Squamous cell carcinoma of bladder after successful intravesical therapy with Bacillus Calmette-Guérin.
A case of invasive squamous cell carcinoma of the bladder following intravesical immunotherapy with Bacillus Calmette-Guérin in a patient with pre-existing squamous dysplasia of the bladder is presented.


Do selective immunisation against tuberculosis and hepatitis B reach the targeted populations? A nationwide register-based study evaluating the recommendations in the Norwegian Childhood Immunisation Programme.
Selective immunisation is an alternative to universal vaccination if children at increased risk of disease can be identified. Within the Norwegian Childhood Immunisation Programme, BCG vaccine against tuberculosis and vaccine against hepatitis B virus (HBV) are offered only to children with parents from countries with high burden of the respective disease. We wanted to study whether this selective immunisation policy reaches the targeted groups. The study population was identified through the Norwegian Central Population Registry and consisted of all children born in Norway 2007-2010 and residing in Norway until their second birthday, in total 240,484 children. Information on vaccinations from the Norwegian Immunisation Registry, and on parental country of birth from Statistics Norway, was linked to the population registry by personal identifiers. The coverage of BCG and HBV vaccine was compared with the coverage of vaccines in the universal programme. Among the study population, 16.1% and 15.9% belonged to the target groups for BCG and HBV vaccine, respectively. Among children in the BCG target group the BCG vaccine coverage was lower than the coverage of pertussis and measles vaccine (83.6% vs. 98.6% and 92.3%, respectively). Likewise, the HBV vaccine coverage was lower than the coverage of pertussis and measles vaccine in the HBV target group (90.0% vs. 98.6% and 92.3%, respectively). The coverage of the targeted vaccines was highest among children with parents from South Asia and Sub-Saharan Africa. The coverage of vaccines in the universal programme was similar in targeted and non-targeted groups. Children targeted by selective vaccination had lower coverage of the target vaccines than of vaccines in the universal programme, indicating that selective vaccination is challenging. Improved routines for identifying eligible children and delivering the target vaccines are needed. Universal vaccination of all children with these vaccines could be considered.


Nonsteroidal anti-inflammatory effect of sulindac sulfoxide and sulfide on gastric mucosa.
Gastric injury resulting from nonsteroidal anti-inflammatory drugs is thought to require direct contact of the drug with the gastric mucosa. An inactive form of a drug (as a prodrug) should protect against mucosal damage. Because sulindac sulfoxide has little effect on prostaglandin synthesis until it is reduced to sulindac sulfide after absorption, we performed a double-blind, crossover endoscopic study in 15 normal subjects to compare the prodrug sulindac sulfoxide (200 mg b.i.d.), the active sulfide metabolite sulindac sulfide (100 mg b.i.d., which yields similar sulfide blood concentrations), a positive control (aspirin, 650 mg q.i.d.), and a negative control (placebo). Each drug was taken for 1 week and gastric mucosa were endoscopically assessed before and after 2, 5, and 7 days of dosing. Aspirin predictably damaged the gastric mucosa, whereas the effects of sulindac sulfoxide and sulindac sulfide could not be distinguished from those of the placebo. We conclude that sulindac sulfoxide as a prodrug is not directly responsible for the reduced severity of gastric mucosal lesions. Both sulindac sulfoxide and sulindac sulfide are poorly soluble in acid gastric contents and the reduced damage may relate to the inability of high concentrations of the drug to enter gastric mucosal cells.


Characterization of the gut microbiome in a porcine model of thoracic spinal cord injury.
The gut microbiome is a diverse network of bacteria which inhabit our digestive tract and is crucial for efficient cellular metabolism, nutrient absorption, and immune system development. Spinal cord injury (SCI) disrupts autonomic function below the level of injury and can alter the composition of the gut microbiome. Studies in rodent models have shown that SCI-induced bacterial imbalances in the gut can exacerbate the spinal cord damage and impair recovery. In this study we, for the first time, characterized the composition of the gut microbiome in a Yucatan minipig SCI model. We compared the relative abundance of the most dominant bacterial phyla in control samples to those collected from animals who underwent a contusion-compression SCI at the 2nd or 10th Thoracic level. We identify specific bacterial fluctuations that are unique to SCI animals, which were not found in uninjured animals given the same dietary regimen or antibiotic administration. Further, we identified a specific time-frame, "SCI-acute stage", during which many of these bacterial fluctuations occur before returning to "baseline" levels. This work presents a dynamic view of the microbiome changes that accompany SCI, establishes a resource for future studies and to understand the changes that occur to gut microbiota after spinal cord injury and may point to a potential therapeutic target for future treatment.


Do occlusal splints have an effect on complex regional pain syndrome? A randomized, controlled proof-of-concept trial.
Studies have suggested overlaps between various chronic pain conditions and painful temporomandibular disorders (TMDs). The objective of this pilot study was to assess the effectiveness of occlusal splint (OS) therapy on self-reported measures of pain in patients with chronic complex regional pain syndrome (CRPS) as compared with a nontreatment group. The design was a prospective randomized controlled clinical trial. Twenty patients with CRPS were randomly assigned to either the OS or control group. The patients in the OS group were asked to use the OS at nighttime and for 3 hours during daytime for a total of 7 weeks; the control group had no stomatognathic intervention. The primary outcome was self-reported assessment of CRPS-related pain on numerical rating scales. Secondary outcome measures were the Temporomandibular Index (TMI), and the Short Form 36 Health Survey (SF-36). All patients had TMD signs and symptoms, but OS had no effect on CRPS-related pain on the numerical rating scale (P>0.100). The changes in the TMI scores over time were 16.6%+/-24.6% (improvement) in the OS group and -21.3%+/-25.9% (impairment) in the control group that was significant (P=0.004). There were no differences in the changes of SF-36 scores between groups (P=0.636). The use of OS for 7 weeks has no impact on CRPS-related pain but improved signs and symptoms of TMD pain. Future studies should include an active control group and evaluate if long-term changes in measures of oral health impact general health in CRPS-related pain.


