Analysis of nucleotide sequence of the rightmost 43 kbp of herpesvirus saimiri (HVS) L-DNA: general conservation of genetic organization between HVS and Epstein-Barr virus.
We present an analysis of 43,658 bp of contiguous nucleotide sequence comprising the right terminal region (conventional orientation) of the unique protein-coding component (L-DNA) of the herpesvirus saimiri (HVS) genome. Within this region lie the genes encoding the 160-kDa virion protein, which is homologous to the 140-kDa membrane antigen of Epstein-Barr virus (EBV), thymidylate synthase (TS), and the immediate-early (IE) 52-kDa protein which is homologous to the EBV BMLF1 product. The 160-kDa gene of HVS lies at the right terminus of HVS L-DNA, its homologue in EBV occurring at the left terminus of the EBV genome (conventional orientation). The TS gene of HVS occurs within a group of 5 genes that have no homologues in EBV. The translation product of one of these genes, ECRF3, shows amino acid sequence and hydrophobicity pattern similarities to the HCMV and cellular G-protein-coupled receptor family of proteins. Another, ECLF2, is homologous to the cyclin family of cellular proteins. The 5 nonconserved genes lie adjacent to the 160-kDa gene. In EBV, the region to the right of the 140-kDa gene (BNRF1) contains the latent replication origin (OriP) and the open reading frames BCRF1, BWRF1 (repeated 12 times), BYRF1, BHLF1, and BHRF1, counterparts of which are not present in this position in HVS. The subsequent 18 genes in EBV (BFLF2 to BLRF2, approximate positions 56,000-89,500) are represented in HVS, and the relative positions and orientations of these genes are directly comparable between the two viruses. There then occurs a nonhomologous gene in HVS, and genes BLLF2 to BZLF1 (positions 89,500 to 103,200) in EBV which are not present in this region of HVS, before collinearity resumes. Thus, the HVS sequence presented here shows general collinearity between conserved genes in the right terminal region of HVS and the left terminal region of EBV and reveals the presence of two sets of unique genes which occur in exactly analogous positions in HVS and EBV.


A case-control study of microRNA polymorphisms in gastric cancer screening by SNP chip combined with time of flight mass spectrometry.
Aims: To explore new SNP sites of miRNAs associated with gastric cancer, thereby providing valuable biomarkers to diagnose and screen gastric cancer. Materials & methods: A 1:1 case-control study was carried out. Microarrays were used to screen the SNP loci of miRNAs in the genomes of matched pairs of patients, 96 with gastric cancer and 96 healthy controls. For validation, mass spectrometry was used to classify miRNA SNP loci in 622 pairs of subjects. Results: rs7143252 was linked to a higher occurrence of gastric cancer. Conclusion: These results suggest that rs7143252 could be used as a specific biomarker to diagnose and screen gastric cancer.


A three-year longitudinal study of retinal function and structure in patients with multiple sclerosis.
Researchers have in recent years begun to investigate ophthalmological manifestations of multiple sclerosis (MS) other than optic neuritis (ON), and it is now clear that changes to retinal function (measured using the electroretinogram, ERG) and structure (measured using optical coherence tomography, OCT) are found in MS patients irrespective of prior ON episodes. ERG results are consistent with dysfunctional bipolar cells, as in other autoimmune diseases. To date, studies have presented only cross-sectional data regarding ERG and OCT. We, therefore, studied the longitudinal course of ERG and OCT in patients with MS, as well as the effect of disability changes and non-ON clinical relapses on these functional and structural measures. MS patients (n = 23) participating in an ongoing longitudinal observational study were invited to take part in a 3-year ophthalmological substudy. ERG and OCT were performed, and measures of MS-related disability and relapse history were obtained. Study visits were repeated annually. ERG peak times, rod b-wave amplitude, mixed rod/cone and cone b-/a-wave amplitude ratios, thickness of the peripapillary retinal nerve fibre layer, and volumes of the segmented retinal layers/complexes were analysed. Using generalised estimating equation models adjusted for age, ON, and MS treatment status, we assessed changes to ERG and OCT over the study duration, the effect of changes in disability and recent non-ON MS relapses on ERG and OCT, and the effect of selected OCT parameters on corresponding ERG parameters. At the group level, small fluctuations of several ERG peak times were recorded, with OCT values remaining stable. Increased disability between visits was associated with significant prolongation of mixed rod-cone ERG b-wave peak times. No evidence of associations between OCT and ERG parameters was observed. Retinal bipolar cell function may be affected by changes in disability in patients with MS; however, recent non-ON MS clinical relapses appear not to affect ERG or OCT results. As ERG changes in MS patients over 3 years are likely to be small and of uncertain clinical relevance, longitudinal studies of retinal function in MS should be planned over an extended period.


Clinical decision support tools: personal digital assistant versus online dietary supplement databases.
Clinical decision support tools (CDSTs) on personal digital assistants (PDAs) and online databases assist healthcare practitioners who make decisions about dietary supplements. To assess and compare the content of PDA dietary supplement databases and their online counterparts used as CDSTs. A total of 102 question-and-answer pairs were developed within 10 weighted categories of the most clinically relevant aspects of dietary supplement therapy. PDA versions of AltMedDex, Lexi-Natural, Natural Medicines Comprehensive Database, and Natural Standard and their online counterparts were assessed by scope (percent of correct answers present), completeness (3-point scale), ease of use, and a composite score integrating all 3 criteria. Descriptive statistics and inferential statistics, including a chi(2) test, Scheffé's multiple comparison test, McNemar's test, and the Wilcoxon signed rank test were used to analyze data. The scope scores for PDA databases were: Natural Medicines Comprehensive Database 84.3%, Natural Standard 58.8%, Lexi-Natural 50.0%, and AltMedDex 36.3%, with Natural Medicines Comprehensive Database statistically superior (p < 0.01). Completeness scores were: Natural Medicines Comprehensive Database 78.4%, Natural Standard 51.0%, Lexi-Natural 43.5%, and AltMedDex 29.7%. Lexi-Natural was superior in ease of use (p < 0.01). Composite scores for PDA databases were: Natural Medicines Comprehensive Database 79.3, Natural Standard 53.0, Lexi-Natural 48.0, and AltMedDex 32.5, with Natural Medicines Comprehensive Database superior (p < 0.01). There was no difference between the scope for PDA and online database pairs with Lexi-Natural (50.0% and 53.9%, respectively) or Natural Medicines Comprehensive Database (84.3% and 84.3%, respectively) (p > 0.05), whereas differences existed for AltMedDex (36.3% vs 74.5%, respectively) and Natural Standard (58.8% vs 80.4%, respectively) (p < 0.01). For composite scores, AltMedDex and Natural Standard online were better than their PDA counterparts (p < 0.01). Natural Medicines Comprehensive Database achieved significantly higher scope, completeness, and composite scores compared with other dietary supplement PDA CDSTs in this study. There was no difference between the PDA and online databases for Lexi-Natural and Natural Medicines Comprehensive Database, whereas online versions of AltMedDex and Natural Standard were significantly better than their PDA counterparts.


Catheter-related sepsis in long-term parenteral nutrition with Broviac catheters. An evaluation of different disinfectants.
From April 1976 to January 1988, 58 patients received home parenteral nutrition for 2-138 months, median 36 months, corresponding to a total treatment period of 233 patient years. Before 1980 and after 1985, 0.5-2% iodine tincture or 0.5% chlorhexidine in 70% ethyl alcohol were used to disinfect the exit site of the catheter and the connections of the infusion line. In these periods the sepsis incidence was 0.25-0.28 per catheter year, corresponding to one episode of sepsis per 3.6-4.0 catheter years. In the period 1980 to 1985, 10% povidone-iodine (Isobetadine) was used, and the incidence in this period was 0.58, corresponding to one episode of sepsis per 1.7 catheter year. This suggests that 10% povidone-iodine may be inferior to iodine-tincture and chlorhexidine alcohol in this type of catheter care. The incidence of catheter sepsis was 0.32 per catheter year when the catheter was placed on the chest and 0.86 per catheter year with the catheter on the thigh. Klebsiella pneumoniae was the most common microorganism grown when the catheter was placed on the thigh, while coagulase-negative staphylococci were most common when the catheter was placed on the chest.


Structural characteristic and molecular docking simulation of fish protein-derived peptides: Recent updates on antioxidant, anti-hypertensive and anti-diabetic peptides.
Over the decade, fish protein-derived peptides (FPDP) have been evaluated for various biological activities including their mechanism of action through structure-activity relationship (SAR) and molecular simulation. SAR studies are known to provide the basic structural information of the active site which can be used for designing synthetic bioactive peptides for application in therapeutics and medicinal purposes. In light of the above discussion, this review discusses the mechanism of action and SAR of the FPDP with a focus on three widely studied bioactive properties including antioxidant, antihypertensive and anti-diabetic activities. The emphasis is given to the recently purified and identified FPDP from various seafood resources. A brief discussion has been made on their structural characteristics and mechanism of action towards antioxidant, angiotensin-I converting enzyme (ACE) inhibition, and dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. Additionally, the importance and future perspective of SAR of food-derived bioactive peptides have been addressed.


Removal of nickel from neutral mine drainage using peat-calcite, compost, and wood ash in column reactors.
The effectiveness of compost, peat-calcite, and wood ash to remove Ni from a circum-neutral-contaminated mine water was tested in continuous flow experiments. Materials were compared in 4.8-L columns at hydraulic residence times (HRT) of ∼ 16.5 h over the course of 2.5-4 months. During this period, all columns successfully treated over 400 L of synthetic contaminated neutral drainage (4.05 mg/L Ni), mainly through sorption processes. Mid-column results (HRT ∼ 9 h) indicated that wood ash was the most effective material for Ni removal, and chemical extractions revealed that retained Ni was less mobile in this spent material. The pH-increasing properties of wood ash played a major role in this material's performance, but a pH correction would be required in the initial stages of full-scale treatment to maintain the effluent within regulatory limits (6-9.5). Scaled to full-sized, mid-column results indicated that treatment cell sizes, designed for the 1-year treatment of a high discharge (10 m3/h)-contaminated effluent (4.05 mg/L Ni), would be the smallest with wood ash (< 500 m3), followed by compost (600 ± 140 m3) and peat-calcite (720 ± 50 m3).


