Health promotion in local churches in Victoria: an exploratory study.
Church-based health promotion has increasingly gained attention in strategies to address health disparities. In Australia, we have limited understanding of the role of local churches in health promotion and without this, how they might be involved in meaningful partnerships to tackle public health challenges. The objective of this qualitative study was to explore how churches are involved in health promotion in the state of Victoria. The research involved in-depth interviews with ministers from 30 churches in urban and rural Victoria, and case studies with 10 of these churches to enable further exploration. These case studies, conducted in 2010, included interviews with church staff, focus groups with volunteers, participant observation and document analysis. Analysis was iterative, utilising open, axial and thematic coding. Three different expressions of church - traditional, new modern and emerging - were identified and found to differentiate the levels and types of health promotion activity. Case studies illustrate the different expressions of how church mission influences health promotion activity. The traditional churches were involved particularly in disease screening and health education activities with their own, predominantly older congregation members. The new modern churches tended to have the material and human resources to be harnessed in health promotion activities involving congregation members and others. Emerging churches, in contrast, engaged in broad health-promoting activities, including disease prevention, lifestyle activities and socio-ecological approaches at a community level. These research findings highlight the opportunities and challenges of engaging with local churches in health promotion efforts and public health programmes to address health inequities.


The latency-associated promoter of herpes simplex virus type 1 requires a region downstream of the transcription start site for long-term expression during latency.
The latency-associated transcript (LAT) promoter of herpes simplex virus type 1 (HSV-1) is unique among the many promoters on the viral genome in that it remains active during the latent state. We have previously shown that a DNA fragment comprising the LAT promoter element through the cap site, when moved from the LAT locus to the glycoprotein C gene, is capable of only short-term expression. These and other data suggested that an HSV DNA element from the repeat region, not included in the LAT promoter itself, might be needed to preserve long-term expression. Based on a number of recombinant viruses, we narrowed our search for this putative element to a region 3' of the LAT transcription start site. In the present study, we have shown that a 1.1-kb DNA fragment containing the putative long-term expression element (LTE) is able to restore latent-phase gene expression to the LAT promoter. The element appeared to function best when it was placed in its natural location, which is 3' of the LAT promoter; however, partial function was obtained when the LTE was inserted upstream of the LAT promoter in the reverse direction. These data indicate that the LAT promoter region is more complex than originally anticipated and that in addition to requiring both core promoter and neuronal transcription factor binding sites, the promoter requires a specific region of DNA to prevent its shutoff during a latent infection.


Reproduction in the era of genomics and automation.
Much progress has been made in the reproductive efficiency of lactating dairy cows across the USA in the past 20years. The standardisation of evaluation of reproductive efficiency, particularly with greater focus on metrics with lesser momentum and less lag-time such as 21-day pregnancy rates (21-day PR), and the recognition that subpar reproductive efficiency negatively impacted profitability were major drivers for the changes that resulted in such progress. Once it became evident that the genetic selection of cattle for milk yield regardless of fertility traits was associated with reduced fertility, geneticists raced to identify fertility traits that could be incorporated in genetic selection programs with the hopes of improving fertility of lactating cows. Concurrently, reproductive physiologists developed ovulation synchronisation protocols such that after sequential treatment with exogenous hormones, cows could be inseminated at fixed time and without detection of oestrus and still achieve acceptable pregnancy per service. These genetic and reproductive management innovations, concurrently with improved husbandry and nutrition of periparturient cows, quickly started to move reproductive efficiency of lactating dairy cows to an upward trend that continues today. Automation has been adopted in Israel and European countries for decades, but only recently have these automated systems been more widely adopted in the USA. The selection of dairy cattle based on genetic indexes that result in positive fertility traits (e.g. daughter pregnancy rate) is positively associated with follicular growth, resumption of ovarian cycles postpartum, body condition score and insulin-like growth factor 1 concentration postpartum, and intensity of oestrus. Collectively, these positive physiological characteristics result in improved reproductive performance. Through the use of automated monitoring devices (AMD), it is possible to identify cows that resume cyclicity sooner after calving and have more intense oestrus postpartum, which are generally cows that have a more successful periparturient period. Recent experiments have demonstrated that it may be possible to adopt targeted reproductive management, utilising ovulation synchronisation protocols for cows that do not have intense oestrus postpartum and relying more heavily on insemination at AMD-detected oestrus for cows that display an intense oestrus postpartum. This strategy is likely to result in tailored hormonal therapy that will be better accepted by the public, will increase the reliance on oestrus for insemination, will improve comfort and reduce labour by reducing the number of injections cows receive in a lactation, and will allow for faster decisions about cows that should not be eligible for insemination.


Ontogenetic contingency of tolerance mechanisms in response to apical damage.
Plants are able to tolerate tissue loss through vigorous branching which is often triggered by release from apical dominance and activation of lateral meristems. However, damage-induced branching might not be a mere physiological outcome of released apical dominance, but an adaptive response to environmental signals, such as damage timing and intensity. Here, branching responses to both factors were examined in the annual plant Medicago truncatula. Branching patterns and allocation to reproductive traits were examined in response to variable clipping intensities and timings in M. truncatula plants from two populations that vary in the onset of reproduction. Phenotypic selection analysis was used to evaluate the strength and direction of selection on branching under the damage treatments. Plants of both populations exhibited an ontogenetic shift in tolerance mechanisms: while early damage induced greater meristem activation, late damage elicited investment in late-determined traits, including mean pod and seed biomass, and supported greater germination rates. Severe damage mostly elicited simultaneous development of multiple-order lateral branches, but this response was limited to early damage. Selection analyses revealed positive directional selection on branching in plants under early- compared with late- or no-damage treatments. The results demonstrate that damage-induced meristem activation is an adaptive response that could be modified according to the plant's developmental stage, severity of tissue loss and their interaction, stressing the importance of considering these effects when studying plastic responses to apical damage.


Chest CT Findings of COVID-19 Patients with Mild Clinical Symptoms at a Single Hospital in Korea.
To retrospectively evaluate the chest computed tomography (CT) findings of coronavirus disease 2019 (COVID-19) in patients with mild clinical symptoms at a single hospital in South Korea. CT scans of 87 COVID-19 patients [43 men and 44 women; median age: 41 years (interquartile range: 26.1-51.0 years)] with mild clinical symptoms (fever < 38℃ and no dyspnea) were evaluated. CT findings were normal in 39 (44.8%) and abnormal in 48 (55.2%) patients. Among the 48 patients with lung opacities, 17 (35.4%) had unilateral disease and 31 (64.6%) had bilateral disease. One (2.1%) patient showed subpleural distribution, 9 (18.8%) showed peribronchovascular distribution, and 38 (79.2%) showed subpleural and peribronchovascular distributions. Twenty-two (45.8%) patients had pure ground-glass opacities (GGOs) with no consolidation, 17 (35.4%) had mixed opacities dominated by GGOs, and 9 (18.8%) had mixed opacities dominated by consolidation. No patients demonstrated consolidation without GGOs. The most common CT finding of COVID-19 in patients with mild clinical symptoms was bilateral multiple GGO-dominant lesions with subpleural and peribronchovascular distribution and lower lung predilection. The initial chest CT of almost half of COVID-19 patients with mild clinical symptoms showed no lung parenchymal lesions. Compared to relatively severe cases, mild cases were more likely to manifest as unilateral disease with pure GGOs or GGO-dominant mixed opacities and less likely to show air bronchogram.


DNA methylation associates with survival in non-metastatic clear cell renal cell carcinoma.
Clear cell renal cell carcinoma (ccRCC) is the most common subtype among renal cancer and is associated with poor prognosis if metastasized. Up to one third of patients with local disease at diagnosis will develop metastasis after nephrectomy, and there is a need for new molecular markers to identify patients with high risk of tumor progression. In the present study, we performed genome-wide promoter DNA methylation analysis at diagnosis to identify DNA methylation profiles associated with risk for progress. Diagnostic tissue samples from 115 ccRCC patients were analysed by Illumina HumanMethylation450K arrays and methylation status of 155,931 promoter associated CpGs were related to genetic aberrations, gene expression and clinicopathological parameters. The ccRCC samples separated into two clusters (cluster A/B) based on genome-wide promoter methylation status. The samples in these clusters differed in tumor diameter (p < 0.001), TNM stage (p < 0.001), morphological grade (p < 0.001), and patients outcome (5 year cancer specific survival (pCSS5yr) p < 0.001 and cumulative incidence of progress (pCIP5yr) p < 0.001. An integrated genomic and epigenomic analysis in the ccRCCs, revealed significant correlations between the total number of genetic aberrations and total number of hypermethylated CpGs (R = 0.435, p < 0.001), and predicted mitotic age (R = 0.407, p < 0.001). We identified a promoter methylation classifier (PMC) panel consisting of 172 differently methylated CpGs accompanying progress of disease. Classifying non-metastatic patients using the PMC panel showed that PMC high tumors had a worse prognosis compared with the PMC low tumors (pCIP5yr 38% vs. 8%, p = 0.001), which was confirmed in non-metastatic ccRCCs in the publically available TCGA-KIRC dataset (pCIP5yr 39% vs. 16%, p < 0.001). DNA methylation analysis at diagnosis in ccRCC has the potential to improve outcome-prediction in non-metastatic patients at diagnosis.


Glycolytic ATP and its production during ischemia in isolated Langendorff-perfused rat hearts.
The perfused rat heart was used to assess the possible contribution of glycolytically produced ATP to the maintenance of the action potential in the normoxic heart, and to the maintenance of membrane integrity in the underperfused, ischemic heart. During normoxia, pyruvate (10 mM) was nearly as able as glucose (10 mM) to maintain the normal action potential. During ischemia (reduction of perfusion pressure of Langerdorff heart from 100 to 20 cm H2O), total tissue values of ATP and creatine phosphate were similar in pyruvate and in glucose hearts. However, pyruvate-perfused hearts had higher tissue levels of cyclic AMP during the ischemic period, and during the reperfusion period they had an increased release of lactate dehydrogenase and an increased incidence of arrhythmias when compared with glucose hearts. It is proposed that these differences can be related to a higher rate of production of glycolytic ATP. The anatomical, biochemical, and pharmacological evidence favoring a cytoplasmic compartment of ATP located in relation to the cell membrane is reviewed.