One Way Traffic: Base-to-Backbone Hole Transfer in Nucleoside Phosphorodithioate.
Invited for the cover of this issue are the groups of Roman Dembinski, Mehran Mostafavi, and Amitava Adhikary at the Polish Academy of Sciences, Université Paris-Saclay, and Oakland University. The image depicts a doughnut as a way of illustrating the hole transfer process. Read the full text of the article at 10.1002/chem.202000247.


A 5-year retrospective study of survival of zirconia single crowns fitted in a private clinical setting.
The aim of this report was to evaluate the 5-year clinical performance and survival of zirconia (NobelProcera™) single crowns. All patients treated with porcelain-veneered zirconia single crowns in a private practice during the period October 2004 to November 2005 were included. The records were scrutinized for clinical data. Information was available for 162 patients and 205 crowns. Most crowns (78%) were placed on premolars and molars. Out of the 143 crowns that were followed for 5 years, 126 (88%) did not have any complications. Of those with complications, the most common were: extraction of abutment tooth (7; 3%), loss of retention (15; 7%), need of endodontic treatment (9; 4%) and porcelain veneer fracture (6; 3%). No zirconia cores fractured. In total 19 restorations (9%) were recorded as failures: abutment tooth extraction (7), remake of crown due to lost retention (6), veneer fracture (4), persistent pain (1) and caries (1). The 5-year cumulative survival rate (CSR) was 88.8%. According to the present 5-year results zirconia crowns (NobelProcera™) are a promising prosthodontic alternative also in the premolar and molar regions. Out of the 143 crowns followed for 5 years, 126 (88%) did not have any complications. However, 9% of the restorations were judged as failures. Further studies are necessary to evaluate the long-term success.


The influence of patellar dislocation on the femoro-tibial loading during total knee arthroplasty.
Balancing the gap is essential in total knee arthroplasty (TKA). The purpose of this study was to quantify the influence of patellar position on femoro-tibial joint load in TKA. We hypothesized that resetting of the patella increased medial joint load and decreased lateral joint load. Our original tensor system was used during posterior-stabilized (PS) and cruciate-retaining (CR) total knee arthroplasty (TKA) using medial para-patellar approach (MPP) or sub-vastus approach (SV). In PS-TKA, by resetting the patella, the ratios between medial and lateral compartments were not changed in both extension and flexion position using MPP and were significantly changed in flexion position using SV. In CR-TKA, by resetting the patella, the load of the lateral component decreased and the ratios between medial and lateral compartments were changed significantly in both extension and flexion position using SV. It is important to be aware that, when performing CR-KA, the load of the lateral compartment will decrease by resetting the patella using SV.


Optimized methods for production and purification of Titanium-45.
Titanium-45 (t1/2 = 3.08 h) is a radiometal with excellent nuclear characteristics, including a high positron branching ratio (85%) and low average positron energy (0.439 MeV), for the development of PET imaging agents. 45Ti was produced via the 45Sc(p,n)45Ti reaction on the University of Alabama at Birmingham TR24 cyclotron in GBq quantities. Optimized separation methods were developed and preliminary radiochemistry studies were also carried out. This work shows 45Ti is a promising radiometal for future studies.


The co-effect of vanadium and fermented mushroom of Coprinus comatus on glycaemic metabolism.
The effect of fermented mushroom of Coprinus comatus rich in vanadium (CCRV) on glycaemic metabolism was studied in this paper. Alloxan-induced hyperglycemic mice were used in this study. The insulin secretion and glycogen synthesis of the mice were analyzed. At the same time, the gluconeogenesis of the normal mice was also determined. The alloxan-damaged pancreatic beta-cells of the mice were also studied in this paper. After the mice were administered (i.g.) with CCRV, the level of insulin secretion and glycogen synthesis of alloxan-induced hyperglycemic mice elevated (p<0.05, p<0.01) and the gluconeogenesis of the normal mice was inhibited (p<0.01). Also, the alloxan-damaged pancreatic beta-cells of the mice were partly recovered gradually after the mice were administered (i.g.) with CCRV 15 days later. These may account for the causes of CCRV-induced significant decreases of the blood glucose in hyperglycemic mice.


Effect of opioids on CXCL-8 production in healthy cats.
The aim of this study was to evaluate the effect of opioid exposure on CXC chemokine ligand (CXCL)-8 production in cats using whole blood culture. Morphine, buprenorphine, fentanyl, and saline control were administered intravenously to five cats and whole blood pathogen associated molecular pattern motif-induced CXCL-8 production capacity was evaluated. Morphine potentiated CXCL-8 production. To further characterize this effect of morphine, morphine was incubated with whole blood ex vivo and pathogen associated molecular pattern motif-induced CXCL-8 production capacity was measured. There was a time and concentration dependent effect on CXCL-8 production, suggesting the proinflammatory effect of morphine is at least partially mediated by direct stimulatory effects on leukocytes. Additional investigation is indicated to assess the implications of the immunomodulatory actions of opioids in cats.


Meta-analysis of accuracy of left ventricular mass measurement by three-dimensional echocardiography.
Left ventricular (LV) hypertrophy is a fundamental prognostic factor in a variety of cardiac diseases. Three-dimensional echocardiography (3DE) has achieved better estimation of LV mass than 2-dimensional echocardiography. However, significant underestimation has often been reported, and no previous study has synthesized these data. The aim of this meta-analysis was to investigate if there has been improvement in the accuracy in LV mass measurement by 3DE over time. Studies comparing LV mass between 3DE and magnetic resonance imaging were eligible. A cumulative meta-analysis was performed to investigate improvement in accuracy, followed by subgroup and meta-regression analysis to reveal factors affecting the bias. A total of 25 studies including 671 comparisons were analyzed. Studies published in or before 2004 showed high heterogeneity (I(2) = 69%) and significant underestimation of LV mass by 3DE (-5.7 g, 95% confidence interval -11.3 to -0.2, p = 0.04). Studies published from 2005 to 2007 were still heterogenous (I(2) = 60%) but showed less systematic bias (-0.5 g, 95% confidence interval -2.5 to 1.5, p = 0.63). In contrast, studies published in or after 2008 were highly homogenous (I(2) = 3%) and showed excellent accuracy (-0.1 g, 95% confidence interval -2.2 to 1.9, p = 0.90). Investigation of factors affecting the bias revealed that evaluation of cardiac patients compared to healthy volunteers led to larger bias (p <0.05). In conclusion, this meta-analysis elucidates the underestimation of LV mass by 3DE, its improvement over the past decade, and factors affecting the bias. These data provide a more detailed basis for improving the accuracy of 3DE, an indispensable step toward further clinical application.