Antibody response against SARS-CoV-2 variants of concern in children infected with pre-Omicron variants: An observational cohort study.
Despite that pediatric COVID-19 is usually asymptomatic or mild, SARS-CoV-2 infection typically results in the development of an antibody response. Contradictory observations have been reported when the antibody response of children and adults were compared in terms of strength, specificity and perdurability. This observational study includes three cohorts infected with SARS-CoV-2 between March 2020-July 2021: unvaccinated infected children (n=115), unvaccinated infected adults (n=62), and vaccinated infected children (n=76). Plasma anti-spike IgG antibodies and neutralising activity against Wuhan, Delta and Omicron variants after 7-17 months post-infection were analysed. More than 95% of unvaccinated infected children and adults remained seropositive when evaluated at 382-491 and 386-420 days after infection, respectively. Anti-spike IgG titers and plasma neutralising activity against Wuhan, Delta and Omicron variants were higher in children compared to adults. No differences were found when unvaccinated infected children were stratified by age, gender or presence/absence of symptoms in the acute phase of SARS-CoV-2 infection, but a slight decrease in the antibody response was observed in those with comorbidities. Vaccination of previously infected children with two doses of the inactivated BBIBP-CorV or the mRNA vaccines, BNT162b2 and/or mRNA-1273, further increased anti-spike IgG titers and neutralising activity against Wuhan, Delta and Omicron variants. Unvaccinated infected children mount a more potent and sustained antibody response compared with adults, which is significantly increased after vaccination. Further studies including not only the analysis of the immune response but also the effectiveness to prevent reinfections by the different Omicron lineages are required to optimise vaccination strategy in children. National Agency for Scientific and Technological Promotion from Argentina (PICTO-COVID-SECUELAS-00007 and PMO-BID-PICT2018-2548).


Regulation of p97 in the ubiquitin-proteasome system by the UBX protein-family.
The AAA protein p97 is a central component in the ubiquitin-proteasome system, in which it is thought to act as a molecular chaperone, guiding protein substrates to the 26S proteasome for degradation. This function is dependent on association with cofactors that are specific to the different biological pathways p97 participates in. The UBX-protein family (ubiquitin regulatory X) constitutes the largest known group of p97 cofactors. We propose that the regulation of p97 by UBX-proteins utilizes conserved structural features of this family. Firstly, they act as scaffolding subunits in p97-containing multiprotein complexes, by providing additional interaction motifs. Secondly, they provide regulation of multiprotein complex assembly and we suggest two possible models for p97 substrate recruitment in the UPS pathway. Lastly, they impose constraints on p97 and its interaction with substrates and further cofactors. These features allow the regulation, within the UPS, of the competitive interactions on p97, a regulation that is crucial to allow the diverse functionality of p97.


Development of DNA polymer films as a drug delivery system for the treatment of oral cancer.
DNA polymer films (DNA-PFs) hold promise for use in drug delivery systems (DDS). In this study, the growth pattern of oral squamous cell carcinoma (OSCC) cells was evaluated on DNA-PFs incorporated with a photoactive compound chlorine aluminum phthalocyanine (DNA-PFs-AlClPc) and the efficacy of DNA-PFs-AlClPc as a DDS for photodynamic therapy (PDT) for the treatment of mucosal cancer. Flow cytometry was used to evaluate cell viability following application of DNA-PFs-AlClPc during PDT; the results demonstrated a positive response to photo stimulation within the range of light doses used (300, 600, and 1200 mJ/cm2). Reduced viability and increased cell death were observed with increasing doses than in the controls. As expected, the viability was reduced by more than 30% at the highest dose (1200 mJ/cm2). Flow cytometry revealed that the main mechanism of cell death induction was apoptosis (early and late apoptosis). These results demonstrate the potential of applying DNA-PFs-AlClPc as a DDS for other active molecules in the treatment of other pathologies. Furthermore, this system allows other drugs to be associated with DNA-PFs, indicating the potential use of this nanostructure in novel ways for the treatment of different neoplasms, such as oral cancer. Additionally, DNA nanostructured films may be used to support cell growth and subsequently as a "curative material" incorporated with an active or photoactive compound that can induce tissue regeneration. Graphical abstract .


Experimental gram-negative septicemia: thromboplastin generation in mononuclear phagocytes from different anatomical sites.
Rats were subjected to gram-negative septicemia induced by cecal perforation or were sham-operated. Thromboplastin values increased in blood monocytes (40-fold), peritoneal macrophages (115-fold) pleural macrophages (5-fold), splenic macrophages (3-fold), and lung alveolar macrophages (1.4-fold) in septic animals as compared to controls. In septic animals disseminated intravascular coagulation was evidenced by a significant (p less than 0.05) fall in fibrinogen, factor VII, X and platelets. A simultaneous and significant (p less than 0.05) decrease in thromboplastin content of tissue-specimens from lung and spleen was observed in rats with septicemia, whereas increased thromboplastin values were demonstrated in tissue-samples from cecum - the infectious focus. This might reflect mobilization of mononuclear phagocytes in favour of the site of infection.


Comparison of prognostic importance of latest CD4+ cell count and HIV RNA levels in patients with advanced HIV infection on highly active antiretroviral therapy.
The comparative prognostic importance of latest plasma HIV RNA levels (viral loads) and CD4+ cell counts among patients prescribed highly active antiretroviral therapy (HAART) has not been well characterized. We assessed the prognostic value of latest CD4+ cell counts and latest viral loads for progression to AIDS or death and explored their interaction among 432 HIV-infected persons with advanced HIV who were prescribed a protease inhibitor (PI) as their first HAART regimen. Pre-HAART median CD4+ cell count and viral load were 41 cells/mm3 and 126,331 copies/mL, respectively. After 12 months of HAART, the median CD4+ cell count was 154 cells/mm3; 39% of patients had a viral load of 400 copies/mL or lower. Over a median follow-up of 33 months, 109 (25%) of the 432 patients experienced an AIDS event or died. The hazard ratio for AIDS or death for those with latest CD4+ cell count <50 cells/mm3 versus > or =200 cells/mm3 was 13.9 (95% CI 6.5 to 29.7) without adjustment for latest viral load measurements and 9.5 (95% CI 4.0 to 22.5) after adjustment for latest viral load. In contrast, the hazard ratio for AIDS or death for those with viral load > or =100,000 versus <400 copies/mL was 4.2 (95% CI 2.3 to 7.7) without adjustment for latest CD4+ level and 1.2 (95% CI 0.6 to 2.4) with adjustment for latest CD4+ cell count. We conclude that when latest CD4+ cell count and viral load are considered separately, both are significantly related to AIDS or death; when these markers are jointly considered, the association of viral load with AIDS or death is substantially diminished. Latest CD4+ levels are more strongly related to AIDS or death than latest viral load levels in patients on HAART.


Grassland greening impacts on global land surface temperature.
Grassland vegetation greenness has been increasing globally during the past decades. Although the vegetation coverage change could have significant effects on climate by affecting albedo and evapotranspiration (ET), the effects of global grassland greening on climate remain unclear due to the lack of long-term field observation data. Here, we used satellite measurements of land surface temperature (LST) from high coverage grassland and adjacent low coverage grassland (divided according to the leaf area index) to quantify, for the first time, the biogeophysical effects of global grassland greening on surface temperatures. Results showed that grassland greening decreased the annual mean LST and daytime LST (LSTD), but did not significantly change nighttime LST (LSTN) globally from 2003 to 2017. Spatially, grassland greening had significant cooling effects on the annual mean LST and LSTD for latitudes south of 50°N due to the cooling effect of increased ET, whereas warming affects on the annual mean LST and LSTD in the high northern latitudes (> 50°N) because of the warming effects of decreased albedo. This study revealed that the effects of grassland greening on surface temperatures changed with latitude. During June, July, and August (JJA), the increasing grassland vegetation coverage decreased the LST between 25°S and 50°N, but increased the mean LST in high northern latitudes. By contrast, grassland greening has no significant effect on the mean LST in the temperate southern hemisphere (> 25°S) during JJA due to cooling and warming effects on LSTD and LSTN, respectively. During December, January, and February, grassland greening decreased the mean LST and LSTD for latitudes south of 25°N, but increased the mean LST and LSTN for latitudes north of 25°N. This study highlights the importance of including grassland vegetation coverage in models of regional surface temperature dynamics and future climate forecast.


Hormonally induced tumors of the reproductive system of parabiosed male rats.
Parabiosis of intact male rats to castrated males or oophorectomized females for a period of approximately 20 months resulted in three interstitial cell tumors of the testis. When unilateral nephrectomy was added to the parabiotic procedure in ten pairs, eight interstitial cell tumors of the testis and four adenocarcinomas of the prostate occurred in the target male parabionts. These changes were preceded by elevations in luteinizing and follicle-stimulating hormone levels in the serum of the castrates and high levels of testosterone and, to a lesser degree, of androstenedion in the target partners developing the tumors.


Application of deep learning to auto-delineation of target volumes and organs at risk in radiotherapy.
The technological advancement heralded the arrival of precision radiotherapy (RT), thereby increasing the therapeutic ratio and decreasing the side effects from treatment. Contour of target volumes (TV) and organs at risk (OARs) in RT is a complicated process. In recent years, automatic contouring of TV and OARs has rapidly developed due to the advances in deep learning (DL). This technology has the potential to save time and to reduce intra- or inter-observer variability. In this paper, the authors provide an overview of RT, introduce the concept of DL, summarize the data characteristics of the included literature, summarize the possible challenges for DL in the future, and discuss the possible research directions.


Partial protection from fluctuating selection leads to evolution towards wider population size fluctuation and a novel mechanism of balancing selection.
When a population is partially protected from fluctuating selection, as when a seed bank is present, variance in fitness will be reduced and reproductive success of the population will be promoted. This study further investigates the effect of such a 'refuge' from fluctuating selection using a mathematical model that couples demographic and evolutionary dynamics. While alleles that cause smaller fluctuations in population density should be positively selected according to classical theoretic predictions, this study finds the opposite: alleles that increase the amplitude of population size fluctuation are positively selected if population density is weakly regulated. Under strong density regulation with a constant carrying capacity, long-term maintenance of polymorphism caused by the storage effect emerges. However, if the carrying capacity of the population is oscillating, mutant alleles whose fitness fluctuates in the same direction as population size are positively selected, eventually reaching fixation or intermediate frequencies that oscillate over time. This oscillatory polymorphism, which requires fitness fluctuations that can arise with simple trade-offs in life-history traits, is a novel form of balancing selection. These results highlight the importance of allowing joint demographic and population genetic changes in models, the failure of which prevents the discovery of novel eco-evolutionary dynamics.