Epidemiology, Incidence, and Survival of Rhabdomyosarcoma Subtypes: SEER and ICES Database Analysis.
Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and adolescents and accounts for 3% of all pediatric tumors. Subtypes include alveolar, spindle cell, embryonal, mixed-type, pleomorphic, and rhabdomyosarcoma with ganglionic differentiation. The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was queried for patients diagnosed with any type of rhabdomyosarcoma between 1973 and 2014. Patient demographics, tumor characteristics, and incidence were studied with χ2 analysis. Survival was modeled with Kaplan-Meier survival curves and Cox proportional hazards models were used to assess the effect of age and gender on survival. Pleomorphic subtype had higher grade and larger sized tumors compared to other subtypes (p < 0.05). Pleomorphic and alveolar rhabdomyosarcoma had the worst overall survival with a 26.6% and 28.9% 5-year survival, respectively. Embryonal rhabdomyosarcoma had the highest 5-year survival rate (73.9%). Tumor size was negatively correlated with survival months, indicating patients with larger tumors had shorter survival times (p < 0.05). Presence of higher-grade tumors and metastatic disease at presentation were negatively correlated with survival months (p < 0.05). No significant differences in the survival were found between gender or race between all of the subtypes (p > 0.05). This study highlights key differences in the demographic and survival rates of the different types of rhabdomyosarcoma that can be used for more tailored patient counseling. We also demonstrate that large, population-level databases provide sufficient data that can be used in the analysis of rare tumors. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2226-2230, 2019.


Abnormal expression and processing of keratins in pupoid fetus (pf/pf) and repeated epilation (Er/Er) mutant mice.
The pupoid fetus (pf) and repeated epilation (Er) mutations of mice result in a failure of epidermal differentiation in homozygotes. Expression of the epidermal keratins has been followed in pf/pf and Er/Er mice by two-dimensional gel electrophoresis, and by immunohistochemistry and Western blotting using polyclonal antibodies that are monospecific for individual keratin polypeptides. Our results show that expression of the differentiation-specific keratins (K1 and K10) is delayed in both the pf/pf and Er/Er mutants and that, when these keratins do appear later in development, they are localized in the deeper layers of the thickened mutant epidermis. Conversely, K6 and K16, two keratins found in low abundance in normal epidermis, are abundant in mutant epidermis. In newborn mutant epidermis, K6 and K16 are found to be most abundant in the outermost epidermal cells, a distribution opposite to that of K1 and K10. These findings suggest that the expression of these hyperplastic keratins in mutant mice may occur to the exclusion of the differentiation-specific keratins both during development and in newborn animals. Differentiation, and an apparently normal pattern of keratin expression, occur when whole pf/pf or Er/Er skin is grafted to normal mice. These results suggest that the pf and Er genes may be expressed systemically and that transfer of the mutant skin to a "normal" environment results in the recovery of a normal phenotype.


Aphasic and tactile--perceptual deficits of disabled readers.
As part of a psychoeducational battery, 36 children, referred for reading and/or other learning difficulties, were administered the Aphasia Screening Test. the Tactile Finger Recognition Test, and the Finger-tip Number Writing Perception Test from the Halstead-Reitan Neuropsychological Test Battery for Older Children. The children were divided into two groups: 18 determined on the basis of a severe discrepancy to be eligible for learning disabilities services in the area of reading (RD) and 18 determined to be ineligible for such services (NRD). Statistical comparisons of the two groups revealed the RD group to display significantly more impairment on the Aphasia Screening Test and the Finger-tip Number Writing Perception Test.


Does serum hexosaminidase activity play a role in the diagnosis of strangulated bowel obstruction? An experimental study.
Strangulation is associated with an increased risk of mortality and morbidity in patients with mechanical bowel obstruction. The accurate and early recognition of the presence of strangulation is important to allow safe nonoperative treatment. A number of studies have shown that there was no single and reliable test to detect or exclude the presence of strangulation. The aim of this study was to evaluate the role of serum hexosaminidase (Hex) levels in recognition of strangulation in an experimental model of closed loop small bowel obstruction. Forty-two Wistar albino rats were divided into four groups: I, control (n = 5); II, sham laparotomy (n = 5); III, simple obstruction (n = 16); and IV, strangulation groups (n = 16). Activity levels of total Hex and its fractions (Hex A and B) were assayed in serum samples obtained from rats after 3 and 8 hr. Samples of small bowel were also evaluated histologically. Histological evaluation of bowel sections obtained from the strangulation group after 8 hr, revealed transmural hemorrhagic infarction in all animals with a mean +/- SD total Hex activity of 978.25 +/- 150 nmol/hr/ml, which was significantly higher than that in the other groups (P < 0.001). Although sections of bowel from the strangulation group after 3 hr showed severe ischemic injury, the activities of total Hex, Hex A, and Hex B were not different from those of the control, sham, and simple obstruction groups. Histological examination of these groups did not show any sign of ischemia. Total Hex, Hex A, and Hex B activities in the strangulation group were all significantly greater than the activities seen in the simple obstruction group (P < 0.001, for all). In conclusion, increased serum hex levels indicate irreversible transmural infarction only in the late period of strangulation in the closed loop small bowel obstruction model. It seems unuseful for detecting reversible and/or irreversible ischemia in the early period of strangulation.


[3+2] Cycloaddition of Alkynyl Boronates and in situ Generated Azomethine Ylide.
Scalable [3+2] cycloaddition of alkynyl boronates and in situ generated unstabilized azomethine ylide is reported for the first time. The selective formation of either 1:1 or 1:2 cycloaddition products was achieved by carefully optimizing the reaction conditions, mainly by controlling the reactant stoichiometry, catalyst loading, and internal temperature. The developed protocol tolerated many valuable functional groups, including TMS, protected alcohol (as ether or THP derivatives), or aldehyde (as acetal). Further common C-C and C - heteroatom bond-forming reactions, as well as scaled-up procedures demonstrate the utility of the prepared compounds as building blocks for organic synthesis and drug discovery.


Biomedical prevention: state of the science.
Preexposure prophylaxis (PrEP) and treatment as prevention (TasP) involve the use of antiretroviral (ARV) drugs by human immunodeficiency virus (HIV)-negative and -positive individuals to reduce HIV acquisition and transmission, respectively. Clinical science has delivered a consistently high effect size for TasP and a range from 0%-73% reduction in incidence across placebo-controlled PrEP trials. However, the quality of evidence for PrEP compares favorably with evidence for postexposure prophylaxis (PEP). It is clear from treatment programs and PrEP trials that daily adherence presents challenges to a large proportion of the population. Although there are factors associated with inconsistent use (ie, younger age), they do not assist clinicians at the point of care. There are additional provider concerns about PrEP (covering cost of drug and delivery, undermining condom promotion, and facilitating resistant strains) that have delayed widespread acceptance. These issues need to be addressed in order to realize the full public health potential of antiretrovirals.


Naso-lacrimal by-pass surgery. An easier approach.
An easier method of naso-lacrimal by-pass surgery is described in which a large anterior mucosal flap is fashioned from the lacrimal sac and the nasal mucosa. The short posterior lacrimal mucosal flap is completely excised. Particular operative, and postoperative techniques. Over 95 per cent of the 46 eyes in this series of 45 patients no longer have epiphora.


Illuminating single molecules in condensed matter.
Efficient collection and detection of fluorescence coupled with careful minimization of background from impurities and Raman scattering now enable routine optical microscopy and study of single molecules in complex condensed matter environments. This ultimate method for unraveling ensemble averages leads to the observation of new effects and to direct measurements of stochastic fluctuations. Experiments at cryogenic temperatures open new directions in molecular spectroscopy, quantum optics, and solid-state dynamics. Room-temperature investigations apply several techniques (polarization microscopy, single-molecule imaging, emission time dependence, energy transfer, lifetime studies, and the like) to a growing array of biophysical problems where new insight may be gained from direct observations of hidden static and dynamic inhomogeneity.


Nucleosome structure and function.
It is now widely recognized that the packaging of genomic DNA, together with core histones, linker histones, and other functional proteins into chromatin profoundly influences nuclear processes such as transcription, replication, DNA repair, and recombination. How chromatin structure modulates the expression of knowledge encoded in eukaryotic genomes, and how these processes take place within the context of a highly complex and compacted genomic chromatin environment remains a major unresolved question in biology. Here we review recent advances in nucleosome structure and dynamics.


Lidocaine Induces Apoptosis and Suppresses Tumor Growth in Human Hepatocellular Carcinoma Cells In Vitro and in a Xenograft Model In Vivo.
Recent epidemiologic studies have focused on the potential beneficial effects of regional anesthetics, and the differences in cancer prognosis may be the result of anesthetics on cancer biologic behavior. However, the function and underlying mechanisms of lidocaine in hepatocellular carcinoma both in vitro and in vivo have been poorly studied. Human HepG2 cells were treated with lidocaine. Cell viability, colony formation, cell cycle, and apoptosis were assessed. The effects of lidocaine on apoptosis-related and mitogen-activated protein kinase protein expression were evaluated by Western blot analysis. The antitumor activity of lidocaine in hepatocellular carcinoma with or without cisplatin was investigated with in vitro experiments and also with animal experiments. Lidocaine inhibited the growth of HepG2 cells in a dose- and time-dependent manner. The authors also found that lidocaine arrested cells in the G0/G1 phase of the cell cycle (63.7 ± 1.7% vs. 72.4 ± 3.2%; P = 0.0143) and induced apoptosis (1.7 ± 0.3% vs. 5.0 ± 0.7%; P = 0.0009). Lidocaine may exert these functions by causing an increase in Bax protein and activated caspase-3 and a corresponding decrease in Bcl-2 protein through the extracellular signal-regulated kinase 1/2 and p38 pathways. More importantly, for the first time, xenograft experiments (n = 8 per group) indicated that lidocaine suppressed tumor development (P < 0.0001; lidocaine vs. control) and enhanced the sensitivity of cisplatin (P = 0.0008; lidocaine plus cisplatin vs. cisplatin). The authors' findings suggest that lidocaine may exert potent antitumor activity in hepatocellular carcinoma. Furthermore, combining lidocaine with cisplatin may be a novel treatment option for hepatocellular carcinoma.