Protective activity of tert-butylhydroquinone against oxidative stress and apoptosis induced by glutamate agonizts in R28 cells and mice retina.
Glutamate excitotoxicity can cause cell damage and apoptosis and play an important role in a variety of retinal diseases. Tertiary-butylhydroquinone (tBHQ) is an approved food-grade phenolic antioxidant with antioxidant activity in a variety of cells and tissues. We observed the protective effect of tBHQ on glutamatergic agonist-induced retina and explored its possible mechanism of action through in vitro cell experiments. The results showed that tBHQ had protective effects on NMDA-induced mouse retinal excitotoxicity and glutamate-induced excitotoxicity in rat retinal precursor cells (R28 cells). tBHQ reversed glutamate-induced apoptosis, production of intracellular reactive oxygen species, and reduction of mitochondrial membrane potential. Western blot analysis showed that tBHQ could increase the expression of procaspase-3, Bcl-2, AIF precursor, CAT, SOD2, Nrf2, NQO1, HO-1 and NF-κB in glutamate-treated cells, and decrease the expression of AIF cleavage products. Furthermore, we discovered that tBHQ activated müller glial cells. Based on these results, tBHQ may have antioxidant and anti-apoptotic properties, thus serving as a potential retinal protective agent. Its anti-oxidative stress effect was attributed to up-regulation of Nrf2, and its anti-apoptotic effect was related to its up-regulation of Bcl-2 expression and inhibition of mitochondria-dependent apoptosis.


Long non-coding RNA LRRC75A-AS1 facilitates triple negative breast cancer cell proliferation and invasion via functioning as a ceRNA to modulate BAALC.
As a common female malignancy, triple-negative breast cancer (TNBC) is the most serious subtype in breast cancer (BC). BAALC binder of MAP3K1 and KLF4 (BAALC) is a common oncogene in acute myelocytic leukemia (AML). We sought to explore the role of BAALC in TNBC. In this study, BAALC was significantly upregulated in TNBC tissues and cells. Then, the results of functional assays disclosed that BAALC facilitated cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) processes, but repressed cell apoptosis in TNBC. Next, miR-380-3p was identified as the upstream of BAALC in TNBC cells. Moreover, LRRC75A-AS1 (also named small nucleolar RNA host gene 29: SNHG29) was verified to act as the sponge of miR-380-3p to elevate BAALC expression in TNBC. Besides, LRRC75A-AS1 could negatively regulate miR-380-3p but positively regulate BAALC expression. Finally, rescue assays elucidated that LRRC75A-AS1 facilitated cell proliferation, invasion, and EMT processes in TNBC by targeting miR-380-3p/BAALC pathway. Taken together, our study revealed a novel ceRNA network of LRRC75A-AS1/miR-380-3p/BAALC in accelerating TNBC development, indicating new promising targets for TNBC treatment.


Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial.
For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8-3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference -7·00% [95% CI -12·69 to -1·32]; p=0·016). For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. British Heart Foundation and Pharmacosmos.


The intriguing heterogeneity of human salivary proline-rich proteins: Short title: Salivary proline-rich protein species.
The most heterogeneous family of human salivary proteins is represented by proline-rich proteins (PRPs) divided in acidic, basic, and basic glycosylated (aPRPs, bPRPs, gPRPs). They are encoded by six genes, clustered on chromosome 12p13.2: PRH1-2 encode aPRPs, PRB1-4 encode bPRPs and gPRPs. Each gene exists in different allelic forms: two for PRH2, three for PRH1, PRB2, and PRB4, four for PRB1, and PRB3. During granule maturation, PRP proproteins undergo proteolysis by the action of convertases and carboxypeptidases. Differently from bPRPs, proteolysis of aPRPs is not complete, and, besides fragments, entire protein species are also secreted. Maturation process generates ten aPRPs (PRP-1, PRP-2, PIF-s, Db-s, Pa, PRP-3, PRP-4, PIF-f, Db-f, P-C), and at least 18 bPRPs (II-2, P-E, IB-6, Ps-1, Ps-2, IB-1, P-J, IB-8a, P-F, P-H, P-D, II-1, protein glycosylated A, CD-IIg, and Gl1-4). In addition, single nucleotide and length polymorphisms, and differentially spliced transcripts originate several natural variants. Phosphorylation, N-pyroglutaminylation, dimerization, and N-/O-glycosylation also occur during maturation, enlarging the number of protein species, further increased by proteolytic events governed by carboxy- and endo-peptidases during and after secretion, and giving rise to a huge number of small peptides. The PRP functional role is still poorly understood. The high polymorphism of PRPs gives an important contribution to the high heterogeneity and inter-individual variability of the human salivary proteome. The products of six genes clustered on chromosome 12p13.2 comprise a mixture of entire, truncated, phosphorylated, glycosylated and dimerized protein/peptide species, sharing large part of their sequences, and possibly involved in different biological activities. Whatever the role of PRP species is, it should be crucial, given that PRPs are the most conserved oral salivary proteins among mammals.