Dorsal premotor areas of nonhuman primate: functional flexibility in time domain.
A voluntary motor act requires recognition of the informational content of an instruction. An instruction may contain spatial and temporal information. The recently proved role of the monkey frontal cortex in time computation, as well as in motor preparation and motor learning, suggested that we investigate the relationship between premotor neuron discharges and the temporal feature of the visual instructions. To this purpose, we manipulated the duration of an instructional cue in a visuomotor task while recording unit activity. We found two types of premotor neurons characterised by a discharge varying in relation to the duration of the cue: (1) "motor-linked" neurons, with a specific premotor activity constantly bounded to the motor act; (2) "short-term encoders" neurons, with a premotor activity depending on the cue duration. The cue duration was the critical factor in determining the behaviour of the short-term encoders cells: when the cue ranged from 0.5 s to 1 s, they presented a preparatory activity; when the cue was longer, up to 2 s, they lost their preparatory activity; when the cue was blinked the cells anticipated their discharge. The activity changed in few trials. These data confirm and highlight the role of frontal cortex in encoding specific cues with a temporal flexibility, which may be the expression of temporal learning and represent an extended aspect of cortical plasticity in time domain.


Nrf2 deficiency deteriorates diabetic kidney disease in Akita model mice.
Oxidative stress is an essential component in the progression of diabetic kidney disease (DKD), and the transcription factor NF-E2-related factor-2 (Nrf2) plays critical roles in protecting the body against oxidative stress. To clarify the roles of Nrf2 in protecting against DKD, in this study we prepared compound mutant mice with diabetes and loss of antioxidative defense. Specifically, we prepared compound Ins2Akita/+ (Akita) and Nrf2 knockout (Akita::Nrf2-/-) or Akita and Nrf2 induction (Akita::Keap1FA/FA) mutant mice. Eighteen-week-old Akita::Nrf2-/- mice showed more severe diabetic symptoms than Akita mice. In the Akita::Nrf2-/- mouse kidneys, the glomeruli showed distended capillary loops, suggesting enhanced mesangiolysis. Distal tubules showed dilation and an increase in 8-hydroxydeoxyguanosine-positive staining. In the Akita::Nrf2-/- mouse kidneys, the expression of glutathione (GSH) synthesis-related genes was decreased, and the actual GSH level was decreased in matrix-assisted laser desorption/ionization mass spectrometry imaging analysis. Akita::Nrf2-/- mice exhibited severe inflammation and enhancement of infiltrated macrophages in the kidney. To further examine the progression of DKD, we compared forty-week-old Akita mouse kidney compounds with Nrf2-knockout or Nrf2 mildly induced (Akita::Keap1FA/FA) mice. Nrf2-knockout Akita (Akita::Nrf2-/-) mice displayed severe medullary cast formation, but the formation was ameliorated in Akita::Keap1FA/FA mice. Moreover, in Akita::Keap1FA/FA mice, tubule injury and inflammation-related gene expression were significantly suppressed, which was evident in Akita::Nrf2-/- mouse kidneys. These results demonstrate that Nrf2 contributes to the protection of the kidneys against DKD by suppressing oxidative stress and inflammation.


Actinobaculum massiliae: a new cause of superficial skin infection.
Actinomycete-like organisms are well recognised members of normal mucosal flora but some strains are thought to contribute to commensal skin flora too. From here they may become pathogenic. The actinomyces family has undergone significant taxonomic revision in recent years. A new species, Actinobaculum massiliae, closely related to Actinomyces spp., was first discovered in 2002. This case describes only the second human infection and the first reported skin infection due to this organism, whose normal habitat is currently unknown.


Determination of antibodies against cytomegalovirus-induced early antigens by using rabbit lung fibroblasts. Brief report.
The determination of antibodies against cytomegalovirus-induced antigens in 30 patients with acute cytomegalovirus infection and in 100 healthy control persons, using early antigen preparations of human lung fibroblasts and of rabbit lung fibroblasts, yielded results showing a high degree of agreement. For such investigations, however, the use of rabbit cells proved to be of advantage because the preparation of the early antigens can be carried out without inhibition of the DNA synthesis of the host cells.


Thalidomide: an old drug with new action.
Thalidomide is a drug that, since its development, has made history in the world of medicine--having been withdrawn and now has returned with a boom as an anticancer and immunomodulatory drug. However, its mode of action in various diseases (i.e. different types of hematologic malignancies, solid tumors) as well as in various infections (i.e. pneumonia, tuberculosis, HIV infection etc.) and related inflammatory conditions is not well understood. As the immune system plays an important role in the pathogenesis of both infection-related as well as noninfectious (i.e. cancer) inflammatory diseases, much research has been done in the past few years to discover and design better immunomodulatory agents. Such immunomodulatory agents should be able to target the immune system in such a way that host suffers minimum damage and normal function of the immune system remains intact. In the present review an attempt is made to highlight the immunomodulatory action of thalidomide in various pathologic conditions.


Immunological heterogeneity of the RCC microenvironment: do targeted therapies influence immune response?
The introduction of targeted agents has substantially improved treatment of metastatic clear-cell renal cell carcinoma (RCC). However, complete responses are rare and therapy is not curative. Moreover, information on the latest generation of potent and selective vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) suggests that a plateau has been reached in terms of efficacy. Recent data reveal that targeted agents are involved in modulating immune responses in RCC. In addition, current research adds to our understanding of how RCC escapes an effective anti-tumor response with the potential to modulate these processes by drug development. This review provides specific insight into targeted therapy induced changes in the immunological microenvironment of RCC, summarizes the available evidence, and discusses potential therapeutic implications.


From Natural Product to the First Oral Treatment for Multiple Sclerosis: The Discovery of FTY720 (Gilenya™)?
Multiple sclerosis is a devastating chronic autoimmune disease affecting women and men of all ages. Inflammation of the central nervous system causes demyelination and ultimately neuropsychological dysfunction. Myriocin, a natural product with strong immunosuppressant activity was interrogated leading to a new class of immunomodulator with a unique mode of action. In this review, we will summarize these findings, the mechanism hypothesis and discuss the data's ultimately leading to the approval of Gilenya™ as the first oral treatment for multiple sclerosis.


Perioperative protocols in ambulatory breast reconstruction: A systematic review.
Recent studies have successfully employed perioperative protocols and Enhanced Recovery After Surgery (ERAS) protocols to promote and increase the range of breast reconstruction procedures performed in ambulatory settings. This systematic review aims to identify the common perioperative protocol items associated with successful ambulatory breast reconstruction. A systematic review of electronic databases (Ovid Medline, EMBASE, and Cochrane) was conducted. Studies that described the perioperative care protocol for postmastectomy breast reconstruction in ambulatory settings (discharge within 24 h) were included. Two reviewers independently screened the literature and extracted the data. Risk of bias was assessed with the National Heart, Lung, and Blood Institute quality tool. The perioperative protocol details, type of reconstruction, information regarding patient selection criteria, successful discharge rates, and complication rates were extracted. Twelve studies were included in the systematic review, with 1484 patients undergoing ambulatory breast reconstruction with a well-defined perioperative protocol. Sixteen perioperative items were identified. The most discussed items were preoperative counseling (11/12), preoperative and intraoperative multimodal analgesia (11/12), and postoperative analgesia (10/12). Our recommendation includes two new items and seven modified items compared to previous ERAS guidelines. Overall, the mean number of items was 9.22 in same-day discharge and 6.75 in 24-h discharge (P = 0.169). 78.4% of the patients (1123 of 1433) were successfully discharged within 24 h. No studies identified an increase in readmission or complications with ambulatory discharge. Sixteen core items were defined for a successful perioperative ERAS protocol for 24-h discharge breast reconstruction. Implementing perioperative protocols can facilitate under-24-h discharge for alloplastic and autologous surgery.


Glomerular endothelial cell-podocyte stresses and crosstalk in structurally normal kidney transplants.
Increased podocyte detachment begins immediately after kidney transplantation and is associated with long-term allograft failure. We hypothesized that cell-specific transcriptional changes in podocytes and glomerular endothelial cells after transplantation would offer mechanistic insights into the podocyte detachment process. To test this, we evaluated cell-specific transcriptional profiles of glomerular endothelial cells and podocytes from 14 patients of their first-year surveillance biopsies with normal histology from low immune risk recipients with no post-transplant complications and compared these to biopsies of 20 healthy living donor controls. Glomerular endothelial cells from these surveillance biopsies were enriched for genes related to fluid shear stress, angiogenesis, and interferon signaling. In podocytes, pathways were enriched for genes in response to growth factor signaling and actin cytoskeletal reorganization but also showed evidence of podocyte stress as indicated by reduced nephrin (adhesion protein) gene expression. In parallel, transcripts coding for proteins required to maintain podocyte adherence to the underlying glomerular basement membrane were downregulated, including the major glomerular podocyte integrin α3 and the actin cytoskeleton-related gene synaptopodin. The reduction in integrin α3 protein expression in surveillance biopsies was confirmed by immunoperoxidase staining. The combined growth and stress response of patient allografts post-transplantation paralleled similar changes in a rodent model of nephrectomy-induced glomerular hypertrophic stress that progress to develop proteinuria and glomerulosclerosis with shortened kidney life span. Thus, even among patients with apparently healthy allografts with no detectable histologic abnormality including alloimmune injury, transcriptomic changes reflecting cell stresses are already set in motion that could drive hypertrophy-associated glomerular disease progression.


DL0410 ameliorates cognitive deficits in APP/PS1 transgenic mice by promoting synaptic transmission and reducing neuronal loss.
At present, few available drugs can be used to either improve pathological features or prevent the progression of Alzheimer's disease (AD). DL0410 ((1,1'-([1,1'-biphenyl]-4,4'-diyl) bis (3-(piperidin-1-yl) propan-1-one) dihydrochloride) is a multiple-target small molecule that has been found to reverse cognitive impairment in different animal models of AD. In this study we evaluated the cognition-improving effects of DL0410 in APP/PS1 transgenic mice and explored the underlying mechanisms. APP/PS1 transgenic mice were administered DL0410 (3, 10, 30 mg· kg-1· d-1, ig) for 2 months. We found that DL0410 administration significantly ameliorated cognitive deficits in both the nest-building and Morris water maze tests. In electrophysiological analysis of hippocampal slices, we showed that DL0410 administration significantly enhanced the field EPSP slope and HFS-induced LTP in CA1 area. Furthermore, we revealed that DL0410 administration significantly increased the phosphorylation of AKT and the activity of GSK-3β in the hippocampus and cortex. Moreover, DL0410 administration dose-dependently increased the expression level of phosphorylated ERK1/2 in the hippocampus and cortex. In addition, DL0410 dose-dependently decreased the neuronal loss by decreasing the production of Aβ deposition, inhibited glial overactivation, and the production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6. We conclude that DL0410 ameliorates cognitive deficits in APP/PS1 transgenic mice by promoting synaptic transmission via activating the AKT/GSK-3β and MAPK/ERK signaling pathway and reducing neuronal loss. DL0410 may be an effective agent for AD treatment in the future.