On Identification of Critical Material Attributes for Compression Behaviour of Pharmaceutical Diluent Powders.
As one of the commonly-used solid dosage forms, pharmaceutical tablets have been widely used to deliver active drugs into the human body, satisfying patient's therapeutic requirements. To manufacture tablets of good quality, diluent powders are generally used in formulation development to increase the bulk of formulations and to bind other inactive ingredients with the active pharmaceutical ingredients (APIs). For formulations of a low API dose, the drug products generally consist of a large fraction of diluent powders. Hence, the attributes of diluents become extremely important and can significantly influence the final product property. Therefore, it is essential to accurately characterise the mechanical properties of the diluents and to thoroughly understand how their mechanical properties affect the manufacturing performance and properties of the final products, which will build a sound scientific basis for formulation design and product development. In this study, a comprehensive evaluation of the mechanical properties of the widely-used pharmaceutical diluent powders, including microcrystalline cellulose (MCC) powders with different grades (i.e., Avicel PH 101, Avicel PH 102, and DG), mannitol SD 100, lactose monohydrate, and dibasic calcium phosphate, were performed. The powder compressibility was assessed with Heckel and Kawakita analyses. The material elastic recovery during decompression and in storage was investigated through monitoring the change in the dimensions of the compressed tablets over time. The powder hygroscopicity was also evaluated to examine the water absorption ability of powders from the surroundings. It was shown that the MCC tablets exhibited continuous volume expansion after ejection, which is believed to be induced by (1) water absorption from the surrounding, and (2) elastic recovery. However, mannitol tablets showed volume expansion immediately after ejection, followed by the material shrinkage in storage. It is anticipated that the expansion was induced by elastic recovery to a limited extent, while the shrinkage was primarily due to the solidification during storage. It was also found that, for all powders considered, the powder compressibility and the elastic recovery depended significantly on the particle breakage tendency: a decrease in the particle breakage tendency led to a slight decrease in the powder compressibility and a significant drop in immediate elastic recovery. This implies that the particle breakage tendency is a critical material attribute in controlling the compression behaviour of pharmaceutical powders.


Myosin Va movements in normal and dilute-lethal axons provide support for a dual filament motor complex.
To investigate the role that myosin Va plays in axonal transport of organelles, myosin Va-associated organelle movements were monitored in living neurons using microinjected fluorescently labeled antibodies to myosin Va or expression of a green fluorescent protein-myosin Va tail construct. Myosin Va-associated organelles made rapid bi-directional movements in both normal and dilute-lethal (myosin Va null) neurites. In normal neurons, depolymerization of microtubules by nocodazole slowed, but did not stop movement. In contrast, depolymerization of microtubules in dilute-lethal neurons stopped movement. Myosin Va or synaptic vesicle protein 2 (SV2), which partially colocalizes with myosin Va on organelles, did not accumulate in dilute-lethal neuronal cell bodies because of an anterograde bias associated with organelle transport. However, SV2 showed peripheral accumulations in axon regions of dilute-lethal neurons rich in tyrosinated tubulin. This suggests that myosin Va-associated organelles become stranded in regions rich in dynamic microtubule endings. Consistent with these observations, presynaptic terminals of cerebellar granule cells in dilute-lethal mice showed increased cross-sectional area, and had greater numbers of both synaptic and larger SV2 positive vesicles. Together, these results indicate that myosin Va binds to organelles that are transported in axons along microtubules. This is consistent with both actin- and microtubule-based motors being present on these organelles. Although myosin V activity is not necessary for long-range transport in axons, myosin Va activity is necessary for local movement or processing of organelles in regions, such as presynaptic terminals that lack microtubules.


Nascent peptide-dependent translation arrest leads to Not4p-mediated protein degradation by the proteasome.
The potentially deleterious effects of aberrant mRNA lacking a termination codon (nonstop mRNA) are ameliorated by translation arrest, proteasome-mediated protein destabilization, and rapid mRNA degradation. Because polylysine synthesis via translation of the poly(A) mRNA tail leads to translation arrest and protein degradation by the proteasome, we examined the effects of other amino acid sequences. Insertion of 12 consecutive basic amino acids between GFP and HIS3 reporter genes, but not a stem-loop structure, resulted in degradation of the truncated green fluorescent protein (GFP) products by the proteasome. Translation arrest products derived from GFP-R12-FLAG-HIS3 or GFP-K12-FLAG-HIS3 mRNA were detected in a not4Delta mutant, and MG132 treatment did not affect the levels of the truncated arrest products. Deletion of other components of the Ccr4-Not complex did not increase the levels of the translation arrest products or reporter mRNAs. A L35A substitution in the Not4p RING finger domain, which disrupted its interaction with the Ubc4/Ubc5 E2 enzyme and its activity as an ubiquitin-protein ligase, also abrogated the degradation of arrest products. These results suggest that Not4p, a component of the Ccr4-Not complex, may act as an E3 ubiquitin-protein ligase for translation arrest products. The results let us propose that the interaction between basic amino acid residues and the negatively charged exit tunnel of the ribosome leads to translation arrest followed by Not4p-mediated ubiquitination and protein degradation by the proteasome.


Prospective role of ascorbic acid (vitamin C) in attenuating hexavalent chromium-induced functional and cellular damage in rat thyroid.
Occupational exposure to toxic heavy metals may render industrial workers with thyroid-related problems. Here, we examined the role of ascorbic acid (vitamin C) against hexavalent chromium Cr (VI)-induced damage in rat thyroid gland. Potassium dichromate (K2Cr2O7) and ascorbic acid doses were 60 microg and 120 mg kg(-1) body wt (intraperitoneally [i.p.]) respectively. Treatment regimens were group I rats, saline treated control; group II, only K2Cr2O7; group III, ascorbic acid 1 hour prior K2Cr2O7; group IV, simultaneous doses of ascorbic acid and K2Cr2O7, and group V, a combined premix dose of ascorbic acid and K2 Cr2O7 (2:1 ratio). Blood samples were taken before dosing the animals and 48 hours post exposure to determine the serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) concentrations. Toward end of experiment, rats were sacrificed and thyroid glands were processed to evaluate the extent of cellular insult. Results showed significantly increased TSH and decreased FT3 and FT4 concentrations in groups II, III and IV rats as compared to control levels (p < 0.05). In contrast, in group V rats, serum TSH, FT3 and FT4 concentrations neared control concentrations. Histopathologically, protective effect of ascorbic acid was found in group V rats only, where thyroid gland structure neared control thyroid except the follicular size that was decreased (p < 0.05). Follicular density was no different from control. Basal laminae were intact, interfollicular spaces were normal. Colloid retraction and/or reabsorption were reduced maximally. Epithelial cell height was no different from control; epithelial follicular index increased only 1.3 fold, whereas nuclear-cytoplasmic (N/C) ratio was decreased by 14% only. The study indicates that the ascorbic acid may have the potential to protect thyroid gland from chromium toxicity; however, the study warrants further in-depth experimentation to precisely elucidate this role.


Progress towards a Leishmania vaccine.
Leishmaniasis is a vector-born protozoan disease. Approximately 12 million individuals are affected worldwide with an estimated annual incidence of 1.5-2 million. Two clinical manifestations are recognized, cutaneous, and visceral, both of which are common in the Middle East. In both forms, infection is chronic, with potential deformities, persistence following cure, and lifelong risk of reactivation. Attempts to develop an effective human Leishmania vaccine have not yet succeeded. Leishmanization, a crude form of live vaccination historically originated in this part of the world. Experimental vaccination has been extensively studied in model animals in the past 2 decades. In this review, major human killed vaccine trials are surveyed, and modern trends in Leishmania vaccine development, including subunit vaccines, naked DNA vaccines, and transmission blocking vaccines are explored. Recent findings of a link between persistence of live parasites, and maintenance of long-term immunity suggest live vaccination with attenuated strains, as a future vaccination strategy.


Language ability in children with permanent hearing impairment: the influence of early management and family participation.
The goal was to examine the relationships between management after confirmation, family participation, and speech and language outcomes in the same group of children with permanent childhood hearing impairment. Speech, oral language, and nonverbal abilities, expressed as z scores and adjusted in a regression model, and Family Participation Rating Scale scores were assessed at a mean age of 7.9 years for 120 children with bilateral permanent childhood hearing impairment from a 1992-1997 United Kingdom birth cohort. Ages at institution of management and hearing aid fitting were obtained retrospectively from case notes. Compared with children managed later (> 9 months), those managed early (< or = 9 months) had higher adjusted mean z scores for both receptive and expressive language, relative to nonverbal ability, but not for speech. Compared with children aided later, a smaller group of more-impaired children aided early did not have significantly higher scores for these outcomes. Family Participation Rating Scale scores showed significant positive correlations with language and speech intelligibility scores only for those with confirmation after 9 months and were highest for those with late confirmed, severe/profound, permanent childhood hearing impairment. Early management of permanent childhood hearing impairment results in improved language. Family participation is also an important factor in cases that are confirmed late, especially for children with severe or profound permanent childhood hearing impairment.