The F3/11 cell adhesion molecule mediates the repulsion of neurons by the extracellular matrix glycoprotein J1-160/180.
The oligodendrocyte-derived extracellular matrix protein J1-160/180 displays repellent substrate properties toward neurons. In a search for neuronal ligands mediating the response to J1-160/180, we have identified the F3/11 cell surface protein, a glyco-phosphatidylinositol-anchored member of the immunoglobulin superfamily. F3/11 mediates the initial recognition between a J1-160/180 substrate and cerebellar neurons or F3-transfected CHO cells. In cerebellar neurons, the F3/11-J1-160/180 interaction induces a repulsion consisting of the loss of substrate adhesion with time in culture and inhibition of neurite outgrowth. Antibody blocking experiments show that the avoidance response of neurites at J1-160/180 substrate borders is also mediated by F3/11. Active cell-cell and cell-substrate repulsion is considered a major mechanism governing the extent and directionality of axonal growth, but the ligand-receptor interactions involved have remained unknown. Our results show that F3/11 mediates the neuronal response to the repellent molecule J1-160/180 and may thus be involved in signal transduction leading to cell repulsion.


Fusion of the endoplasmic reticulum by membrane-bound GTPases.
The endoplasmic reticulum (ER) membrane forms an elaborate network of tubules and sheets that is continuously remodeled. This dynamic behavior requires membrane fusion that is mediated by dynamin-like GTPases: the atlastins in metazoans and Sey1p and related proteins in yeast and plants. Crystal structures of the cytosolic domains of these membrane proteins and biochemical experiments can now be integrated into a model that explains many aspects of the molecular mechanism by which these membrane-bound GTPases mediate membrane fusion.


Nicotine effects on affective response in depression-prone smokers.
Comorbidity between cigarette smoking and depression is thought to arise because depression-prone smokers self-administer nicotine to improve mood. Yet little evidence supports this view, and nicotine's effect on positive affect deficiency in depression remains largely unstudied. We hypothesized that (1) nicotine would dispel negative affect and enhance positive affect and (2) effects would be stronger for smokers vulnerable to depression, particularly during a depressed state. Regular smokers (N = 165) were recruited from the community: 63 with no history of major depressive disorder (MDD), 61 with recurrent past but no current MDD, and 41 with both current and past MDD. During four sessions, participants smoked either a nicotinized (NIC+) or denicotinized (NIC-) cigarette double blind after experiencing a negative mood induction or while undergoing a positive mood induction. Positive and negative affects were measured at baseline and at two time points after smoking. Previously depressed smokers showed a heightened positive mood response to positive mood induction when smoking a nicotinized cigarette. Nicotine also increased the degree to which positive mood induction dispelled negative mood in depression-vulnerable smokers. Finally, nicotine worsened the negative affect response to negative mood induction for all groups. Self-administering nicotine appears to improve depression-prone smokers' emotional response to a pleasant stimulus.


An in-situ blocking strategy for improved anti-interference inspection of AFB1 based on hollow covalent organic framework capsules with commodious and undisturbed microenvironment.
This work proposed an in-situ blocking strategy for improved anti-interference and signal-amplified inspection of hazards via constructing hollow covalent organic framework (HCOF) capsules. An aptamer-FRET nanoprobe integrated with carbon dots and CuS was introduced into the micro-capsule as signal indicator to demonstrate the proof-of-concept. The HCOF was successfully prepared by removing the metal-organic frameworks (MOF) core from the MOF@COF that had been preloaded with the nanoprobes under mild conditions. Meanwhile, the hydrophobic surface of HCOF enhanced the adsorption and penetration of aflatoxin B1 (AFB1) into the capsule to interact with the nanoprobes. This strategy was applied to detect AFB1 in food samples, achieving a linear response of 1-300 nM along with a detection limit of 0.3 nM. Selectivity test verified that the prepared sensing platform could specifically recognize AFB1 without complex sample pretreatment. This study provides new ideas for improved anti-interference inspection of hazards against complex sample matrix.


Fractures of the neck of the talus and the Blair fusion: a review of the literature and case report.
Historically, fractures of the neck of the talus have been serious injuries with sometimes devastating results. Several mechanisms have been reviewed to explain the types of injuries most commonly seen. Hawkin's classification of the types of talar neck fractures has been explained and used as a guideline in a review of treatment and results of talar neck fractures. Hawkin's group I fractures generally require only immobilization and are frequently without serious sequelae. Hawkin's group II fractures are more serious injuries, which may frequently be treated with closed reduction. Open reduction is occasionally necessary. Hawkin's group III fractures have the most potentially devastating results. These generally require open reduction with internal fixation or occasionally primary salvage procedures. Secondary salvage procedures are also sometimes necessary. Avascular necrosis of the talar body is reviewed in detail, including correlation with the type of fracture as well as diagnostic techniques and treatment. Other complications, including soft-tissue damage, osteomyelitis, malunion, and posttraumatic arthrosis, are discussed. The Blair tibiotalar arthrodiesis is reviewed in detail, with the consideration that it may be used as a primary or secondary salvage procedure with good results. Finally, a case in which the Blair fusion was used successfully is reported with 1-year follow-up.


Some aspects of proximal tubular sodium chloride reabsorption in Necturus kidney.
Some aspects of proximal tubular sodium chloride reabsorption in Necturus kidney. Renal tubular reabsorption of fluid and sodium was measured by clearance methods in the doubly perfused Necturus kidney in which the bicarbonate concentration was varied between 0 and 60 mEq/liter. The effects of Damox (2.2 times 10-3M), ocubain (10-5M) and ethacrynic acid (10-4M) and of acidosis were also investigated. In addition to clearance experiments, stationary microperfusion experiments were carried out on promimal tubules to measure volume flow and steady-state sodium and chloride concentration differences across the tubular epithelium. In some experiments, the transepithelial electrical potential difference was also measured using an axial electrode system. The following results were obtained: 1) Bicarbonate is not essential to the operation of renal tubular fluid and sodium transport. 2) Total renal and proximal tubular fluid and sodium transport are partially inhibited by Diamox, ouabian and ethacrynic acid. 3) The proximal tubule maintains a significant transepithelial sodium and chloride concentration difference and a significant electrical potential difference (lumen-negative) in the presence of a poorly permeant nonelectrolyte. The direction and magnitude of the electrical polarization fully accounts for the observed chloride concentration difference. The data support the thesis that sodium chloride transport accross the proximal tubular epithelium takes place by active sodium transport and electically coupled passive chloride reabsorption. Important species differences with respect to mammalian transport mechanisms are discussed.