Identification of defense related gene families and their response against powdery and downy mildew infections in Vitis vinifera.
Grapevine (Vitis vinifera) productivity has been severely affected by various bacterial, viral and fungal diseases worldwide. When a plant is infected with the pathogen, various defense mechanisms are subsequently activated in plants at various molecular levels. Thus, for substantiating the disease control in an eco-friendly way, it is essential to understand the molecular mechanisms governing pathogen resistance in grapes. In our study, we performed genome-wide identification of various defensive genes expressed during powdery mildew (PM) and downy mildew (DM) infections in grapevine. Consequently, we identified 6, 21, 2, 5, 3 and 48 genes of Enhanced Disease Susceptibility 1 (EDS1), Non-Race-specific Disease Resistance (NDR1), Phytoalexin deficient 4 (PAD4), Nonexpressor of PR Gene (NPR), Required for Mla-specified resistance (RAR) and Pathogenesis Related (PR), respectively, in the grapevine genome. The phylogenetic study revealed that V. vinifera defensive genes are evolutionarily related to Arabidopsis thaliana. Differential expression analysis resulted in identification of 2, 4, 7, 2, 4, 1 and 7 differentially expressed Nucleotide-binding leucine rich repeat receptor (NLR), EDS1, NDR1, PAD4, NPR, RAR1 and PR respectively against PM infections and 28, 2, 5, 4, 1 and 19 differentially expressed NLR, EDS1, NDR1, NPR, RAR1 and PR respectively against DM infections in V. vinifera. The co-expression study showed the occurrence of closely correlated defensive genes that were expressed during PM and DM stress conditions. The PM and DM responsive defensive genes found in this study can be characterized in future for impelling studies relaying fungal and oomycete resistance in plants, and the functionally validated genes would then be available for conducting in-planta transgenic gene expression studies for grapes.


Plasma neurofilament light chain in relation to 10-year change in cognition and neuroimaging markers: a population-based study.
Neurofilament light chain (NfL) is a promising biomarker for risk stratification and disease monitoring of dementia, but its utility in the preclinical disease stage remains uncertain. We determined the association of plasma NfL with (change in) neuroimaging markers and cognition in the population-based Rotterdam Study, using linear and logistic regression and mixed-effects models. Plasma NfL levels were measured using the Simoa NF-light™ assay in 4705 dementia-free participants (mean age 71.9 years, 57% women), who underwent cognitive assessment and brain MRI with repeated assessments over a 10-year follow-up period. Higher plasma NfL was associated with worse cognitive performance at baseline (g-factor: β = - 0.12 (- 0.15; - 0.09), p < 0.001), and accelerated cognitive decline during follow-up on the Stroop color naming task (β = 0.04 (0.02; 0.06), p < 0.001), with a smaller trend for decline in global cognition (g-factor β = - 0.02 (- 0.04; 0.00), p = 0.044). In the subset of 975 participants with brain MRI, higher NfL was associated with poorer baseline white matter integrity (e.g., global mean diffusivity: β = 0.12 (0.06; 0.19), p < 0.001), with similar trends for volume of white matter hyperintensities (β = 0.09 (0.02; 0.16), p = 0.011) and presence of lacunes (OR = 1.55 (1.13; 2.14), p = 0.007). Plasma NfL was not associated with volumes or thickness of the total gray matter, hippocampus, or Alzheimer signature regions. In conclusion, higher plasma NfL levels are associated with cognitive decline and larger burden of primarily white matter pathology in the general population.


Effect of 1alpha-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on intestine and bone in glucocorticoid-treated patients.
The effect of 1alpha-hydroxyvitamin D3 (1alpha-OHD3) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on the intestinal calcium absorption was studied in twenty patients with rheumatoid arthritis treated with prednisone at daily doses of 5--15 mg for 1/2--20 years. The fractional calcium absorption, measured before and after the treatment with the vitamin D compounds, increased in nineteen of the twenty patients. This was, however, accompanied by marked rises in the urinary calcium excretion. There was no correlation between the fractional calcium absorption and the duration of the prednisone treatment or the doses given.


Artificial regulatory networks and cascades for discrete multilevel transgene control in mammalian cells.
Prototype drug-adjustable heterologous transcription control systems designed for gene therapy applications typically show sigmoid dose-response characteristics and enable fine-tuning of therapeutic transgenes only within a narrow inducer concentration range of a few nanograms. However, the design of clinical dosing regimes which achieve tissue-specific concentrations with nanogram precision is yet a "mission impossible." Therefore, most of today's transcription control systems operate as ON/OFF switches and not in a true adjustable mode. The availability of robust transcription control configurations which lock expression of a single therapeutic transgene at desired levels in response to fixed clinical doses of different inducers rather than minute concentration changes of a single inducer would be highly desirable. Based on in silico predictions, we have constructed a variety of mammalian artificial regulatory networks by interconnecting the tetracycline- (TET(OFF)), streptogramin- (PIP(OFF)), and macrolide- (E(OFF)) repressible gene regulation systems as linear (auto)regulatory cascades. These networks enable multilevel expression control of several transgenes in response to different antibiotics or allow titration of a single transgene to four discrete expression levels by clinical dosing of a single antibiotic: 1) high expression in the absence of any antibiotic (+++), 2) medium level expression following addition of tetracycline (++), 3) low level expression in response to the macrolide erythromycin (+), and 4) complete repression by streptogramins such as pristinamycin (-). The first-generation artificial regulatory networks exemplify modular interconnections of different heterologous gene regulations systems to achieve multigene expression, fine-tuning, or to design novel control networks with unprecedented transgene regulation properties. Such higher-level transcription control modalities will lead the way towards composite artificial regulatory networks able to effect complex therapeutic interventions in future gene therapy and tissue engineering scenarios.


Idiopathic catatonic syndrome in a young male with no prior psychiatric history: a case report.
Catatonia is a syndrome characterized by severe psychomotor disturbances such as hypomotility, bradykinesia, and unusual movements. The condition has been described in the context of a wide variety of primary disease processes, including psychotic and mood disorders and numerous general medical conditions. In the medical community, catatonia is misunderstood, under-recognized, and under-treated. There continues to be debate about whether catatonia is an independent syndrome or a secondary expression of other conditions. This is a unique case presentation, as there are few reports describing cases of isolated catatonic syndrome in the absence of any other psychiatric or medical condition. We present the case of a 20-year-old previously healthy Caucasian male whose initial presentation to psychiatric care was in the form of an acute catatonic syndrome dominated by mutism, blank staring, and poverty of movement. As the nature of the patient's symptoms precluded the collection of a complete psychiatric and medical history, we employed a broad differential diagnosis including catatonia due to another medical condition, catatonia as a specifier for a number of mental disorders, and catatonia not otherwise specified. The presentation of an acute onset of psychomotor symptoms in the absence of a history of mental illness warrants extensive workup to rule out medical causes to ensure effective treatment of any underlying illness. Benzodiazepines are the first-line treatment for catatonic symptoms, and electroconvulsive therapy can be used to resolve symptoms in patients who do not respond to medical intervention.


Brief Report: Telehealth Satisfaction Among Caregivers of Pediatric and Adult Psychology and Psychiatry Patients with Intellectual and Developmental Disability in the Wake of Covid-19.
Telehealth has been shown to be both acceptable and effective in many areas of healthcare, yet it was not widely adopted prior to the SARS-CoV-2 (COVID-19) pandemic. Additionally, previous evaluations of telehealth for autism spectrum condition (ASC) and intellectual and developmental disability (IDD) populations are limited in both number and scope. Here, we investigated satisfaction amongst Psychology and Psychiatry patient caregivers at Cincinnati Children's Hospital Medical Center (CCHMC) after the onset of the COVID-19 pandemic. Results (640 responses) showed high rates of satisfaction across departments, appointment types, and diagnoses, with 92% indicating overall satisfaction with their appointment. There were, however, notable decreases in satisfaction among Group Therapy respondents, and those whose diagnosis was classified as Other.


Cytogenetic toxicity of neem.
The cytogenetic toxicity of the leaf extract of neem was evaluated in murine germ cells. The extract was found to induce structural and numerical changes in the spermatocyte chromosomes as well as synaptic disturbances in them at their first metaphase. A significant increase in the frequency of sperms with abnormal head morphology and the decrease in mean sperm count were also observed. This spermatotoxic effect of the neem extract corroborates its germ cell mutagenicity. The possible role of azadirachtin, the most active principle present in the neem extract, in producing the observed genotoxic effect is discussed.


Aggregate formation affects ultrasonic disruption of microalgal cells.
Ultrasonication is a cell disruption process of low energy efficiency. This study dosed K(+), Ca(2+) and Al(3+) to Chlorella vulgaris cultured in Bold's Basal Medium at 25°C and measured the degree of cell disruption under ultrasonication. Adding these metal ions yielded less negatively charged surfaces of cells, while with the latter two ions large and compact cell aggregates were formed. The degree of cell disruption followed: control=K(+)>Ca(2+)>Al(3+) samples. Surface charges of cells and microbubbles have minimal effects on the microbubble number in the proximity of the microalgal cells. Conversely, cell aggregates with large size and compact interior resist cell disruption under ultrasonication. Staining tests revealed high diffusional resistance of stains over the aggregate interior. Microbubbles may not be effective generated and collapsed inside the compact aggregates, hence leading to low cell disruption efficiencies. Effective coagulation/flocculation in cell harvesting may lead to adverse effect on subsequent cell disruption efficiency.


Virtual Self-learning Modules Integrating Pharmacology Concepts into a Geriatric Elective.
Given barriers to vertical integration during clinical rotations, many struggle with employing effective virtual strategies to revisit foundational sciences during clerkship. To address this, we developed virtual geriatric pharmacology self-learning modules (SLMs) for a fourth-year geriatric elective using cases, interactive exercises, resources, feedback, and quizzes. To evaluate effectiveness, learners were administered a pre- and post-elective quiz with survey. Learners improved performance after using SLMs, valued pharmacology clerkship integration and reinforcement, and agreed SLMs improved understanding, confidence, and attitudes. Thus, SLMs were an effective virtual method for integrating pharmacology that could be modified to teach other foundational sciences during clerkships.