Transcriptome analysis reveals molecular signature and cell-type difference of Homo sapiens endothelial-to-mesenchymal transition.
Endothelial-to-mesenchymal transition (EndoMT), a specific form of epithelial-to-mesenchymal transition, drives a growing number of human (Homo sapiens) pathological conditions. This emerging knowledge opens a path to discovering novel therapeutic targets for many EndoMT-associated disorders. Here, we constructed an atlas of the endothelial-cell transcriptome and demonstrated EndoMT-induced global changes in transcriptional gene expression. Our gene ontology analyses showed that EndoMT could be a specific checkpoint for leukocyte chemotaxis, adhesion, and transendothelial migration. We also identified distinct gene expression signatures underlying EndoMT across arterial, venous, and microvascular endothelial cells. We performed protein-protein interaction network analyses, identifying a class of highly connected hub genes in endothelial cells from different vascular beds. Moreover, we found that the short-chain fatty acid acetate strongly inhibits the transcriptional program of EndoMT in endothelial cells from different vascular beds across tissues. Our results reveal the molecular signature and cell-type difference of EndoMT across distinct tissue- and vascular-bed-specific endothelial cells, providing a powerful discovery tool and resource value. These results suggest that therapeutically manipulating the endothelial transcriptome could treat an increasing number of EndoMT-associated pathological conditions.


Subtelomeric Rearrangements in Patients with Recurrent Miscarriage.
The subtelomeric rearrangements are increasingly being investigated in cases of idiopathic intellectual disabilities (ID) and congenital abnormalities (CA) but are also thought to be responsible for unexplained recurrent miscarriage (RM). Such rearrangements can go unnoticed through conventional cytogenetic techniques and are undetectable even with high-resolution molecular cytogenetic techniques such as array comparative genomic hybridization (aCGH), especially when DNA of the stillbirth or families are not available. The aim of the study is to evaluate the rate of subtelomeric rearrangements in patients with RM. In this cross-sectional study, fluorescent in situ hybridization (FISH), based on ToTelVysion telomeric probes, was undertaken for 21 clinically normal couples exhibiting a "normal" karyotype with at least two abortions. Approximately 62% had RM with a history of stillbirth or CA/ID while the other 38% had only RM. FISH detected one cryptic rearrangement between chromosomes 3q and 4p in the female partner of a couple (III:4) [46,XX,ish t(3;4)(q28-,p16+;p16-,q28+)(D3S4559+,D3S4560-,D4S3359+; D3S4560+, D4S3359- ,D4S2930+)] who presented a history of RM and family history of ID and CA. Analysis of the other family members of the woman showed that her sisters (III:6 and III:11) and brother (III:8) were also carriers of the same subtelomeric translocation t(3;4)(q28;p16). We conclude that subtelomeric FISH should be undertaken in couples with RM especially those who not only have abortions but also have had at least one child with ID and/or CA, or other clinically recognizable syndromes. For balanced and cryptic anomalies, subtelomeric FISH still remains the most suitable and effective tool in characterising such chromosomal rearrangements in RM couples.


Enzyme amplifier kinetics.
Enzyme amplifier systems have been implicated in such diverse physiological phenomena as vision and blood coagulation. Such systems are considered from a general point of view and the concept of steady state gain of the enzyme amplifier is introduced. Expressions for the latter are obtained, and several of the main factors influencing gain are discussed. The effect of the duration of the activation on the characteristics of the response is discussed, and the influence of small changes in the rate constants on the steady state gain is considered.


Scatter correction for three-dimensional PET based on an analytic model dependent on source and attenuating object.
Three-dimensional positron emission tomography admits a significant scatter fraction due to the large aperture of the detectors, and requires accurate scatter subtraction. A scatter-correction method, applicable to both emission and transmission imaging, calculates the projections of the single-scatter distribution, using an approximate image of the source and attenuating object. The scatter background is subtracted in projection space for transmission data and in image space for emission data, yielding corrected attenuation and emission images. The accuracy of this single-scatter distribution is validated for the authors' small imaging system by comparison with Monte Carlo simulations. The correction is demonstrated using transmission and emission data obtained from measurements on the authors' QPET imaging system using two acrylic phantoms. For the transmission data, generated with a flood source, errors of up to 24% in the linear attenuation coefficients resulted with no scatter subtraction, but the correction yielded an accurate value of mu =0.11+or-0.01 cm-1. For the emission data, the corrected images show that the scattered background has been removed to within the level of the background noise outside the source. The residual amplitude within a cold spot in one of the phantoms was reduced from 21% to 3% of the image amplitude.


Body communication is a continuous process. The first encounter between patient and physiotherapist.
First encounters between patients and physiotherapists have been video-taped and analysed as part of a research project encompassing manual, psychomotor, and district physiotherapists. The main focus in this article is on body communication. The common features and differences between the patterns of communication established by the three categories of therapists are described and compared. Since human beings function and relate to each other as physical subjects, messages of interest and involvement will in some way be conveyed through their bodies. The recognition of this fact means that body communication is a central aspect of patient-centredness. The relationship, context, and actual basis of cooperation can only be understood by analysing the way in which professionals relate to their patients through their bodies. This is because body messages are conveyed continuously in any encounter between two people, while verbal communication is discontinuous.


Loss of imprinting of insulin growth factor II gene: a potential heritable biomarker for colon neoplasia predisposition.
Loss of genomic imprinting (LOI) of insulin-like growth factor II gene (IGF2) involves abnormal activation of the normally silent maternally inherited allele. LOI of IGF2 has been associated with personal and family history of colorectal neoplasia (CRN), supporting a role for LOI in colorectal carcinogenesis. Whether LOI of IGF2 is associated with known environmental risk factors for CRN is unknown. We performed quantitative hot-stop PCR for imprinting analysis of IGF2 on normal peripheral blood lymphocytes (PBL) of individuals. Environmental exposures including tobacco, alcohol, NSAIDs, and nutrient consumption (calcium, folate, selenium, fiber, and fat) were correlated with LOI expression in PBL. Odds ratios (OR) and 95% CI were calculated. The prevalence of LOI of IGF2 was examined in 172 individuals. Persons with CRN (adenomas/cancer) had 5.1-fold (95% CI: 1.92-13.6) increased risk of having LOI of IGF2 in PBL compared with those without CRN. In contrast, tobacco smoking (OR = 0.96, 95% CI: 0.36-2.55), alcohol consumption (OR = 1.22, 95% CI: 0.45-3.3), and NSAIDs use (OR = 1.21, 95% CI: 0.38-3.94) were not significantly associated with LOI of IGF2. Nutrient ingestion including calcium (P = 0.61), folate (P = 0.23), selenium (P = 0.19), fiber (P = 0.63), and fat (P = 0.14) was not statistically correlated with LOI of IGF2. Abnormal imprinting of IGF2 gene was strongly associated with CRN but not with any of the environmental exposures examined. LOI of IGF2 does not appear to be an environmentally acquired phenomenon but rather a hereditary risk factor for CRN.


Non-specific uptake of the radioligand 125I-IHYP by intact human lymphocytes: reversal of the uptake process.
Binding of (+/-)[125I]iodohydroxybenzylpindolol (IHYP) to beta-adrenoceptors on intact human peripheral blood lymphocytes was found to be associated with a high degree of non-specific intracellular uptake of the radioligand. Non-specific binding on cellular surfaces was identified by displacing IHYP from its specific binding sites with the cold competing antagonist (+/-)-propranolol. Another methodological approach, however, was necessary to eliminate the uptake problem: release of intracellularly accumulated IHYP was achieved by sedimentation of the IHYP-loaded cells and resuspension in hypotonic buffer (HME buffer) for 10 min at +4 degrees C. The true value of maximal IHYP binding measured after IHYP release was 970 binding sites/cell as compared with 2300 receptors/cell found under standard binding conditions. This difference in maximal IHYP binding obtained by the 2 methods is attributed to the strong interference of the uptake process with the measurement of specific IHYP binding. Further evidence for the efficiency of the procedure to reverse the uptake process was obtained with the very slowly dissociable beta-adrenoceptor antagonist FM 24. Pre-incubation of the cells with 5 x 10(-5) M FM 24 totally prevented specific IHYP binding. Any IHYP measured on cells in the presence of FM 24, therefore, must have been due to mere non-specific binding and cellular uptake of the radioligand. Even though the uptake of IHYP was enhanced in FM-24-treated cells, this influx could be completely reversed by exposing the IHYP-loaded cells to HME buffer for 10 min at +4 degrees C. Our findings indicate that our experimental conditions are suitable for beta-receptor binding studies on intact cells with IHYP, because the uptake of the labeled ligand is eliminated.


[The influence of anatomical and functional failure of the abdominal wall on the prognosis of postoperative ventral hernias].
It was analyzed the results of clinical and ultrasound examination of the abdominal wall in 180 patients with different surgical diseases of the abdominal cavity. All patients were divided into 3 groups of 60 persons on the basis of the preoperative examination results. The first group included patients without clinical and ultrasound disorders, the second and the third - with mild and severe anatomical and functional failure of the abdominal wall. 20% of patients from the first group had single strain of the abdominal wall after operation without the development of postoperative hernias. 3.3% of patients in the second group had defects and 15% of patient from the same group had severe thinning of the abdominal wall. 45% of patients in the third group had postoperative hernias. Relative and absolute indications for preventive replacement of the abdominal wall were defined.


Regulation of tissue factor cytoplasmic domain phosphorylation by palmitoylation.
The tissue factor (TF)-initiated coagulation pathway plays important roles in hemostasis, inflammation, metastasis, and angiogenesis. Phosphorylation of the TF cytoplasmic domain is functionally relevant in metastasis. How TF cytoplasmic domain phosphorylation downstream of protein kinase C (PKC) activation is regulated in primary vascular cells remains poorly understood. Here, phosphorylation of Ser258, rather than the PKC consensus site Ser253, is identified as the major conformational switch required for recognition by a phosphorylation-specific antibody. With this novel reagent, we demonstrate that the TF cytoplasmic domain is primarily unphosphorylated in confluent endothelial cells. TF cytoplasmic domain phosphorylation can occur in the absence of the autologous TF transmembrane and extracellular domains but requires maturation of TF in the Golgi compartment and cell surface expression. Site-directed mutagenesis and 2-bromopalmitate treatment provide evidence that palmitoylation of the cytoplasmic Cys245 is a negative regulatory mechanism of Ser258 phosphorylation. Profiling with PKC-selective inhibitors identifies PKCalpha as important for TF cytoplasmic domain phosphorylation. Mutagenesis of protein kinase consensus sites are consistent with a model in which PKC-dependent phosphorylation of Ser253 enhances subsequent Ser258 phosphorylation by a Pro-directed kinase. Thus, cell surface location-dependent phosphorylation of the TF cytoplasmic domain is regulated at multiple levels.