Reproductive factors and cancers of the breast, ovary and endometrium.
In contrast to cancers of non-hormone-dependent sites, cancers of the breast, ovary and endometrium show a slowing down of the rate of increase in incidence at around age 50, as if ceasing menstrual activity reduced risk. Also nulliparous women appear more prone to these three cancers as compared to parous women, thus suggesting that pregnancies also represent a 'protected' time. Epidemiological studies on breast cancer, the only ones sufficiently large to try to disentangle meaningfully the effects of collinear reproductive variables such as parity and ages at first and last birth, show, however, that the effect of pregnancy is not simple and depends on how many births take place and at what age. Larger population-based investigations able to obtain with greater precision information not only on reproductive factors but also on possible confounding variables (e.g. socio-economic status, dietary habits, etc.) are mandatory, particularly as regards ovarian cancer and endometrial cancer. The lesson from the recent studies on pregnancy-related events and breast cancer is, however, that initially a decrease of old certainties must be expected to derive from the accumulation of new, better epidemiological data.


Non-pharmacological interventions for chronic cough: The past, present and future.
Non-pharmacological interventions have been explored in people with refractory chronic cough. Normally delivered by Physiotherapists and or Speech and Language Therapists, these interventions aim to educate patients about their cough, provide them with cough suppression techniques and breathing exercises, improve vocal/laryngeal hydration and psychoeducational counselling to help them gain greater control of their cough. Six key studies have been completed over the past 12 years that have consistently found non-pharmacological interventions help to improve quality of life and reduce cough frequency. Some studies also found improvements in cough reflex sensitivity and severity. Despite promising results there now needs to be further work to optimise these interventions. There is a need to standardise terminology used such as relabelling the intervention as cough control therapy and move away from uni-disciplinary terms. Standardised patient selection, including screening protocols, optimal timing and delivery of the interventions as well as the outcome measures used to evaluate interventions need further exploration.


Steroid-induced suppression of gallium uptake in tumors of the central nervous system: concise communication.
The effect of steroids given in greater than replacement doses on the gallium and technetium glucoheptonate brain scan is evaluated by comparing the relative sensitivity of both radiopharmaceuticals in patients both on and off steroids. The study shows a significant steroid effect on the sensitivity of 95% to 64% following steroids. Steroids did not significantly alter the sensitivity of the technetium glucoheptonate study. The superiority of the TcGH brain scan over the gallium citrate brain scan in the steroid population suggests a difference in the uptake mechanism for the two radiopharmaceuticals.


Fc-gamma receptor 3A polymorphism predicts the incidence of urinary tract infection in kidney-transplant recipients.
We investigated the impact of polymorphisms in host innate immunoregulatory genes on the development of infectious complications after kidney transplantation (KT). The single-nucleotide polymorphisms (SNPs) of C1QA [276 A/G], FCGR2A [131 H/R], and FCGR3A [158 F/V], genes encoding the Fc gamma receptor (FcγR), were analyzed in 81 KT recipients in relation to the occurrences of postoperative infectious complications within 30days after KT. Consistent with a lower affinity of the isoform encoded by the FCGR3A [158 F] to both IgG1 and IgG3, a significantly higher incidence of urinary tract infections (UTIs) was observed in the FCGR3A [158 F/V or F/F] individuals (65.5%) than in the FCGR3A [158 V/V] individuals (34.5%) following KT. The combination of FCGR2A and FCGR3A SNPs further stratified the incidence of UTIs, regardless of C1QA SNP following KT. No differences were observed in the incidence of fungal or cytomegalovirus infections with respect to the 3 gene polymorphisms. In conclusion, our findings indicate that FcγR SNPs are predisposing factors for UTIs after KT. This study provides a foundation for further prospective studies on a larger scale.


Soluble expression and purification of the oxidoreductase component of toluene 4-monooxygenase.
Toluene 4-monooxygenase (T4MO) is a member of the bacterial multicomponent monooxygenases, an enzyme family that utilizes a soluble diiron hydroxylase to oxidize a variety of hydrocarbons as the initial step in their metabolism. The hydroxylases obtain reducing equivalents from NAD(P)H via an electron transfer chain that is initiated by an oxidoreductase containing an N-terminal ferredoxin domain and C-terminal flavin- and NAD-binding domains. T4moF, the NADH oxidoreductase of T4MO, was expressed as a soluble protein in Escherichia coli BL21(DE3) from the pUC-derived expression vector pRS205. This vector contains a lac promoter instead of a T7 promoter. A three step purification from the soluble cell lysate yielded approximately 1 mg of T4moF per gram of wet cell paste with greater than 90% purity. The purified protein contained 1 mol of FAD and 2 mol of Fe per mol of T4moF; quantitative EPR spectroscopy showed approximately 1 mol of the S=1/2 signal from the reduced [2Fe-2S] cluster per mol of T4moF. Steady state kinetic analysis of p-cresol formation activity treating T4moF as the variable substrate while all other proteins and substrates were held constant gave apparent K(M-) and apparent k(cat)-values of 0.15 microM and 3.0 s(-1), respectively. This expression system and purification allows for the recovery of the soluble oxidoreductase in yields that facilitate further biochemical and structural characterizations.


"Ask me what I need": A call for shifting responsibility upwards and creating inclusive learning environments in clinical placement.
Ontario's human-rights legislation and institutions' support for students with disabilities have influenced these students' increased enrolment in the postsecondary environment. Yet more attention is paid to in-classroom than to out-of-classroom experiences. Students with disabilities enrolled in nursing are least likely to be accommodated. This has significant implications for access and equity upon graduation, as clinical placements are a bridge between school and employment. To explore clinical instructors' and students who identify with disabilities' perspectives on nursing clinical placements. A descriptive case-report was used: interactive take-home diaries were completed and semi-structured interviews were conducted with clinical instructors (n-14) and nursing students with disabilities (n-14) in Ontario. An iterative inductive analysis was undertaken. Three overarching themes were identified: (a) an immovable clinical environment in relation to technology and time, (b) a perceived conflict between nursing and disability identity, and (c) a need to shift responsibility upwards while listening to lived experience. The clinical environment is a highly contested space; different identity groups have distinct roles and differing degrees of power within it. Our research calls for a shift in the nursing landscape to be led by education and medical institutions that can build supportive networks, develop clear policies and listen to nursing students with disabilities.