Dysfunctional Effects of a Conflict in a Healthcare Organization.
Conflicts in healthcare settings are quite common events because of the continuous changes and transformations today's healthcare organizations are undergoing and the vigorous interaction between the medical professionals working in them. To survey the opinions of medical professionals about the possible destructive effects of conflicts on them in the workplace. We conducted a direct individual survey of 279 medical employees at four general hospitals. We used a set of questions that reflect the negative effects and consequences of conflict on healthcare professionals as direct or indirect participants. All data were analysed using the descriptive statistics and non-parametric analysis at a significance level for the null hypothesis of p < 0.05. Workplace conflicts contribute a lot to the stress, psychological tension and emotional exhaustion medical professionals are exposed to. The confrontation the conflict brings the participants into acts as a catalyst of the conflict and enhances the manifestation of hostile actions. A conflict generates a situation which has an impact on the behaviour of all participants involved in it giving rise to emotional states such as anger, aggression and reproaches. The destructive consequences resulting from a conflict are seen in the reduced work satisfaction and demotivation to perform the work activity. The contradictions that arise as a result affect negatively the team cooperation and obstruct the collaborative efforts in solving the problems in the healthcare setting. A conflict in a healthcare setting exerts a considerable destructive effect on an employee, therefore it requires prompt identification and effective intervention to minimise its unfavourable outcomes.


Starvation, Ferroptosis, and Prodrug Therapy Synergistically Enabled by a Cytochrome c Oxidase like Nanozyme.
Nanozymes, which are inorganic nanomaterials mimicking natural enzyme activities, are bringing enormous opportunities to theranostics. Herein, a cytochrome c oxidase-like nanozyme (copper-silver alloy nanoparticle, Cu-Ag NP) is demonstrated for nanocatalytic cancer therapy. Loaded with bioreductive predrug (AQ4N), this Cu-Ag nanozyme unprecedentedly enables simultaneous starvation, ferroptosis, and chemical therapy with high specificity, and is able to totally eliminate tumor and greatly prolong the survival rate for 4T1-tumor-bearing mice. The underlying working mechanism is revealed both experimentally and theoretically.


Step-up fecal microbiota transplantation strategy: a pilot study for steroid-dependent ulcerative colitis.
The strategy of using fecal microbiota transplantation (FMT) for refractory ulcerative colitis (UC) remains unclear if single FMT failed to induce remission. This study aimed to evaluate the efficacy and safety of a designed step-up FMT strategy for the steroid-dependent UC. Fifteen patients with steroid-dependent UC were enrolled, and treated with step-up FMT strategy. Follow-up clinical data was collected for a minimum of 3 months. Fecal microbiota composition before and post FMT of patients and related donors were analyzed by 16S rRNA sequencing. Eight of fourteen (57.1 %) patients achieved clinical improvement and were able to discontinue steroids following step-up FMT. One patient was lost to follow-up. Among the 8 patients who responded, five (35.7 %) received one FMT therapy, one (7.1 %) received two FMTs, and two (14.2 %) received two FMTs plus a scheduled course of steroids. Four (28.6 %) of the 8 patients who responded maintained long-term remission during follow-up (3-18 months). Six patients (42.9 %) failed to meet the criteria of clinical improvement and maintained steroid dependence, though three experienced transient or partial improvement. Microbiota analysis showed that FMT altered the composition greatly, and a microbiota composition highly similar to that of the donor emerged in the patients with successful treatment. No severe adverse events occurred during treatment and follow-up. Step-up FMT strategy shows promise as a therapeutic strategy for patients with steroid-dependent UC, likely due to the successful restructuring of gut microbial composition. ClinicalTrials.gov, Number NCT01790061.


The effectiveness of high-dose intravenous vitamin C for patients with coronavirus disease 2019: A systematic review and meta-analysis.
Vitamin C has anti-inflammatory effects. This review aimed to investigate the therapeutic effect of high-dose intravenous vitamin C (HDIVC) in patients with coronavirus disease 2019 (COVID-19). The following key phrases were searched for article inclusion: "Vitamin C OR ascorbic acid" AND "COVID-19 OR coronavirus disease 2019 OR severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2″. Articles that utilized HDIVC for the management of patients with COVID-19 were included, whereas review articles and case reports were excluded from this review. Moreover, we performed a meta-analysis to evaluate whether HDIVC can reduce the length of hospital stay and in-hospital mortality rate of patients with severe COVID-19. In total, eight articles were included in this review, and five studies were included in the meta-analysis. The length of hospital stay was not significantly different between the HDIVC and control groups. Also, although our meta-analysis showed a tendency for HDIVC to reduce the in-hospital mortality rate in patients with severe COVID-19, the in-hospital mortality rate was not significantly different between patients treated with HDIVC and those who did not receive HDIVC. Evidence supporting the therapeutic use of HDICV in COVID-19 patients is lacking. Further studies are required for drawing a clear conclusion on this topic.


Does the one-leg rise test reflect quadriceps strength in individuals following anterior cruciate ligament reconstruction?
To explore if one-leg rise test performance is associated with quadriceps strength following anterior cruciate ligament reconstruction (ACLR). Cross-sectional. 100 individuals (50 females, 50 males) aged 18-40 years, 9-36 months post-ACLR with ongoing knee symptoms (KOOS4 <80/100). Number of one-leg rise repetitions (using an adjustable-height plinth) and isometric quadriceps strength using isokinetic dynamometry (60° flexion, normalised to body mass). Multivariable fractional polynomial regression models adjusted for sex explored relationships between one-leg rise performance (repetitions) and quadriceps strength (Nm/kg) for each limb. A non-linear, increasing association between one-leg rise performance and quadriceps strength was observed, with the rate of increase attenuating at higher values of one-leg rise performance. Similar relationships were observed in the ACLR (β = 0.15, 95%CI 0.10 to 0.20; adjusted r2 = 0.51) and contralateral limb (β = 0.14, 95%CI 0.08 to 0.19; r2 = 0.42). The one-leg rise test can be an indicator of quadriceps strength in individuals after ACLR, enabling clinicians to easily monitor quadriceps strength recovery without specialised equipment. With the relationship between one-leg rise performance and quadriceps strength attenuating with a larger number of one-leg rises achieved, other factors (e.g., motivation, endurance) likely contribute to one-leg rise performance at higher values.


Role of nitric oxide in the radiation-induced bystander effect.
Cells that are not irradiated but are affected by "stress signal factors" released from irradiated cells are called bystander cells. These cells, as well as directly irradiated ones, express DNA damage-related proteins and display excess DNA damage, chromosome aberrations, mutations, and malignant transformation. This phenomenon has been studied widely in the past 20 years, since its first description by Nagasawa and Little in 1992, and is known as the radiation-induced bystander effect (RIBE). Several factors have been identified as playing a role in the bystander response. This review will focus on one of them, nitric oxide (NO), and its role in the stimulation and propagation of RIBE. The hydrophobic properties of NO, which permit its diffusion through the cytoplasm and plasma membranes, allow this signaling molecule to easily spread from irradiated cells to bystander cells without the involvement of gap junction intercellular communication. NO produced in irradiated tissues mediates cellular regulation through posttranslational modification of a number of regulatory proteins. The best studied of these modifications are S-nitrosylation (reversible oxidation of cysteine) and tyrosine nitration. These modifications can up- or down-regulate the functions of many proteins modulating different NO-dependent effects. These NO-dependent effects include the stimulation of genomic instability (GI) and the accumulation of DNA errors in bystander cells without direct DNA damage.


Impact of maternal protein restriction on Hypoxia-Inducible Factor (HIF) expression in male fetal kidney development.
Kidney developmental studies have demonstrated molecular pathway changes that may be related to decreased nephron numbers in the male 17 gestational days (17GD) low protein (LP) intake offspring compared to normal protein intake (NP) progeny. Here, we evaluated the HIF-1 and components of its pathway in the kidneys of 17-GD LP offspring to elucidate the molecular modulations during nephrogenesis. Pregnant Wistar rats were allocated into two groups: NP (regular protein diet-17%) or LP (Low protein diet-6%). Taking into account miRNA transcriptome sequencing previous study (miRNA-Seq) in 17GD male offspring kidneys investigated predicted target genes and proteins related to the HIF-1 pathway by RT-qPCR and immunohistochemistry. In the present study, in male 17-GD LP offspring, an increased elF4, HSP90, p53, p300, NFκβ, and AT2 gene encoding compared to the NP progeny. Higher labeling of HIF-1α CAP cells in 17-DG LP offspring was associated with reduced elF4 and phosphorylated elF4 immunoreactivity in LP progeny CAP cells. In 17DG LP, the NFκβ and HSP90 immunoreactivity was enhanced, particularly in the CAP area. The current study supported that the programmed reduced nephron number in the 17-DG LP offspring may be related to changes in the HIF-1α signaling pathway. Factors that facilitate the transposition of HIF-1α to progenitor renal cell nuclei, such as increased NOS, Ep300, and HSP90 expression, may have a crucial role in this regulatory system. Also, HIF-1α changes could be associated with reduced transcription of elF-4 and its respective signaling path.


Antimitochondrial (pyruvate dehydrogenase) antibodies in leprosy.
Sera from 69 patients with leprosy but without liver involvement were assayed for the presence of mitochondrial pyruvate dehydrogenase (PDH)-specific autoantibodies by enzyme-linked immunoabsorbent assay (ELISA), immunoblotting using PDH as an antigen and by enzymatic inhibition test. Twenty-seven of the leprosy serum samples (39.1%) were found to react with PDH by ELISA. However, unlike sera from primary biliary cirrhosis (PBC) patients, none of these were able to inhibit the PDH enzymatic activity. By immunoblotting, it was found that only 2 of the 27 positive sera recognized the 74-kD protein of the PDH complex, which is recognized by sera of most PBC patients. The antimitochondrial antibodies in lepra most probably recognize different epitopes than those in PBC. These findings may indicate that anti-PDH autoantibodies in patients with leprosy may arise by polyclonal B cell stimulation and may represent natural anti-PDH autoantibodies.