Long lasting postoperative ileus after surgery for intestinal obstruction due to left paraduodenal hernia (LPDH). Case report.
Left paraduodenal hernia is a rare congenital anomaly which arises from an error of rotation of the midgut; sometimes can be responsible for intestinal occlusion, that require surgery. In many cases of literature a prompt diagnosis and therapy reduced morbidity and mortality and almost all patients were discharged on 4th or 5th postoperative day (POD). We report a case of a 59 years old patient who underwent surgery for intestinal obstruction due to a massive left paraduodeneal hernia, that had a very long period (20 days) of postoperative ileus.


Twelve tips for supervisors to move towards person-centered research supervision in health care sciences.
The research supervisory role is becoming increasingly complex due to issues such as diversity of students; mismatched expectations between the student, supervisor and higher education institution and shorter and specific time-bound research outcomes. The current postgraduate research supervision culture and supervision practices should change. Moving towards person-centered research supervision practices may enhance the research environment, as healthful relationships between supervisors and postgraduate students may lead to increased postgraduate research outcomes. Using a World Café, we critically reflected on our existing research supervision practices. All healthcare educators involved in postgraduate research supervision were purposively selected to participate. During the café, we explored and shared ideas in a safe space. Twelve tips emerged, which can be implemented to move existing supervision practices towards person-centered research supervision practices. We present these twelve tips from the perspective of the four constructs of person-centeredness as outlined by McCormack and McCance - pre-requisites, environment, process, and outcomes. The use of these tips may enable both supervisors and students to flourish. Avoiding routine, ritual supervision practices and embracing person-centredness, will enable supervisors to form healthful relationships and put the postgraduate student at the heart of our supervision practices.


Electrokinetic trapping and concentration enrichment of DNA in a microfluidic channel.
We report a simple and efficient method for enriching the concentration of charged analytes within microfluidic channels. The method relies on exerting spatial control over the electrokinetic velocity of an analyte. Specifically, the electroosmotic (eo) velocity of the buffer solution in one region of the microfluidic system opposes the electrophoretic (ep) velocity of the analyte in the other region. This results in ep transport of DNA to the location where the ep and eo velocities are equal and opposite. Accumulation of the analyte occurs at this location. This enrichment method is conceptually distinct from field-amplification stacking, isotachophoresis, micelle sweeping, size exclusion, and other methods that have been previously reported. The method requires no complex microfabricated structures, no special manipulation of the solvent, and the enriched analyte remains in solution rather than being captured on a solid support. A concentration enrichment factor of 800 can be achieved for 20mer DNA in a fluidic channel having dimensions of 100 mum x 25 mum x 5 mm. The time required to achieve this level of enrichment is 300 s, and the enriched zone has a minimum width of 100 mum.


Safety, efficacy and lessons from continuous infusion with rFVIIa. rFVIIa-CI Group.
Continuous infusion with coagulation factor concentrates has only been widely adopted during the last decade and with recombinant activated factor VII (rFVIIa) only during the last 2 years. Still the accumulated number of days on continuous infusion with this product amounts by now to more than one year, 35 patients and 26 surgical procedures. The experience is reviewed here and compared with data from the conventional bolus dose regimen.


The impact of age-related changes on working memory functional activity.
This work investigated associations of age-related brain atrophy and functional neural networks identified using multivariate analyses of BOLD fMRI data in young and elder participants (young, N=37; mean age=25; elders, N=15; mean age=74). Two networks were involved in retaining increasing loads of verbal information in working memory. Network utilizations were used to test associations between function and indices of grey matter volume changes using voxel based morphometry. Global changes in brain volume were not associated with the secondary network. Lower regional grey matter volume in the left pre-central gyrus within the primary network was associated with increased secondary network utilization independent of age group. Decreased regional grey matter volume was associated with increased age only in the elders. Increased secondary network expression was associated with increased slope of reaction times across memory load, in the elders. These results support the theory of neural compensation, that elder participants recruit additional neural resources to maintain task performance in the face of age-related decreases in regional grey matter volume.


Botulinum toxin treatment of temporomandibular joint pain in patients with bruxism: A prospective and randomized clinical study.
Bruxism is a parafunctional habit, usually performed in sleep, by rhythmic and involuntary teeth being squeezed or squeaked. The most common methods of treatment are the use of occlusal splints. The aim of this study was to compare the efficacy of occlusal splinting with botulinum toxin administration in the treatment of TMJ pain. For this purpose, 40 patients with bruxism were divided into two groups and one group was treated with occlusal splint and the other group received masseter muscle botulinum toxin injection. Then, the participants in both groups were evaluated in terms of pain, functional movement, and maximum bite force change at 2 weeks, 6 weeks, 3 months, and 6 months. Mann-Whitney U test was used to examine the differences between two independent groups. While Friedman test was used for differences between dependent groups, the Wilcoxon test was used for the differences between two repetitive measurements. Chi-square test was used to examine the relationship between categorical variables. Results: When pain was evaluated, both methods were effective in pain reduction, botulinum toxin injection was found to be less effective in reducing pain but no difference was found between the two methods. The maximum bite force decreased in the 2nd and 6th weeks and increased in the 3rd and 6th months in patients receiving botulinum toxin. In patients using occlusal splints, there was no change until the 3rd month and an increase was seen in the 6th month. In this study, it was observed that low dose BTX-A and occlusal splint use were effective in eliminating bruxism-related pain but not superior to each other. According to these results, low dose botulinum toxin can be considered as an alternative treatment in patients who cannot use occlusal splint for various reasons.


The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice.
The type II activin receptors, ActRIIA and ActRIIB, have been shown to play critical roles in axial patterning and organ development in mice. To investigate whether their function is required for mesoderm formation and gastrulation as implicated in Xenopus studies, we generated mice carrying both receptor mutations by interbreeding the ActRIIA and ActRIIB knockout mutants. We found that embryos homozygous for both receptor mutations were growth arrested at the egg cylinder stage and did not form mesoderm. Further analyses revealed that ActRIIA(-/-)ActRIIB(+/-) and about 15% of the ActRIIA(-/-) embryos failed to form an elongated primitive streak, resulting in severe disruption of mesoderm formation in the embryo proper. Interestingly, we observed similar gastrulation defects in ActRIIA(-/-)nodal(+/-) double mutants, which, if they developed beyond the gastrulation stage, displayed rostral head defects and cyclopia. These results provide genetic evidence that type II activin receptors are required for egg cylinder growth, primitive streak formation, and rostral head development in mice.


Natural Course of Chlamydia trachomatis Bacterial Load in the Time Interval between Screening and Treatment in Anogenital Samples.
Although Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection worldwide, little is known about the natural course of the bacterial load during infection. We investigated the natural course of the bacterial load in the interval between screening and returning for treatment in genital and anorectal CT-infections. CT-positive patients, visiting our STI-clinic in the Netherlands from June 2011-January 2014, provided a second urogenital and/or anorectal sample when returning for treatment (diagnostic sample = T1; treatment sample = T2). Patient-record provided data about the days between samples and the date of last unsafe sex. Included patients were ≥18 years old, HIV-negative and did not report antibiotic use in the study-interval. CT load was quantified using qPCR. CT load was log-transformed, and a CT load difference (Δ-CT load) of >1 log was deemed clinically relevant. Chi-square test compared load category distributions over time (decrease/equal/increase), between sample types. 274 patients provided 296 paired samples. Majority of samples had a stable CT load in the interval T1-T2 (66.3%, 73.1% and 48.6% for vaginal swabs, urine and anorectal swabs resp. p = 0.07). Load decreased in 17-41% of patients, while ±10% of patients showed an increase in CT load. No association between Δ-CT load and the interval T1-T2 was observed. Large variations can be seen in CT load at T1 and over time. The majority (±90%) of patients have a stable or decreasing CT load in the time interval between screening and returning for treatment. The number of days between sampling was not associated with change in CT load. In the first month after the last unsafe sex, only stable CT loads were seen. Our data seems to indicate that when most patients visit an STI-clinic, recommended 2 weeks after infection, the infection has already been established or is in its downward phase.


Risk assessment of the overweight and obese patient.
Risk assessment of the overweight and obese patient is an important and necessary first step in the treatment process. Risk classification begins with determination of body mass index (BMI), waist circumference for those with a BMI of 35 or less, and presence of comorbid conditions. With the exception of measuring a fasting blood glucose and lipid panel on all patients, other diagnostic laboratory tests are selected based on the patient's risk factor status. Understanding the reasons leading to and sustaining the patient's overweight and obesity is the next major step and is paramount to designing individualized and targeted treatment. This information is ascertained by having the patient graph his or her weight pattern with associated life events and by assessing detailed dietary and physical activity histories. Calculating estimated energy balance has both benefits and limitations in clinical practice. Pediatric and geriatric patients represent special populations that require additional focus. Improvement in the assessment process will likely be achieved by using a team approach along with future developments in practical measurement of body composition and energy expenditure.


Homicide-suicide in Victoria, Australia.
Thirty-nine incidents of homicide-suicide occurring in Victoria, Australia between 1985 and 1989 were examined. In 33 cases the assailants were men. The victims were spouses or women living in a de facto marriage. The majority of the victims were shot, and this was also the most frequent method of suicide. Breakdown in a relationship was the most frequent reason for killing. Mental illness of the assailant accounted for the killing in approximately 20% of cases. Physical ill health and financial stress were identified as important associative factors, particularly in the elderly. The pattern of homicide-suicide in Victoria is similar to that observed in other jurisdictions and represents an important and distinct subgroup of homicide.