Cluster sampling with referral to improve the efficiency of estimating unmet needs among pregnant and postpartum women after disasters.
Women of reproductive age, in particular women who are pregnant or fewer than 6 months postpartum, are uniquely vulnerable to the effects of natural disasters, which may create stressors for caregivers, limit access to prenatal/postpartum care, or interrupt contraception. Traditional approaches (e.g., newborn records, community surveys) to survey women of reproductive age about unmet needs may not be practical after disasters. Finding pregnant or postpartum women is especially challenging because fewer than 5% of women of reproductive age are pregnant or postpartum at any time. From 2009 to 2011, we conducted three pilots of a sampling strategy that aimed to increase the proportion of pregnant and postpartum women of reproductive age who were included in postdisaster reproductive health assessments in Johnston County, North Carolina, after tornadoes, Cobb/Douglas Counties, Georgia, after flooding, and Bertie County, North Carolina, after hurricane-related flooding. Using this method, the percentage of pregnant and postpartum women interviewed in each pilot increased from 0.06% to 21%, 8% to 19%, and 9% to 17%, respectively. Two-stage cluster sampling with referral can be used to increase the proportion of pregnant and postpartum women included in a postdisaster assessment. This strategy may be a promising way to assess unmet needs of pregnant and postpartum women in disaster-affected communities.


Apolipoprotein E in Cardiovascular Diseases: Novel Aspects of an Old-fashioned Enigma.
The presence of different APOE isoforms represents a well-known risk factor for cardiovascular diseases. Besides the pleiotropic effects of APOE polymorphism on heart and neurological diseases, this review summarizes the less-known functions of APOE and the possible implications for cardiovascular disorders. Beyond the role as lipid transporting protein, its involvement in lipid membrane homeostasis and signaling, as well as its nuclear transcriptional effects suggests a more complex role of APOE, receiving great interest from researchers and physicians from all medical fields. Due to the presence of different APOE isoforms in human population, understanding APOE's role in pathological processes represents not only a challenge, but a demand for further development of therapeutic strategies for cardiovascular diseases.


In vitro derivation and expansion of endothelial cells from embryonic stem cells.
Vascular endothelial cells or endothelial progenitor cells derived from stem cells could potentially lead to a variety of clinically relevant applications, including cell-based therapies and tissue engineering. Embryonic stem (ES) cells serve as an excellent in vitro system for studying differentiation events and for developing methods of generating various specialized cells for future regenerative therapeutic applications. Two obstacles associated with using embryonic stem cells include (1) isolating homogeneous populations of differentiated cells and (2) obtaining terminally differentiated cell populations that are capable of proliferating further. Here, we describe methods for isolating purified proliferating populations of endothelial cells from mouse ES cells using Flk-1-positive cells, vascular endothelial growth factor supplementation, and a highly selective manual selection technique. This methodology, although rigorous, overcomes two current obstacles in ES derivation and culture by generating highly purified (>96%) populations of actively proliferating endothelial cells from mouse ES cells. Using this in vitro derivation procedure, millions of cells at various stages of differentiation may be obtained and expanded up to 25 population doublings.


Ethanol exposure enhances cell death in the developing cerebral cortex: role of brain-derived neurotrophic factor and its signaling pathways.
Exposure to ethanol during fetal development induces brain damage, causing cell loss in several brain areas and affecting synaptic connections. Because neurotrophin signaling plays an important role in neuronal survival and differentiation, we have investigated the effect of ethanol exposure on cell death in the developing cerebral cortex and whether this effect correlates with alterations in brain-derived neurotrophic factor (BDNF) levels, expression of its receptors, TrkB, and its signaling. We report that chronic ethanol intake during gestation and lactation enhances natural cell death and induces cell necrosis, decreases BDNF levels, and increases the ratio of the truncated to full-length TrkB mRNA receptors during postnatal developing cerebral cortex. Furthermore, we provide evidence that during brain development BDNF activates the extracellular signal-regulated kinases (ERK1 and ERK2) and the phosphoinoside-3-kinase (PI-3-K/Akt) pathways. However, BDNF-induced cell signaling throughout the above-mentioned survival pathways is significantly reduced by ethanol exposure. These findings suggest that ethanol-induced alterations in BDNF availability and in its receptor function might impair intracellular signaling pathways involved in cell survival, growth, and differentiation, leading to enhanced natural cell death during cerebral cortex development.


Genetics and function of isocitrate lyase in Coprinus.
Thirteen chromosomal loci have been identified which affect acetate metabolism in Coprinus. Mutants at only two loci, acu-l and acu-7, are deficient in isocitrate lyase (ICL) (EC 18.104.22.168) activity. acu-1 mutants are unable to induce ICL because they lack acetyl-CoA synthetase which is required to convert acetate to the metabolic inducer of ICL. acu-7 is the structural gene for ICL. This was shown by selecting temperature sensitive acu+ revertants resulting from a second mutation within the acu-7 gene. One such revertant was shown to produce an ICL protein which was more thermolabile than the wild type enzyme. Other workers have postulated that ICL activity is important during asexual morphogenesis in fungi. No evidence was found for this in Coprinus. The morphological mutant oidial, which produces abundant asexual spores even in submerged culture, had the same low uninduced level of ICL activity as the wild type. Moreover, an acu-7 mutation had no effect on the expression of the oidial phenotype.