Simulation experiments illustrating stabilization of animal numbers by spreading of risk.
1. This paper discusses results of simulation studies with population models that were set up to illustrate the ideas about stabilization of population fluctuations and spreading of the risk of extinction expounded by den Boer (1968). In particular, the number of factors influencing net reproduction, the heterogeneity of the habitat and the possibility of a population's containing animals of different age classes were considered as possibly contributing to stabilization and to spreading of risk. 2. The model defined by equation (3.1.2), where r(t) denotes the net reproduction from t to t+1, f i (t) denotes the value of the i-th environmental factor in year t, and where the other symbols denote positive constants, was simulated by choosing for the f i(t) sequences of meteorological data from published tables. Such sequences may be serially correlated as well as correlated among themselves and using such real data was considered to be more realistic than working with sequences of independent random numbers, for example. Increasing the number k of factors turned out to stabilize fluctuations in the density. This fact could also be mathematically proved under not very restrictive assumptions. In a model where the logarithm of the net reproduction on the average is some-what greater than zero, and where "crashes" may occur at high densities, the population may persist for a very long time, even if the "size" of the crashes does not depend on density, and the times at which the crashes occur are chosen at random. 3. A model formulated in terms of matrices and vectors, in which a population was supposed to consist of 9 subpopulations and of several age classes was simulated. It was assumed that after a reproduction period the animals migrate between the subpopulations or emigrate from the whole population. It turned out that increasing the number of age classes may increase stability and that models where there is exchange of individuals between subpopulations by \ldmigration\rd are more stable than populations consisting of isolated subpopulations. Letting the exchange between subpopulations be \lddensity-dependent\rd had some stabilizing effect too, but not very conspicuously so.


Purification, partial characterization and antitumor effect of an exopolysaccharide from Rhizopus nigricans.
In this study, a homogeneous exopolysaccharide (EPS1-1) was purified from the fermentation broth of Rhizopus nigricans. EPS1-1 was composed of glucose, mannose, galactose and fructose in the molar ratio of 5.89:3.64:3.20:1.00 with weight average molecular weight of 9.7×10(3)g/mol. EPS1-1 could significantly inhibit proliferation of human colorectal carcinoma HCT-116 cells in vitro. EPS1-1 also induced S phase cell cycle arrest and increased sub-G0/G1 population, a hallmark of apoptosis. The results of morphological characterization and flow cytometry showed that EPS1-1 induced apoptotic cell death in HCT-116 cells. EPS1-1 caused dissipation of mitochondrial membrane potential, accumulation of reactive oxygen species, up-regulation of Bax and p53 mRNA expression and down-regulation of Bcl-2 mRNA expression, which suggested that mitochondrial pathway was involved in the EPS1-1-induced apoptosis. These findings bring new insights into the potential use of EPS1-1 as antitumor drug against human colorectal carcinoma.


Prospective study of the aetiology of adult community acquired bacterial pneumonia needing hospitalisation in Singapore.
A prospective survey of 96 consecutive adult patients with community acquired pneumonia requiring hospitalisation was carried out at National University Hospital, Singapore. Causative pathogens were identified in 58% of patients. Mycobacterium tuberculosis was the most common pathogen (21%), followed by Streptococcus pneumoniae (12%), Haemophilus influenzae (5.2%), Mycoplasma pneumoniae (5.2%) and Staphylococcus aureus (4.2%). Gram-negative organisms (apart from Haemophilus influenzae) were found in 10% of pneumonia patients. More than half of the patients had pre-existing illness, the most common was diabetes mellitus (21%).


Liver transplantation and liver cell transplantation.
Liver transplantation is nowadays the recognized treatment of many liver diseases and liver-based metabolic disorders in childhood. The indications are congenital cholestatic diseases, mainly biliary atresia, metabolic disorders and fulminant hepatic failure. Potential candidates have to be evaluated early in a specialized center, as the survival rate is worse if the child is transplanted with end-stage liver failure. The graft is in most cases partial, either a split liver from a deceased donor (the other part going to an adult recipient), or the left lobe or left liver from a living donor. The patient's survival rate is about 80-90% at 1 year, 70-80% at 10 years, and the graft survival rate 60-70% at 10 years. Immuno-suppression depends on a calcineurin inhibitor (cyclosporin or tacrolimus), and either steroids or an induction with a monoclonal antibody against IL2-receptor. Early surgical complications are a non-function of the graft (rare), arterial or portal thrombosis, biliary problems (more frequent with partial grafts), bleeding. Infections with bacteria and fungi are frequent and often severe. CMV infection is prevented, or screened and preemptively treated. EBV infection is frequent and may induce a posttransplant lymphoproliferative disease, that can develop into a lymphoma. Early stages are treated with reduction of immuno-suppression and monoclonal antibodies against CD20. Acute rejection is frequent but usually easily controlled. Chronic rejection may be due to poor compliance. Late graft loss is due to chronic rejection or long-standing biliary complications. Long-term complications are progressive graft fibrosis, renal failure due to drug toxicity (mainly calcineurin inhibitors), and cancers (skin and lymphoma).


Developmental regulator Le.CDC5 of the mushroom Lentinula edodes: analyses of its amount in each of the stages of fruiting-body formation and its distribution in parts of the fruiting bodies.
Immunoblot analysis of Le.CDC5 (842 amino acid residues), the expressed product of the cDNA of Le.cdc5 gene that has been previously reported to be most actively transcribed in primordia and small immature fruiting bodies of the basidiomycete Lentinula edodes, showed that the primordia, immature fruiting bodies and mature fruiting bodies contain similar amounts of Le.CDC5 protein. This indicates that the Le.CDC5 protein molecules synthesized in the beginning and early stage of fruiting-body formation remains in mycelial tissues even after small immature fruiting bodies developed and matured. Immunohistochemical analysis showed that Le.CDC5 is present everywhere in the mycelial tissues of immature fruiting body, but prehymenophore, the border between pileus and stipe, and the bottom of stipe seem likely to contain larger amounts of Le.CDC5. Within the hymenophore of mature fruiting body, the hymenium (in/on which a large number of basidia and basidiospores are formed) contains the Le.CDC5 most exclusively.


What do we know about astrocytes and the antidepressant effects of DBS?
Treatment-resistant depression (TRD) is a debilitating condition that affects millions of individuals worldwide. Deep brain stimulation (DBS) has been widely used with excellent outcomes in neurological disorders such as Parkinson's disease, tremor, and dystonia. More recently, DBS has been proposed as an adjuvant therapy for TRD. To date, the antidepressant efficacy of DBS is still controversial, and its mechanisms of action remain poorly understood. Astrocytes are the most abundant cells in the nervous system. Once believed to be a "supporting" element for neuronal function, astrocytes are now recognized to play a major role in brain homeostasis, neuroinflammation and neuroplasticity. Because of its many roles in complex multi-factorial disorders, including TRD, understanding the effect of DBS on astrocytes is pivotal to improve our knowledge about the antidepressant effects of this therapy. In depression, the number of astrocytes and the expression of astrocytic markers are decreased. One of the potential consequences of this reduced astrocytic function is the development of aberrant glutamatergic neurotransmission, which has been documented in several models of depression-like behavior. Evidence from preclinical work suggests that DBS may directly influence astrocytic activity, modulating the release of gliotransmitters, reducing neuroinflammation, and altering structural tissue organization. Compelling evidence for an involvement of astrocytes in potential mechanisms of DBS derive from studies suggesting that pharmacological lesions or the inhibition of these cells abolishes the antidepressant-like effect of DBS. In this review, we summarize preclinical data suggesting that the modulation of astrocytes may be an important mechanism for the antidepressant-like effects of DBS.


Simultaneous discrimination learning in pigeons: value of S- affects the relative value of its associated S+.
In a simple simultaneous discrimination involving a positive stimulus (S+) and a negative stimulus (S-), it has been hypothesized that positive value can transfer from the S+ to the S- (thus increasing the relative value of the S-) and also that negative value can transfer from the S- to the S+ (thus diminishing the relative value of the S+; Fersen, Wynne, Delius, & Staddon, 1991). Evidence for positive value transfer has been reported in pigeons (e.g. Zentall & Sherburne, 1994). The purpose of the present experiments was to determine, in a simultaneous discrimination, whether the S- diminishes the value of the S+ or the S- is contrasted with the S+ (thus enhancing the value of the S+). In two experiments, we found evidence for contrast, rather than value transfer, attributable to simultaneous discrimination training. Thus, not only does the S+ appear to enhance the value of the S-, but the S- appears to enhance rather than reduce the value of the S+.


The association between different traumatic life events and suicidality.
Background: Traumatic life events have been associated with increased risk of various psychiatric disorders, even suicidality. Our aim was to investigate the association between different traumatic life events and suicidality, by type of event and gender. Methods: Women attending a cancer screening programme in Iceland (n = 689) and a random sample of men from the general population (n = 709) were invited to participate. In a web-based questionnaire, life events were assessed with the Life Stressor Checklist - Revised, and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criterion was used to identify traumatic life events. Reports of lifetime suicidal thoughts, self-harm with suicidal intent and suicide attempt were considered as lifetime suicidality. We used Poisson regression, adjusted for demographic factors, to express relative risks (RRs) as a measure of the associations between traumatic events and suicidality. Results: Response rate was 66% (922/1398). The prevalence of lifetime traumatic events was 76% among women and 77% among men. Lifetime suicidality was 11% among women and 16% among men. An overall association of having experienced traumatic life events with suicidality was observed [RR 2.05, 95% confidence interval (CI) 1.21-3.75], with a stronger association for men (RR 3.14, 95% CI 1.25-7.89) than for women (RR 1.45, 95% CI 0.70-2.99). Increased likelihood for suicidality was observed among those who had experienced interpersonal trauma (RR 2.97, 95% CI 1.67-5.67), childhood trauma (RR 4.09, 95% CI 2.27-7.36) and sexual trauma (RR 3.44, 95% CI 1.85-6.37), with a higher likelihood for men. In addition, an association between non-interpersonal trauma and suicidality was noted among men (RR 3.27, 95% CI 1.30-8.25) but not women (RR 1.27, 95% CI 0.59-2.70). Conclusion: Findings indicate that traumatic life events are associated with suicidality, especially among men, with the strongest association for interpersonal trauma.


Nasal polyps in eosinophilic granulomatosis with polyangiitis: Structured histopathology and CD105 expression.
Distinguishing the prodromal nasal polyposis of eosinophilic granulomatosis with polyangiitis (EGPA) from chronic rhinosinusitis with nasal polyps (CRSwNP) is a challenge for rhinologists and rheumatologists. It has recently been reported that angiogenesis and CD105 expressed on vascular endothelial cells could have a role in the pathogenesis and development of nasal polyps. This exploratory study examined the structured histopathology of nasal polyps in patients with EGPA and CRSwNP, comparing CD105 expression in their nasal tissue with that of a control group with no chronic sinonasal inflammation. A structured histopathological study was performed on surgical specimens of nasal tissue from 32 adults (13 with EGPA, 14 with CRSwNP, 5 controls), considering CD105 as a marker to determine microvessel density (MVD). The mean eosinophil count was higher in EGPA patients with tissue inflammation (p = .002), and in CRSwNP patients with sub-epithelial edema (p = .009). Neutrophil infiltration was significantly associated with severe tissue inflammation in EGPA patients (p = .04), but with the absence of fibrosis in CRSwNP patients (p = .04). In the EGPA group, CD105-MVD correlated with tissue eosinophil count (p = .05). Mean CD105-MVD was significantly higher in EGPA patients with mucosal ulceration (p = .004). In the CRSwNP group, a CD105-MVD correlated positively and significantly with tissue eosinophil count (p = .01). Alongside the known abundance of eosinophils, other cells might contribute to inflammatory processes. Neutrophils may amplify inflammation, eosinophil recruitment and tissue damage. CD105 expression in CRSwNP and EGPA nasal polyps supports the hypothesized involvement of angiogenesis in the pathogenesis and development of nasal polyps.