Gambling-related harms attributable to lotteries products.
Lotteries products (lottery tickets and scratch tickets) are the most popular forms of gambling worldwide, however little research has investigated whether these products are associated with gambling-related harm. The limited available research suggests these products are linked to problematic gambling behaviors and a range of resulting negative outcomes, with certain sub-groups appearing to be more vulnerable to experiencing harms. The present study examined risk of gambling-related harm (measured by the Problem Gambling Severity Index) from lotteries products use in an Australian sample of lotteries-only gamblers (n = 540). Additionally, the study investigated whether risk varied according to a range of sociodemographic and behavioral characteristics (age, gender, household income, location (rural vs. metropolitan), employment status, alcohol consumption, smoking status, frequency of e-cigarette use, frequency of scratch ticket use, frequency of lottery ticket use, expenditure on scratch tickets, and expenditure on lottery tickets). Almost one-third of the sample was found to be at some level of gambling-related risk due to their use of lotteries products. Younger respondents, males, current smokers, e-cigarette users, and those who purchase scratch tickets more frequently were more likely to report problematic use of lotteries products. Policy makers should enact strategies to prevent and reduce harms resulting from lotteries products, especially among the identified at-risk groups.


Efficacy and safety results with the LifeSite hemodialysis access system versus the Tesio-Cath hemodialysis catheter at 12 months.
To compare the performance and safety of a fully subcutaneous vascular access device, the LifeSite hemodialysis access system, versus a tunneled hemodialysis catheter, the Tesio-Cath, at 1 year after implantation. Sixty-eight patients who required hemodialysis received implantation of the LifeSite device or a Tesio-Cath device as a part of this multicenter study. Thirty-four patients were treated in each group. The endpoints observed included blood flow rates and associated venous pressures, overall and device-related adverse events, the need for thrombolytic infusions, device-related infections (DRIs) and associated hospitalizations, and technical device survival. During the 12-month observation period, significantly higher venous pressures were required in patients with the Tesio-Cath to achieve blood flow rates comparable with those achieved with the LifeSite device. Patients in the LifeSite group experienced a significantly lower rate of non-device-related adverse events (P < .001), device-related adverse events (P < .016), need for thrombolytic infusions (P < .002), and DRIs (P < .013) compared with patients in the Tesio-Cath group. There was a trend toward a lower number of hospital days per month for DRIs in the LifeSite group, with the rate for the Tesio-Cath group being twice that in the LifeSite group. The use of the LifeSite device was also associated with a significantly higher probability of device survival for 12 months after censoring for planned removals (P < .031). The results of the present study demonstrate superior device performance and technical device survival, reduced complications, and the need for fewer interventions with the LifeSite hemodialysis access system compared with a standard hemodialysis catheter during a 1-year time period after implantation.


Novel Perfused Compression Bioreactor System as an in vitro Model to Investigate Fracture Healing.
Secondary bone fracture healing is a physiological process that leads to functional tissue regeneration via endochondral bone formation. In vivo studies have demonstrated that early mobilization and the application of mechanical loads enhances the process of fracture healing. However, the influence of specific mechanical stimuli and particular effects during specific phases of fracture healing remain to be elucidated. In this work, we have developed and provided proof-of-concept of an in vitro human organotypic model of physiological loading of a cartilage callus, based on a novel perfused compression bioreactor (PCB) system. We then used the fracture callus model to investigate the regulatory role of dynamic mechanical loading. Our findings provide a proof-of-principle that dynamic mechanical loading applied by the PCB can enhance the maturation process of mesenchymal stromal cells toward late hypertrophic chondrocytes and the mineralization of the deposited extracellular matrix. The PCB provides a promising tool to study fracture healing and for the in vitro assessment of alternative fracture treatments based on engineered tissue grafts or pharmaceutical compounds, allowing for the reduction of animal experiments.


Developing language in a developing body: the relationship between motor development and language development.
ABSTRACTDuring the first eighteen months of life, infants acquire and refine a whole set of new motor skills that significantly change the ways in which the body moves in and interacts with the environment. In this review article, I argue that motor acquisitions provide infants with an opportunity to practice skills relevant to language acquisition before they are needed for that purpose; and that the emergence of new motor skills changes infants' experience with objects and people in ways that are relevant for both general communicative development and the acquisition of language. Implications of this perspective for current views of co-occurring language and motor impairments and for methodology in the field of child language research are also considered.


Ascorbate removes key precursors to oxidative damage by cell-free haemoglobin in vitro and in vivo.
Haemoglobin initiates free radical chemistry. In particular, the interactions of peroxides with the ferric (met) species of haemoglobin generate two strong oxidants: ferryl iron and a protein-bound free radical. We have studied the endogenous defences to this reactive chemistry in a rabbit model following 20% exchange transfusion with cell-free haemoglobin stabilized in tetrameric form [via cross-linking with bis-(3,5-dibromosalicyl)fumarate]. The transfusate contained 95% oxyhaemoglobin, 5% methaemoglobin and 25 microM free iron. EPR spectroscopy revealed that the free iron in the transfusate was rendered redox inactive by rapid binding to transferrin. Methaemoglobin was reduced to oxyhaemoglobin by a slower process (t(1/2) = 1 h). No globin-bound free radicals were detected in the plasma. These redox defences could be fully attributed to a novel multifunctional role of plasma ascorbate in removing key precursors of oxidative damage. Ascorbate is able to effectively reduce plasma methaemoglobin, ferryl haemoglobin and globin radicals. The ascorbyl free radicals formed are efficiently re-reduced by the erythrocyte membrane-bound reductase (which itself uses intra-erythrocyte ascorbate as an electron donor). As well as relating to the toxicity of haemoglobin-based oxygen carriers, these findings have implications for situations where haem proteins exist outside the protective cell environment, e.g. haemolytic anaemias, subarachnoid haemorrhage, rhabdomyolysis.


Clinical and non-clinical variables associated with preventive and curative dental service utilisation: a cross-sectional study among adolescents and young adults in Central Mexico.
The present study aimed to identify preventive and curative dental health service utilisation (DHSU) in the context of associated clinical and non-clinical factors among adolescents and young adults in Mexico. Cross-sectional study. Applicants to a public university in Mexico. Participants were 638 adolescents and young adults aged 16-25 randomly selected from university applicants. Data were collected using a self-administered questionnaire filled out by the students. For assessment of dental caries experience, we used the index of decayed, missing and filled teeth. The dependent variable was DHSU in the previous 12 months, coded as 0=non-use, 1=use of curative services and 2=use of preventive services. The mean age was 18.76±1.76 years, and 49.2% were women. The prevalence of DHSU was 40.9% (95% CI 37.1 to 44.8) for curative services and 22.9% (95% CI 19.7 to 26.3) for preventive services. The variables associated with curative services were age, sex, mother's education, dental pain in the previous 12 months, caries experience, use of self-care devices and oral health knowledge. For preventive services, the variables associated were mother's education, dental pain in the previous 12 months, caries experience, use of self-care devices and self-perception of oral health. While differences emerged by type of service, a number of variables (sociodemographic and socioeconomic characteristics as well as dental factors) remained in the final model. Greater oral health needs and socioeconomic inequalities remained as predictors of both types of DHSU. Given the differences revealed by our study, oral health policies should refer those seeking dental care for oral diseases to preventive services, and promote the use of such services among the poorer and less educated population groups.


Occurrence of High Levels of Cefiderocol Resistance in Carbapenem-Resistant Escherichia coli before Its Approval in China: a Report from China CRE-Network.
Cefiderocol has been approved in the United States and Europe but not in China. We aim to evaluate carbapenem-resistant Enterobacterales (CRE) susceptibility to cefiderocol to provide baseline data and investigate the resistance mechanism. From 2018 to 2019, 1,158 CRE isolates were collected from 23 provinces and municipalities across China. The MICs of antimicrobials were determined via the agar dilution and broth microdilution methods. Whole-genome sequencing was performed for 26 cefiderocol-resistant Escherichia coli isolates to investigate the resistance mechanism. Clone transformations were used to explore the function of cirA, pbp3, and blaNDM-5 in resistance. Among the 21 antimicrobials tested, aztreonam-avibactam had the highest antibacterial activity (98.3%), followed by cefiderocol (97.3%) and colistin (95.3%). A total of 26 E. coli isolates harboring New Delhi metallo-beta-lactamase 5 (NDM-5) showed high levels of cefiderocol resistance, of which sequence type 167 (ST167) accounted for 76.9% (20/26). We found 4 amino-acid insertions (YRIN/YRIK) at position 333 of penicillin-binding protein 3 (PBP3) in the 26 E. coli isolates, and 22 isolates had a siderophore receptor cirA premature stop codon. After obtaining the wild-type cirA supplementation, the MIC of the transformants decreased by 8 to 16 times in two cefiderocol-resistant isolates. A cefiderocol-susceptible isolate harboring NDM-5 has an MIC increased from 1 μg/mL to 64 μg/mL after cirA deletion, and the MIC decreased from 64 μg/mL to 0.5 μg/mL after blaNDM-5 deletion. The MIC of the E. coli DH5α, from which the pbp3 mutant was obtained, increased from 0.064 μg/mL to 0.25 μg/mL. Cefiderocol showed activity against most CRE in China. The resistance of ST167 E. coli to cefiderocol is a combination of the premature stop codon of cirA, pbp3 mutation, and blaNDM-5 existence. IMPORTANCE Cefiderocol, a new siderophore cephalosporin, has been approved in the United States and Europe but not in China. At present, there are almost no antimicrobial susceptibility evaluation data on cefiderocol in China. We evaluated the in vitro susceptibility of 1,158 strains of carbapenem-resistant Enterobacterales to cefiderocol and other antibiotics. We found that a high proportion of Escherichia coli showed high-level resistance to cefiderocol. Whole-genome sequencing (WGS) and molecular cloning experiments confirmed that the synergistic effect of the cirA gene premature stop codon, blaNDM-5 existence, and the pbp3 mutation is associated with high levels of cefiderocol resistance.