Leg lesions and cleanliness of finishing bulls kept in housing systems with different lying area surfaces.
The influence of the quality of different lying surfaces on lesions and swellings at the joints as well as on the cleanliness of finishing bulls throughout the fattening period was studied. On 17 farms (623 bulls), pens with fully slatted concrete floors (CONCRETE), with rubber coated slats (RUBBER), with cubicles (CUBICLES, provided with five different types of soft lying mat) and with a littered lying area (STRAW) were compared. Bulls kept on STRAW developed the smallest lesion scores at the joints. In CUBICLES, there was a huge variability in the lesion scores depending on the type of lying mat, ranging from values comparable to STRAW up to and greater than the values for CONCRETE. The highest lesion scores at the carpal joints were found on CONCRETE, with intermediate values on RUBBER and in CUBICLES. At the tarsal joints, lesion scores were similar on CONCRETE and RUBBER and in the same range or worse on most mats in the CUBICLES. Swelling scores were highest on CONCRETE and intermediate on RUBBER and in CUBICLES compared to STRAW. In general, there was a steady increase in the lesion scores of the leg joints throughout the fattening period on CONCRETE, RUBBER and STRAW, whereas on some of the mats in CUBICLES these scores were at a high level from early on in the fattening period. Animals in all the housing systems were clean over the whole fattening period. Littering the lying area in CUBICLES affected neither the lesion scores nor the swelling scores at the joints nor animal cleanliness. In conclusion, both rubber coated slats and cubicles provided with soft lying mats were favourable with regard to the levels of lesions and swellings of the leg joints of finishing bulls compared to concrete slats. However, these levels were even lower in pens with a straw bedded lying area.


Patterning of NREM sleep periods in normals: an observation revisited.
Both the visual examination of all-night sleep recordings in both normals and patients, generated by a delta wave analyzer, and spectral analysis have suggested that delta wave sleep often appear to rise gradually during a NREM period and then to cease abruptly. Such observations by minute-by-minute computer plots of delta wave activity have strengthened the notion of a REM generator and/or a delta sleep generator in the central nervous system. We now report observations on a sample of 23 normal subjects under the age of 45 in which we investigated the 'rise and fall' of delta sleep activity during successive NREM periods. For these 23 normal subjects, significantly greater maximal decreases throughout the night were noted in each of these 4 NREM periods as compared to the maximal increases. Furthermore, these findings have implications for the understanding of the physiology of sleep and particularly the on- and off-generator of REM and NREM sleep.


Motor neurone acetylcholinesterase release precedes neurotoxicity caused by systemic administration of excitatory amino acids and strychnine.
We have proposed that neuronal overactivation by either stimulation of excitatory receptors or hypofunction of inhibitory circuits is a cause of excessive acetylcholinesterase (AChE) release, which, in turn, can contribute to ALS/MND pathogenesis. We investigated histochemical and histopathological changes in cell populations of the mouse spinal ventral horn upon in vivo stimulation of glutamate receptors with L-aspartate (ASP, 10-50 mg/kg, intraperitoneal: i.p.), or blockade of glycine receptors with strychnine (STRY, 2 mg/kg, i.p.). ASP in P4-P13 (postnatal age in days) but not in older mice, and STRY irrespective of age, provoked rapid, striking depletions of motor neurone AChE, and appearance of AChE activity in astrocytes. This was followed by recovery of the enzyme in most motor neurones, astrocyte activation and statistically significant changes in: brain macrophage infiltration, loss of interneurones and motor neurones and neuronophagic images including rosettes of glial cells surrounding a central 'ghost-like' motor neurone. Although AChE release preceded the neuropathology found, it is not known if its uptake is a cause of glial activation. However, it has been shown that the enzyme potentiates non-N-metyl-D-aspartate receptors identical to those that mediate astrocyte activation. AChE activity produces protons and choline, possible microglial activators. These are putative routes towards long-lasting neuropathology.


Early effects of oestrogen treatment on lipogenesis de novo and on biosynthesis of triacylglycerol from fatty acids in male chick liver.
1. Early changes (0-44 hr) in liver and plasma lipid levels and in the rate of hepatic lipogenesis were measured in male chicks after a single intramuscular injection of oestradiol-17 beta. 2. Chick liver slices were employed to measure the rate of lipogenesis de novo using 3H2O and the rate of triacylglycerol synthesis from [9, 10-3H] palmitate at various times after injection. 3. The results suggest that oestrogen-induced lipogenesis occurs initially by a rapid and coordinated stimulation of the total hepatic capacity for lipogenesis de novo and for triacyglycerol synthesis from fatty acids. 4. The results are discussed in relation to oestrogen-induced changes in hepatic lipogenic enzymes.


Efficacy and Safety of PD-1/PD-L1 Inhibitor as Single-Agent Immunotherapy in Endometrial Cancer: A Systematic Review and Meta-Analysis.
The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway plays a crucial role in the immune escape mechanism and growth of cancer cells in endometrial cancer (EC). Clinical trials investigating PD-1/PD-L1 inhibitor have shown promising results in other cancers, but their efficacy in EC still remains uncertain. Therefore, this meta-analysis aims to provide an updated and robust analysis of the effectiveness and safety of PD-1/PDL1 inhibitor as single-agent immunotherapy in EC, focusing on the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). This meta-analysis utilized STATA version 17 and RevMan version 5.4 software to pool the results of relevant studies. Five studies conducted between 2017 and 2022, comprising a total of 480 EC patients enrolled for PD-1/PD-L1 inhibitor immunotherapy met the inclusion criteria. The pooled proportion of EC patients who achieved ORR through PD-1/PD-L1 inhibitor treatment was 26.0% (95% CI: 16.0-36.0%; p < 0.05). Subgroup analysis based on mismatch repair (MMR) status showed an ORR of 44.0% (95% CI: 38.0-50.0%; p = 0.32) for the deficient mismatch repair (dMMR) group and 8.0% (95% CI: 0.0-16.0%; p = 0.07) for the proficient mismatch repair (pMMR) group. Pooled proportion analysis by DCR demonstrated an odds ratio (OR) of 41.0% (95% CI: 36.0-46.0%, p = 0.83) for patients undergoing PD-1/PD-L1 inhibitor treatment. Subgroup analysis based on MMR status revealed DCR of 54.0% (95% CI: 47.0-62.0%; p = 0.83) for the dMMR group, and 31.0% (95% CI: 25.0-39.0%; p = 0.14) for the pMMR group. The efficacy of PD-1/PD-L1 inhibitors was significantly higher in the dMMR group compared to the pMMR group, in terms of both ORR (OR = 6.30; 95% CI = 3.60-11.03; p < 0.05) and DCR (OR = 2.57; 95% CI = 1.66-3.99; p < 0.05). In terms of safety issues, the pooled proportion of patients experiencing at least one adverse event was 69.0% (95% CI: 65.0-73.0%; p > 0.05), with grade three or higher AEs occurring in 16.0% of cases (95% CI: 12.0-19.0%; p > 0.05). Based on the subgroup analysis of MMR status, PD-1/PD-L1 inhibitor immunotherapy showed significantly better efficacy among dMMR patients. These findings suggest that patients with dMMR status may be more suitable for this treatment approach. However, further research on PD-1/PD-L1 inhibitor immunotherapy strategies is needed to fully explore their potential and improve treatment outcomes in EC.