Infrared femtosecond laser preionization in secondary ion mass spectrometry of silver surface.
An alternative secondary ion mass spectrometry utilizing laser preionization is introduced. The native Ag sample surface is first irradiated with laser pulse (100 fs duration, 10(10)-10(11) W/cm(2) intensity, 1240 nm wavelength) and subsequently bombarded with primary ions (Bi(3)(+), 10 ns duration, 25 keV energy). Multiple correlation patterns are observed in the mass spectra, confirming the mutual laser-secondary ion mass spectrometry (SIMS) interplay in the preionization mechanism. The Ag(+), C(3)H(5)(+), C(3)H(5)O(3)(+), and AgOH(+), C(4)H(5)O(4)(+) are observed with the shallow and steep increasing of intensities at 1.3 × 10(11) W/cm(2) and 1.5 × 10(11) W/cm(2), respectively. Two ionization mechanisms are identified, the ion sputtering regime for intensities of less than 1.4 × 10(11) W/cm(2) and the multiphoton ionization at higher intensities. The Ag saturation intensity obtained from fitting is 2.4 × 10(13) W/cm(2), close to the one reported for postionization. The proposed preionization approach might eliminate the need for high peak power/high intensity laser source and, moreover, the experiment geometry ensures that large areas of the sample are affected by the laser beam.


Effect of mannitol on sodium retention during whole-gut perfusion.
To undergo whole-gut perfusion, normal Chinese subjects drank an isotonic saline solution at a rate of 40 ml/min for 3-6 h. In spite of a diuresis, expansion of the extracellular fluid was evidenced by an increase of body weight and a decrease of haematocrit and plasma specific gravity at the end of perfusion. This fluid expansion resulted from sodium retention at a rate of about 140 mmole/h. When the NaCl of the perfusion solution was gradually replaced by isomotic amounts of mannitol, sodium retention was gradually reduced. Addition to the perfusion solution of up to 144-152 millimolar mannitol reduced the sodium retention rate to 6.5 mmole/h and thus prevented fluid expansion. We found that the sodium retention rate was inversely related to the difference between sodium concentration in the plasma and that in the perfusion solution. Thus, our results suggest that addition of mannitol with a decrease of sodium concentration in the perfusion solution creates a sodium concentration gradient between plasma and intestinal lumen which is unfavourable for intestinal absorption of sodium.


Ester-imine condensations: preparation of racemic intermediates for the synthesis of the carbapenem antibiotics PS-5 and PS-6.
The lithium enolates of ethyl butyrate and ethyl isovalerate react with N-p-methoxyphenylcinnamaldimine in tetrahydrofuran (THF)-hexamethylphosphoric triamide (HMPA) to afford predominantly trans beta-lactams 9 (67%) and 20 (78%), respectively. beta-Lactam 9 was converted to PS-5 intermediate 18 in 21% overall yield (8 steps). Beta-lactam 20 was converted to PS-6 analog 28 in 22% overall yield using an eight step sequence.


Immunohistochemical expression of selected phosphoproteins of the mTOR signalling pathway in canine cutaneous squamous cell carcinoma.
Cutaneous squamous cell carcinoma (cSCC) represents one of the most common malignant skin tumors in dogs. Research aimed at clarifying how the deregulated activity of signalling pathways contributes to cSCC progression can help to identify molecular suitable targets for the development of novel therapies. The present study describes the immunohistochemical expression pattern of two proteins (pAktSer473 and pS6Ser235/236, the latter combined with Ki-67) involved in the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway in canine specimens of normal epidermis, pre-neoplastic epidermis, and cSCC using tissue microarrays. The results suggest that the PI3K/Akt/mTOR signalling pathway has a low expression in the normal canine epidermis, and that selected molecules involved in this signalling pathway are dysregulated during the canine epidermal carcinogenesis process. These findings provide important evidence that the persistent activation of the PI3K/Akt/mTOR signalling pathway represents one of the key events during cSCC progression in canine patients, pointing to the PI3K/Akt/mTOR pathway as a potential therapeutic target.


Renal function following acute renal failure in childhood: a long term follow-up study.
We measured glomerular and tubular function in 10 children, aged 7 to 19 years, 7 to 12 years after apparent recovery from their episodes of acute renal failure. Although glomerular filtration rate was normal in all, filtration fraction (inulin clearance/PAH clearance) was elevated in six of eight patients. Segmental tubular sodium transport was assessed using clearance techniques during hypotonic saline diuresis; both proximal and distal sodium reabsorption were normal when compared with age-appropriate normal standards. Tubular reabsorption of phosphate, glucose and amino acids were also normal, as were urinary concentrating and diluting capacity and distal tubular hydrogen ion secretion. We conclude that, despite normal glomerular filtration rate, glomerular function is abnormal in a significant number of children who have apparently recovered completely from ARF, probably due to destruction of a proportion of the total nephron population, predominantly those located in the superficial layers of the cortex.


[Characteristics of arterial hypertension in psychoemotional burnout of emergency medical staffers].
Medical profession requires not only skills, but also significant emotional dedication that leads to psychoemotional overstrain and frequently to emotional burnout influencing blood pressure level, cardiovascular state and arterial hypertension course. With this, studying influence of psycho-social factors in medical staffers' occupational life, in accordance with length of service, on cardiovascular system with arterial hypertension is topical.


A role for anti-CD45RB monoclonal antibody treatment upon dendritic cells.
Selective interference with CD45RB isoform by monoclonal antibody (anti-CD45RBmAb) reliably induces donor-specific tolerance. Dendritic cells (DCs) are the most potent antigen-presenting cells that are capable of activating naïve T cells. The purposes of the present study were to investigate the roles of anti-CD45RBmAb on the phenotypes and functioning of DCs and to further illustrate the mechanism of anti-CD45RBmAb-inducing immunologic tolerance. DCs from C57BL/6 mice were cultured and treated with various doses of anti-CD45RB monoclonal antibody. Cell phenotype, cycle and phagocytic ability were detected by flow cytometry. The production of IL-10 and IL-12 in the supernatants of mature DCs was measured with ELISA. Exosomes (Dex) were recovered from the supernatant of DCs cultured for 6 days in depleted medium, and effects of DCs and Dex on the ability of T-cell proliferation were detected by mixed lymphocyte culture. Anti-CD45RBmAb could inhibit DCs maturation in a dose-dependent manner, and the effects of exosomes (Dex) on DCs enhance or inhibition proliferation of T cells were also in a dose-dependent manner. Anti-CD45RBmAb could profoundly inhibit the maturation and functioning of DCs and generate tolerogenic dendritic cells (tDCs) as well as Dex, suggesting mechanistic contributions to tolerance development from the DCs through interactions with T cells.


Survival and mitochondrial function in septic patients according to mitochondrial DNA haplogroup.
We recently found that platelet cytochrome c oxidase (COX) activities and quantities in 6-month-survival septic patients are significantly higher than those of patients who died before 6 months. Other studies suggested that the mitochondrial DNA (mtDNA) genotype could play a major role in sepsis survival. Given that COX catalytic subunits are encoded by mtDNA, the objective of the present study was to explore whether mtDNA population genetic variation could affect COX activity and quantity and favors sepsis survival. A prospective, multicenter, observational study was carried out in six Spanish ICUs. We included 96 patients with severe sepsis. We determined the mtDNA haplogroup, the COX specific activity/citrate synthase specific activity (COXa/CSa) ratio and the COX quantity/citrate synthase specific activity (COXq/CSa) ratio in circulating platelets at the time of diagnosis, day 4 and day 8. We used survival at 1 and 6 months as endpoints. Patients with the JT mtDNA haplogroup (n=15) showed higher COXq/CSa ratio at day 4 (P=0.04) and day 8 (P=0.02) than those with other haplogroups (n=81). Logistic regression analysis showed that the JT mtDNA haplogroup (odds ratio=0.18; 95% confidence interval=0.04 to 0.94; P=0.04) and COXq/CSa ratio (odds ratio=0.53; 95% confidence interval=0.30 to 0.93; P=0.03) were associated with 1-month survival after controlling for age and lactic acid levels. The novel findings of our study are that 1-month surviving septic patients showed higher COXq/CSa ratio than nonsurviving individuals, that patients from the JT mtDNA haplogroup showed a higher COXq/CSa ratio and that JT patients had a higher 1-month survival than patients from other mtDNA haplogroups.


Astrocytes mediate long-lasting synaptic regulation of ventral tegmental area dopamine neurons.
The plasticity of glutamatergic transmission in the ventral tegmental area (VTA) represents a fundamental mechanism in the modulation of dopamine neuron burst firing and phasic dopamine release at target regions. These processes encode basic behavioral responses, including locomotor activity, learning and motivated behaviors. Here we describe a hitherto unidentified mechanism of long-term synaptic plasticity in mouse VTA. We found that the burst firing in individual dopamine neurons induces a long-lasting potentiation of excitatory synapses on adjacent dopamine neurons that crucially depends on Ca2+ elevations in astrocytes, mediated by endocannabinoid CB1 and dopamine D2 receptors co-localized at the same astrocytic process, and activation of pre-synaptic metabotropic glutamate receptors. Consistent with these findings, selective in vivo activation of astrocytes increases the burst firing of dopamine neurons in the VTA and induces locomotor hyperactivity. Astrocytes play, therefore, a key role in the modulation of VTA dopamine neuron functional activity.