Elevated S100A12 and sRAGE are associated with increased length of hospitalization after non-urgent coronary artery bypass grafting surgery.
Study's purpose: Plasma levels of soluble receptor for advanced glycation endproducts (sRAGE) and S100A12 are increased in young children after cardiac surgery and correlate with the time spent on cardiopulmonary bypass (CPB). This study was performed to investigate whether plasma levels of sRAGE and S100A12 are affected by the use of CPB. Levels of S100A12 and sRAGE, along with of interleukin-6, tumor necrosis factor-α, myeloperoxidase, and C-reactive protein were measured in 25 adults undergoing non-urgent coronary artery bypass grafting with and without the use of CPB. Significant finding: Plasma levels of S100A12, sRAGE, IL-6, TNF-α and MPO 4h after cardiac surgery were elevated compared to baseline; this increase was equally observed in patients undergoing traditional coronary artery bypass grafting on cardiopulmonary bypass (n = 16), and in patients undergoing robot-assisted coronary artery bypass grafting off pump (OPCAB, n = 9). Patients with prolonged hospitalization of 7 days or longer had significantly higher S100A12 and sRAGE 4 hours post surgery compared to patients hospitalized ≤ 6 days. Increased sRAGE and S100A12 after cardiac surgery is associated with prolonged length of hospitalization in patients after coronary artery bypass grafting; however, we did not observe an intrinsic effect of cardiopulmonary bypass on S100A12 or sRAGE plasma levels in our small pilot study. Further studies are required to confirm the value of sRAGE and S100A12 in predicting postoperative complications after cardiac surgery in a larger study.


MRI of CNS fungal infections: review of aspergillosis to histoplasmosis and everything in between.
Fungal infections of the central nervous system (CNS) represent a wide spectrum of diseases with some common magnetic resonance imaging (MRI) features. Risk factors include immunocompromise of any cause and living in endemic areas. CNS infection occurs through hematogenous spread, cerebrospinal fluid seeding, or direct extension. MRI features include heterogeneous or ring reduced diffusion and weak ring enhancement. Angioinvasive aspergillosis is characterized by multifocal hemorrhagic lesions with reduced diffusion. Cryptococcosis results in gelatinous pseudocyst formation in the basal ganglia. Mucormycosis is characterized by frontal lobe lesions with markedly reduced diffusion. Candidiasis is usually manifest by numerous microabscesses of less than 3 mm occurring at the corticomedullary junction, basal ganglia, or cerebellum. Coccidioidomycosis often results in meningitis with contrast enhancement of the basal cisterns. Blastomycosis and histoplasmosis are rare infections with parenchymal abscesses or meningitis. Recognizing the imaging features of CNS infections allows for early, aggressive treatment of these otherwise rapidly fatal infections.


Interleukin-22: immunobiology and pathology.
Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, γδ T cells, NKT cells, and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has evolved rapidly since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues, including the intestines, lung, liver, kidney, thymus, pancreas, and skin. IL-22 primarily targets nonhematopoietic epithelial and stromal cells, where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function.


Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury.
Optic neuropathies such as glaucoma are characterized by the degeneration of retinal ganglion cells (RGCs) and the irreversible loss of vision. In these diseases, focal axon injury triggers a propagating axon degeneration and, eventually, cell death. Previous work by us and others identified dual leucine zipper kinase (DLK) and JUN N-terminal kinase (JNK) as key mediators of somal cell death signaling in RGCs following axonal injury. Moreover, others have shown that activation of the DLK/JNK pathway contributes to distal axonal degeneration in some neuronal subtypes and that this activation is dependent on the adaptor protein, sterile alpha and TIR motif containing 1 (SARM1). Given that SARM1 acts upstream of DLK/JNK signaling in axon degeneration, we tested whether SARM1 plays a similar role in RGC somal apoptosis in response to optic nerve injury. Using the mouse optic nerve crush (ONC) model, our results show that SARM1 is critical for RGC axonal degeneration and that axons rescued by SARM1 deficiency are electrophysiologically active. Genetic deletion of SARM1 did not, however, prevent DLK/JNK pathway activation in RGC somas nor did it prevent or delay RGC cell death. These results highlight the importance of SARM1 in RGC axon degeneration and suggest that somal activation of the DLK/JNK pathway is activated by an as-yet-unidentified SARM1-independent signal.


Kinase MxMPK4-1 and calmodulin-binding protein MxIQM3 enhance apple root acidification during Fe deficiency.
Iron (Fe) deficiency is a long-standing issue in plant mineral nutrition. Ca2+ signals and the mitogen-activated protein kinase (MAPK) cascade are frequently activated in parallel to perceive external cues, but their interplay under Fe deficiency stress remains largely unclear. Here, the kinase MxMPK4-1, which is induced during the response to Fe deficiency stress in apple rootstock Malus xiaojinensis, cooperates with IQ-motif containing protein3 (MxIQM3). MxIQM3 gene expression, protein abundance, and phosphorylation level increased under Fe deficiency stress. The overexpression of MxIQM3 in apple calli and rootstocks mitigated the Fe deficiency phenotype and improved stress tolerance, whereas RNA interference or silencing of MxIQM3 in apple calli and rootstocks, respectively, worsened the phenotype and reduced tolerance to Fe deficiency. MxMPK4-1 interacted with MxIQM3 and subsequently phosphorylated MxIQM3 at Ser393, and co-expression of MxMPK4-1 and MxIQM3 in apple calli and rootstocks enhanced Fe deficiency responses. Furthermore, MxIQM3 interacted with the central-loop region of the plasma membrane (PM) H+-ATPase MxHA2. Phospho-mimicking mutation of MxIQM3 at Ser393 inhibited binding to MxHA2, but phospho-abolishing mutation promoted interaction with both the central-loop and C terminus of MxHA2, demonstrating phosphorylation of MxIQM3 caused dissociation from MxHA2 and therefore increased H+ secretion. Moreover, Ca2+/MxCAM7 (Calmodulin7) regulated the MxMPK4-1-MxIQM3 module in response to Fe deficiency stress. Overall, our results demonstrate that MxMPK4-1-MxIQM3 forms a functional complex and positively regulates PM H+-ATPase activity in Fe deficiency responses, revealing a versatile mechanism of Ca2+/MxCAM7 signaling and MAPK cascade under Fe deficiency stress.


[Acrodermatitis chronica atrophicans: late manifestation of Lyme borreliosis].
A 71-year-old man was referred to our outpatient clinic because of arthralgia and swelling of his right hand. He also showed a subcutaneous nodule on his left knee. A second patient, a 57-year-old woman, was referred because of painful skin of her legs. Dermatologic examination revealed erythematous livid discoloration on both feet and legs. There were reticular varices, corona flebectatia paraplantaris medialis and minimal pitting oedema. Serology tested positive in both patients for Borrelia and they both recalled tick bites. A third patient, a 73-year-old woman, was referred because of erythema and maculae located at her lower legs and positive Borrelia serology. Pathologic examination was typical for acrodermatitis chronica atrophicans, a late skin manifestation of Lyme borreliosis. In all patients, symptoms improved after treatment with doxycycline for four weeks. A lack of familiarity with this skin condition may lead to unnecessary vascular investigations and considerable delay in adequate treatment.


The impact of telemedicine on the quality and satisfaction with the health care provided during the COVID-19 pandemic in the field of pediatrics with special reference to the surgical professions.
The COVID-19 pandemic has forced healthcare systems around the world to adopt telemedicine at an unprecedented rate. Visits to telemedicine have increased to provide access and maintain continuity of care. Internet access has almost become a necessity, and new technologies allow for the easy flow of data from patient to doctor and vice versa. Doctors of all specialties were forced to adapt to the pandemic and emerging conditions. The provision of surgical services and the learning ability of surgeons are particularly disrupted, and the pediatric surgical community is not exempt. During the pandemic, telemedicine proved to be a viable and safe technique for providing health services. In an environment of a health system that is constantly facing a shortage of resources, effective telemedicine placement can come with a high benefit-cost ratio and quality of care, while ensuring patient satisfaction.


The use of disease-modifying new drugs for multiple sclerosis treatment in private-sector health plans.
The aims of this study were to estimate the effects of demographics, location, severity of multiple sclerosis (MS), comorbidities, plan type, coinsurance levels, and time of entry into the sample on the use of disease-modifying agents. A retrospective analysis of medical claims data from 1996 through 2000 was conducted with a sample of MS patients covered by self-insured, employer-sponsored health plans. Proportional hazard analysis with the SAS procedure for proportional hazards regression was used to estimate the impact of the factors of interest on the use of disease-modifying agents. A simulation was conducted to assess the impact of changing drug copayments on the use of disease-modifying agents for MS. The sample included 1807 patients. Patients were followed for as long as possible, but most were observed for <3 years; the mean (SD) follow-up time was 972.88 (440.59) days. Most factors associated with the use of disease-modifying agents were immutable. They included the following: high severity of illness (only marginally related; P = NS); history of seizures (P = 0.03), depression (P < 0.01), or heart disease (P = 0.01); census region of location (P < 0.01); union membership or association with a union member (P < 0.01); drug copayment requirements (P < 0.05); and year of entry into the sample (P < 0.01). In the simulation, a 50% reduction in drug copayments was associated with an increase of the proportion of patients treated with disease-modifying drugs from 41.2% to 54.7%. Patients' and physicians' preferences for treatment could not be measured directly. The true onset of MS may be unknown for many patients, but this would be the case even if medical records or other data were used for this study. Our analyses showed an association between copayments and the use of disease-modifying drugs for MS. Insurance policies can be tailored to influence the use of disease-modifying drugs, enhancing the quality of care for MS patients and reducing price-related barriers to beneficial treatment. Future research should test whether reducing copayments for MS treatment would reduce the use of other health care services (via better MS treatment that modifies the course of illness), or whether the use of disease-modifying drugs would increase total costs to the plan, resulting in slightly higher premiums.


