole, 6/94 wound related infections (6%) compared to 18/96 (19%) (p = 0.02). In patients with peritonitis caused by a perforated colon or appendix the rates of clinical failure were 6% and 28%, respectively. We consider ceftriaxone plus metronidazole an efficient and easily administered antibiotic regimen in patients with bacterial peritonitis, and both the wide range of activity against Gram-negative aerobic rods and the long half life of ceftriaxone seem to be beneficial.


An in-situ forming skin substitute improves healing outcome in a hypertrophic scar model.
Wound repair requires a sequential series of biological events that begins with the deposition of a temporary scaffold within which cells can repair the skin. Without a scaffold, repair is essentially impossible. Aberrant wound healing, such as hypertrophic scarring or nonhealing, has a tremendous burden on healthcare and quality of life. Timely wound closure dramatically reduces the risk of infection and scarring. Cellular skin substitutes are opportune to meet this need. Our goal was to create an in-situ forming scaffold that can be easily combined with cells to rapidly form a dermal substitute within the wound bed. In this study, we evaluated the application of a polyvinyl alcohol-collagen-glycosaminoglycan-based biohybrid scaffold system in full-thickness wounds on a rabbit fibrotic ear model. Punch wounds (6 mm) were either untreated or filled with an acellular scaffold, a scaffold containing xenofibroblasts, or a scaffold containing xenofibroblasts expressing indoleamine 2,3-dioxygenase (IDO). Results demonstrated that (1) both acellular and IDO-expressing fibroblast in-situ forming scaffolds significantly reduced scar elevation index (1.24±0.05 and 1.25±0.03; p<0.05) and improved overall healing quality compared with xenofibroblast scaffolds and untreated wounds; (2) IDO-expressing fibroblast scaffolds significantly reduced T-cell infiltration into the scaffold-engrafted area (p<0.05); and (3) both IDO-expressing and acellular in-situ forming scaffolds demonstrated increased vessel-like and nerve-like structures (p<0.05). The results demonstrated that the use of the in-situ forming scaffold, and even more so when delivering IDO-expressing cells, improved healing outcome in full-thickness hypertrophic rabbit ear wounds.


Pathophysiology of Ganglioside GM1 in Ischemic Stroke: Ganglioside GM1: A Critical Review.
Ganglioside GM1 is a member of the ganglioside family which has been used in many countries and is thought of as a promising alternative treatment for preventing several neurological diseases, including cerebral ischemic injury. The therapeutic effects of GM1 have been proved both in neonates and in adults following ischemic brain damage; however, its clinical efficacy in patients with ischemic stroke is still uncertain. This review examines the recent knowledge of the neuroprotective properties of GM1 in ischemic stroke, collected in the past two decades. We conclude that GM1 may have potential for stroke treatment, although we need to be cautious in respect of its complications.