Impact of menstrual cycle phase on the exercise status of young, sedentary women.
The purpose of the present study was to compare exercise status during the follicular (FP) and luteal (LP) phases of the menstrual cycle of a single group of young, sedentary women, where the marked differential in the blood concentrations of 17beta-oestradiol ([E(2)]) and progesterone ([P(4)]) has the potential to alter the metabolic response to exercise. Fourteen females [21.8 (4.0) years, peak oxygen uptake ( VO(2peak)) <45 ml x kg (-1) x min(-1)] performed both incremental exercise to exhaustion and steady-state submaximal cycle ergometer exercise while measurements were made of several metabolic and hormonal variables. With the incremental exercise test, time to exhaustion, maximal power output and total work done were not different between the two phases, nor were the absolute values for VO(2peak) or the corresponding values for ventilation ( VE), respiratory frequency ( f(R)) and heart rate (HR). Resting, end-exercise and peak (post-exercise) plasma lactate concentrations and the lactate threshold were not different between the two phases either. However, as the workloads increased during the incremental protocol, plasma lactate concentration, carbon dioxide output ( VCO(2)) and the respiratory exchange ratio (RER) all were lower during LP, while oxygen uptake ( VO(2)) was higher. With steady-state submaximal exercise, at workloads corresponding to 25% and 75% of menstrual cycle phase-specific VO(2peak), VO(2) and the oxygen pulse ( VO(2)/HR) were higher and RER and plasma lactate concentration lower during LP. Regardless of phase, [E(2)] increased with both incremental and steady-state submaximal exercise, while [P(4)] was unchanged. It is concluded that while exercise capacity, as defined by VO(2peak) and the lactate threshold, is unaffected by cycle phase in young, sedentary women, the metabolic responses in the LP during both incremental and steady-state submaximal exercise suggest a greater dependence on fat as an energy source.


Directional Preference in Avian Midbrain Saliency Computing Nucleus Reflects a Well-Designed Receptive Field Structure.
Neurons responding sensitively to motions in several rather than all directions have been identified in many sensory systems. Although this directional preference has been demonstrated by previous studies to exist in the isthmi pars magnocellularis (Imc) of pigeon (Columba livia), which plays a key role in the midbrain saliency computing network, the dynamic response characteristics and the physiological basis underlying this phenomenon are unclear. Herein, dots moving in 16 directions and a biologically plausible computational model were used. We found that pigeon Imc's significant responses for objects moving in preferred directions benefit the long response duration and high instantaneous firing rate. Furthermore, the receptive field structures predicted by a computational model, which captures the actual directional tuning curves, agree with the real data collected from population Imc units. These results suggested that directional preference in Imc may be internally prebuilt by elongating the vertical axis of the receptive field, making predators attack from the dorsal-ventral direction and conspecifics flying away in the ventral-dorsal direction, more salient for avians, which is of great ecological and physiological significance for survival.


5,6,7,3',4',5'-Hexamethoxyflavone from the Australian plant Eremophila debilis (Myoporaceae).
The aerial parts of the endemic Australian plant Eremophila debilis (Myoporaceae) contain 3% dry weight of the biologically active 5,6,7,3',4',5'-hexamethoxyflavone, which had its structured confirmed using X-ray crystal crystallography. The presence of significant levels of the polypharmacologically active 5,6,7,3',4',5'-hexamethoxyflavone in the edible parts of the plant has potential implications for its use as a food and bush medicine.


Reconstructing networks of pathways via significance analysis of their intersections.
Significance analysis at single gene level may suffer from the limited number of samples and experimental noise that can severely limit the power of the chosen statistical test. This problem is typically approached by applying post hoc corrections to control the false discovery rate, without taking into account prior biological knowledge. Pathway or gene ontology analysis can provide an alternative way to relax the significance threshold applied to single genes and may lead to a better biological interpretation. Here we propose a new analysis method based on the study of networks of pathways. These networks are reconstructed considering both the significance of single pathways (network nodes) and the intersection between them (links). We apply this method for the reconstruction of networks of pathways to two gene expression datasets: the first one obtained from a c-Myc rat fibroblast cell line expressing a conditional Myc-estrogen receptor oncoprotein; the second one obtained from the comparison of Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia derived from bone marrow samples. Our method extends statistical models that have been recently adopted for the significance analysis of functional groups of genes to infer links between these groups. We show that groups of genes at the interface between different pathways can be considered as relevant even if the pathways they belong to are not significant by themselves.


The performance of long vs. short questionnaire-based measures of depression, anxiety, and psychological distress among UK adults: A comparison of the patient health questionnaires, generalized anxiety disorder scales, malaise inventory, and Kessler scales.
It is often important to minimise the time participants in social science studies spend on completing questionnaire-based measures, reducing response burden, and increasing data quality. Here, we investigated the performance of the short versions of some widely used depression, anxiety, and psychological distress scales and compared them to the performance of longer versions of these scales (PHQ-2 vs PHQ-9, GAD-2 vs GAD-7, Malaise-3 vs Malaise-9, K6 vs K10). Across a sample of UK adults (N = 987, ages 18-86), we tested the existing factor structure and accuracy of the scales through confirmatory factor analyses and exploration of the total information functions, observing adequate model fit indices across the measures. Measurement invariance was tested across birth sex and age groups to explore whether any differences in measurement properties or measurement bias may exist, finding support for the invariance of most measures. We conducted bivariate correlations across the measures as a way of obtaining evidence of the equivalence in the rank-ordering of short vs long scales. The results followed a similar pattern across the young adult subsample (N = 375, ages 18-39) as in the overall sample. Overall, these results indicate that the short forms of the tested scales may perform similarly to the full versions. Where brevity is important, researchers may opt to use the shorter versions of the scales based on these data.


Macrosomic infants of nondiabetic mothers and elevated C-peptide levels in cord blood.
C-peptide concentrations in the cord blood of 29 macrosomic neonates born of nondiabetic mothers were higher than in 23 control infants whose birth weight was appropriate for gestational age, and there was a significant direct correlation between birth weight and C-peptide concentration. Six of the macrosomic infants studied (20%) had hypoglycemia in the first 24 hours of life, compared with none of the infants born with appropriate weight. We conclude that chronic fetal hyperinsulinemia may be one of the causes of macrosomia and neonatal hypoglycemia in infants of nondiabetic mothers.


High-intensity focused ultrasound induced apoptosis with caspase 3, 8, and 9/6 activation in rat hepatoma.
The purpose of the present study is to investigate anticancer efficacy and apoptosis confirmed by caspase under several exposure conditions of high-intensity focused ultrasound (HIFU). Twenty-five rats with KDH-8 hepatoma were treated by HIFU at several acoustic energies to evaluate treatment efficacy. Apoptosis was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and Hoechst 33258 staining, and caspase 3, 8, and 9/6 activity was respectively assayed. The KDH-8 subcutaneous tumors were reduced by HIFU, and these rats survived longer than the nontreatment rats (P < 0.01). The minimal threshold of HIFU energy was 30 W × 1.0 s for tumor control and long-term survival. The tumors exposed to HIFU exhibited marked apoptotic features under conditions of less than 10 W × 1.0 s. In cultured KDH-8 cells, apoptosis was caused at less than 30 W × 1.0 s (P < 0.01), and more was induced as the energy went down. Caspase 3, 8, and 9/6 were more activated at low energy under 10 W × 1.0 s (P < 0.01), and caspase 8, which is death receptor dependent, was significantly more activated than caspase 9/6, which is mitochondria dependent (P < 0.01). HIFU-induced apoptosis in vivo and in vitro is one of the mechanisms for tumor control and is mediated by caspase 3, 8, and 9/6. The significantly greater activation of caspase 8 than of caspase 9/6 suggests that the apoptosis pathway induced by HIFU might be more mitochondria dependent than death receptor dependent. However, further examination will be needed.


Therapist knowledge, adherence and use of low back pain guidelines to inform clinical decisions--a national survey of manipulative and sports physiotherapists in New Zealand.
Identifying factors which influence guideline-informed clinical decisions by therapists will help tailor implementation strategies to improve guideline use. The aims of this study were to investigate; the extent to which current physiotherapy practice in New Zealand adheres to low back pain (LBP) guidelines and the factors which influence the use of guidelines to inform clinical decisions for patients with non-specific low back pain (NSLBP). A cross-sectional on-line survey of NZ physiotherapists (n = 1039) was conducted which included the guideline adherence measures, therapists' treatment orientation about NSLBP and a question on the perceived helpfulness of guidelines in decisions for patients with NSLBP. Data from 170 physiotherapists were analysed descriptively and univariate and multivariate associations were conducted for therapist factors (predictor variables) which predicted guidelines being helpful in decisions for management of patients with NSLBP (Y|N). The majority of respondents provided advice which was broadly inline with guideline recommendations [work (60%), activity (87.6%), and bed rest (63%)]. A lower biomedical belief orientation for LBP, higher reported LBP caseload and postgraduate qualifications demonstrated significant univariate associations (P ≤ 0.20) for guidelines being helpful to inform decisions for a patient with NSLBP. The only significant (P = 0.043) predictor variable in the multivariate model was the therapists' biomedical treatment orientation (Exp (B): odd ratio: 1.56). Differences between behaviours and beliefs in guideline use were found. A lower focus on a biomedical model for LBP influenced usage of LBP guidelines to inform clinical decisions for patients with LBP. Implications for improving guideline usage are discussed.


Long-Term Changes in Brain Connectivity Reflected in Quantitative Electrophysiology of Symptomatic Former National Football League Players.
Exposure to repetitive head impacts (RHI) has been associated with long-term disturbances in cognition, mood, and neurobehavioral dysregulation, and reflected in neuroimaging. Distinct patterns of changes in quantitative features of the brain electrical activity (quantitative electroencephalogram [qEEG]) have been demonstrated to be sensitive to brain changes seen in neurodegenerative disorders and in traumatic brain injuries (TBI). While these qEEG biomarkers are highly sensitive at time of injury, the long-term effects of exposure to RHI on brain electrical activity are relatively unexplored. Ten minutes of eyes closed resting EEG data were collected from a frontal and frontotemporal electrode montage (BrainScope Food and Drug Administration-cleared EEG acquisition device), as well as assessments of neuropsychiatric function and age of first exposure (AFE) to American football. A machine learning methodology was used to derive a qEEG-based algorithm to discriminate former National Football League (NFL) players (n = 87, 55.40 ± 7.98 years old) from same-age men without history of RHI (n = 68, 54.94 ± 7.63 years old), and a second algorithm to discriminate former players with AFE <12 years (n = 33) from AFE ≥12 years (n = 54). The algorithm separating NFL retirees from controls had a specificity = 80%, a sensitivity = 60%, and an area under curve (AUC) = 0.75. Within the NFL population, the algorithm separating AFE <12 from AFE ≥12 resulted in a sensitivity = 76%, a specificity = 52%, and an AUC = 0.72. The presence of a profile of EEG abnormalities in the NFL retirees and in those with younger AFE includes features associated with neurodegeneration and the disruption of neuronal transmission between regions. These results support the long-term consequences of RHI and the potential of EEG as a biomarker of persistent changes in brain function.