Dietary patterns and their association with food and nutrient intake in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study.
Dietary pattern analysis has recently received growing attention, as it might be more appropriate in studies of diet-disease associations than the single food or nutrient approach that has dominated past epidemiological research. Factor analysis is a technique which is commonly used to identify dietary patterns within study populations. However, the ability of factor solutions to account for variance of food and nutrient intake has so far remained unclear. The present study therefore explored the statistical properties of dietary patterns with regard to the explained variance. Food intake of 8975 men and 13 379 women, assessed by a food-frequency questionnaire, was aggregated into forty-seven separate food groups. Dietary patterns were identified by principal component analysis and subsequent varimax rotation. Seven factors were retained for both men and women, which accounted for about 31 % of the total variance. The explained variance was relatively high (>40 %) for cooked vegetables, sauce, meat, dessert, cake, bread other than wholemeal, raw vegetables, processed meat, high-fat cheese, butter and margarine. Factor scores were used to investigate associations between the factors and nutrient intake. The patterns accounted for relatively large proportions of variance of energy and macronutrient intake, but for less variance of alcohol and micronutrient intake, especially of retinol, beta-carotene, vitamin E, Ca and ascorbic acid. In addition, factors were related to age, BMI, physical activity, education, smoking and vitamin and mineral supplement use.


[Tick-borne encephalitis in the Estonian SSR].
The foci of tick-borne encephalitis (TBE) of 2 types, differing in their morbidity rates, the character of their immunological structures, the species composition of carrier mites and their capacity for TBE virus carriership, have been shown to exist in Estonia. TBE morbidity is characterized by 4- to 5-year cycles, the overwhelming majority of TBE cases being registered in the area of the joint habitat of both species of mites. During the epidemic season 2 peaks of morbidity rise are registered, which corresponds to peaks in the number of mites in nature. Different epidemic importance of 2 species of carrier mites in TBE morbidity in Estonia has been shown.


Derm diagnoses you can't afford to miss.
Management of hereditary angioedema should include fresh frozen plasma containing C1 inhibitor (C1-INH), whenever possible; if C1-INH-containing plasma is unavailable, fresh frozen plasma can be used instead. Do not give neomycin to patients with suspected cellulitis; the drug may promote antibiotic resistance in Staphylococcus aureus, a pathogen often associated with this condition. Whenever a patient presents with erythematous skin lesions and a recent history of receiving penicillin or a cephalosporin antibiotic, a sulfa derivative, or an anticonvulsant, the suspected medication should be stopped until Stevens-Johnson syndrome is ruled out.


[Stereologic analysis of the respiratory zone of the lungs of the laboratory rat and man during aging].
By means of stereological analysis methods, lungs of mature and ageing laboratory rats and those of human beings at the age of 21-40, 41-60 and further have been studied. During the process of ageing the fraction of nonparenchymatous structures increases, while that of parenchyma decreases. Architectonics of acini is described: the volume of central passages increases and the volume of alveolar air decreases. The form of the alveoli approaches the spherical one. The area of the internal surface and the alveolar volume increase. The total number of the alveoli and the area of the respiratory lining decrease. The total number of the alveolar capillaries does not change, however, the density of their distribution grows small. The area and volume of a separate segment of the alveolar capillaries grow large. The age rearrangement of the respiratory zone morphologically differs from the changes that are observed at the obstructive emphysema.


Pulse-voltammetric glucose detection at gold junction electrodes.
A novel glucose sensing concept based on the localized change or "modulation" in pH within a symmetric gold-gold junction electrode is proposed. A paired gold-gold junction electrode (average gap size ca. 500 nm) is prepared by simultaneous bipotentiostatic electrodeposition of gold onto two closely spaced platinum disk electrodes. For glucose detection in neutral aqueous solution, the potential of the "pH-modulator" electrode is set to -1.5 V vs saturated calomel reference electrode (SCE) to locally increase the pH, and simultaneously, either cyclic voltammetry or square wave voltammetry experiments are conducted at the sensor electrode. A considerable improvement in the sensor electrode response is observed when a normal pulse voltammetry sequence is applied to the modulator electrode (to generate "hydroxide pulses") and the glucose sensor electrode is operated with fixed bias at +0.5 V vs SCE (to eliminate capacitive charging currents). Preliminary data suggest good linearity for the glucose response in the medically relevant 1-10 mM concentration range (corresponding to 0.18-1.8 g L(-1)). Future electroanalytical applications of multidimensional pulse voltammetry in junction electrodes are discussed.


[The first episode of psychosis in juvenile patients: personality features and cognitive functioning].
A systemic study of personality features and cognitive processes based on the conception of pathopsychological syndrome has been conducted in patients with the first episode of juvenile endogenous psychosis. The association between characteristics of a pathopsychological syndrome and clinically determined premorbid features has been identified. The highest expression of schizotypal features (reduced selectivity, social perception) and cognitive impairment (motivation, mental activity regulation, adequate self-esteem, emotional reaction to success/failure) were characteristic of a group named "deficit variant of pseudopsychopathy" which contained a large number of passive schizoids. It has been shown that premorbid personality features are most distinct in initial stages of disease ("pathos" factors). "Nosos" factors are implicit and can be only presumably regarded as predictors of disease course.


Defining the optimal response criteria for the Crohn's disease activity index for induction studies in patients with mildly to moderately active Crohn's disease.
The Crohn's Disease Activity Index (CDAI) is used to judge efficacy in clinical trials. We explored the effect of CDAI response definitions for induction on study efficiency. We analyzed primary CDAI data from induction studies in patients with mildly to moderately active Crohn's disease, not receiving concomitant aminosalicylates, corticosteroids, or immunomodulator therapy, and without fistulizing or stricturing complications. The 12 definitions of clinical response included: CDAI decrease from baseline by 50, 70, 100, or 150 points; decrease by 25% from baseline and by 70 or 100 points; CDAI <100 or 150 points; CDAI <150 points plus decrease by 70 or 100 points; CDAI <150 points at any time sustained for the duration of the trial; or decrease in the CDAI by 70 points for the last two consecutive visits. Response definitions were ranked according to ability to optimize the effect difference between treatment arms. The effect of time, baseline disease activity (CDAI 200-299 or > or =300 points), and previous surgical resections on response definitions were evaluated and ranked. Multivariate analysis on additional factors of age (<40 or > or =40 yr), gender and duration of disease (<2 or > or =2 yr) were performed to determine predictors of response when applied to these CDAI definitions. Treatment effect differences in placebo-controlled studies were maximized by response definitions that incorporated either a decrease CDAI > or =70 points for the last two consecutive visits or decrease in baseline CDAI > or =100 points, and remained optimal when evaluated for the composite effect of time, baseline activity, and prior resections. A decrease in baseline CDAI > or =100 points had some advantages over a decrease CDAI > or =70 points over two visits in terms of study efficiency, as it produced a lower control response rate and was not influenced by any of the baseline factors. Clinical trial efficiency for induction studies in patients with mildly to moderately active Crohn's disease can be improved by using either a decrease in CDAI by > or =70 points for the last two consecutive visits or a decrease in baseline CDAI by > or =100 points as the primary end point for the trial. These findings are valid for patients with ileocecal Crohn's disease not refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients who do not have stricturing or penetrating complications. It is unclear if these CDAI response criteria would similarly increase study efficiency in trials that recruited patients with moderately to severely active disease, patients refractory to aminosalicylates, corticosteroids, immunomodulators, and biologics, and patients with stricturing or penetrating complications.


Photonic analog-to-digital converters.
This paper reviews over 30 years of work on photonic analog-to-digital converters. The review is limited to systems in which the input is a radio-frequency (RF) signal in the electronic domain and the output is a digital version of that signal also in the electronic domain, and thus the review excludes photonic systems directed towards digitizing images or optical communication signals. The state of the art in electronic ADCs, basic properties of ADCs and properties of analog optical links, which are found in many photonic ADCs, are reviewed as background information for understanding photonic ADCs. Then four classes of photonic ADCs are reviewed: 1) photonic assisted ADC in which a photonic device is added to an electronic ADC to improve performance, 2) photonic sampling and electronic quantizing ADC, 3) electronic sampling and photonic quantizing ADC, and 4) photonic sampling and quantizing ADC. It is noted, however, that all 4 classes of "photonic ADC" require some electronic sampling and quantization. After reviewing all known photonic ADCs in the four classes, the review concludes with a discussion of the potential for photonic ADCs in the future.


Perturbations in the apoptotic pathway and mitochondrial network dynamics in peripheral blood mononuclear cells from bipolar disorder patients.
Bipolar disorder (BD) is a severe psychiatric disorder characterized by phasic changes of mood and can be associated with progressive structural brain change and cognitive decline. The numbers and sizes of glia and neurons are reduced in several brain areas, suggesting the involvement of apoptosis in the pathophysiology of BD. Because the changes in mitochondrial dynamics are closely related with the early process of apoptosis and the specific processes of apoptosis and mitochondrial dynamics in BD have not been fully elucidated, we measured the apoptotic pathway and the expression of mitochondrial fission/fusion proteins from BD patients and healthy controls. We recruited 16 patients with BD type I and sixteen well-matched healthy controls and investigated protein levels of several pro-apoptotic and anti-apoptotic factors, as well as the expression of mitochondrial fission/fusion proteins in peripheral blood mononuclear cells (PBMCs). Our results showed that the levels of the anti-apoptotic proteins Bcl-xL, survivin and Bcl-xL/Bak dimer were significantly decreased, while active caspase-3 protein levels were significantly increased in PBMCs from BD patients. Moreover, we observed the downregulation of the mitochondrial fusion-related proteins Mfn2 and Opa1 and the upregulation of the fission protein Fis1 in PBMCs from BD patients, both in terms of gene expression and protein levels. We also showed a significantly decrease in the citrate synthase activity. Finally, we found a positive correlation between Mfn2 and Opa1 with mitochondrial content markers, as well as a negative correlation between mitochondrial fission/fusion proteins and apoptotic markers. Overall, data reported here are consistent with the working hypothesis that apoptosis may contribute to cellular dysfunction, brain volume loss and progressive cognitive in BD. Moreover, we show an important relationship between mitochondrial dynamics and the cell death pathway activation in BD patients, supporting the link between mitochondrial dysfunction and the pathophysiology of BD.