Physical exercise mitigates behavioral impairments in a rat model of sporadic Alzheimer's disease.
Physical exercise has proven to be beneficial to mitigate several deleterious effects associated with neurodegenerative diseases, including Alzheimer's Disease (AD). Here, we investigated the role of long-term exercise as a preventive and therapeutic tool against AD cognitive and behavioral impairments using a sporadic AD-like rat model, established through the administration of streptozotocin (STZ) inside both cerebral ventricles (icv). Six-weeks-old Wistar male rats (56) were divided into groups (either saline or STZ): sedentary (Sed), voluntary physical activity (VPA), VPA + endurance treadmill training (VPA + ET) and VPA + ET only after the injection (VPA + ET-post). Surgeries occurred at 16wks and the animals were sacrificed at 28 wks. VPA, VPA + ET, and VPA + ET-post had continuous access to the running wheels during the entire experimental protocol. VPA + ET (entire protocol) and VPA + ET-post (only after surgical procedure) ran 60 min/d, 25 m/min, 5d/wk in a treadmill. Both ET regimens led to significant improvements in the compromised spatial learning and long-term memory of STZ-infused animals that were not observed neither in the saline Sed nor in VPA STZ groups. General activity patterns and exploration habits were also ameliorated with chronic-exercise in STZ treated animals, while freezing patterns were decreased in these groups. these results were further. Positive alterations were seen in mitochondrial oxygen consumption endpoints (synaptosomal and non-synaptosomal brain mitochondria) that might underlie the neurobehavioral improvements observed. Data suggest that VPA alone was not able to counteract the AD-related deleterious consequences, although when accompanied by endurance training (either lifelong or later-life) may be able to prevent and reverse cognitive and phenotypic impairments associated with AD.


Conformational rearrangements required of the V3 loop of HIV-1 gp120 for proteolytic cleavage and infection.
HIV gp120 is specifically cleaved at a single site in the V3 loop between Arg315 and Ala316 by thrombin. Previous observations by others have indicated that binding to CD4 enhances the rate of V3 loop cleavage, and that this cleavage is a prerequisite for HIV infection. Other observations also suggest that the cleavage site is in a type II beta-turn centered at Pro313-Gly314. However, our docking experiments indicate that this conformation cannot dock to thrombin and other trypsin-like serine proteases. Thus, based on the thrombin-bound conformation of peptide substrates, we propose that CD4 binding, at a site remote from the V3 loop, induces and stabilizes a trans to cis isomerization of the highly conserved residue Pro313, and that this conformational shift is a prerequisite for cleavage by a 'thrombin-like' cellular protease and subsequent infection.


Lipolytic enzymes as markers of induction and differentiation.
Factors leading to microsomal enzyme induction are associated with hypertriglyceridemia in man. Phenobarbital (PB) increases hepatic synthesis of triglyceride but lowers its serum concentration in rats due to increased postheparin plasma activities of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL); these changes are accompanied by increased activity of these lipolytic enzymes in adipose tissue and liver. The present work explores the cellular mechanisms whereby PB increases the tissue content of these enzymes, using primary cultures of rat liver hepatocytes and a continuous cell line of mouse fibroblasts (preadipocytes) that undergo differentiation into mature fat cells. Secretion and synthesis of HTGL in primary rat hepatocytes increased 50% with insulin; when PB was added with insulin, activity was enhanced an additional 50%. By contrast, insulin inhibited HTGL secretion from the well differentiated rat hepatoma cell line, FU-5-5, C8, and this inhibition was partly overcome by PB. These results suggest that different control mechanisms govern the synthesis and secretion of HTGL in normal rat liver cells and hepatoma. In cultured pre-adipocytes (3T3-F442A) insulin promoted differentiation when added to confluent cultures. PB (0.5 mM) resulted in marked enhancement of conversion of adipocytes characterized by a two- to threefold increase in extracellular LPL and a 10-fold increase in intracellular enzyme. These results suggest that PB promotes conversion of uncommitted cells into pre-adipocytes at an early stage in the differentiation of adipose tissue.


Prostaglandins prevent inducible nitric oxide synthase protein expression by inhibiting nuclear factor-kappaB activation in J774 macrophages.
We investigated the effect of PGE2 and iloprost (a prostacyclin analogue) on inducible nitric oxide synthase (iNOS) protein expression and nuclear factor-kappaB (NF-kappaB) activation in lipopolysaccharide (LPS)-stimulated J774 macrophages. Incubation of J774 cells with LPS (10 microg/ml) caused an increase of iNOS protein expression which was prevented in a concentration-dependent fashion by PGE2 (0.1, 1, 10 microM) and iloprost (0.01, 0.1, 1 microM). Electrophoretic mobility shift assay indicated that both prostanoids blocked the activation of NF-kappaB, a transcription factor necessary for NO synthase induction. PGE2 and iloprost also blocked disappearance of I kappaB-alpha from cytosolic fraction and nuclear translocation of NF-kappaB subunits p50 and p65. These results show for the first time that PGE2 and iloprost down-regulate iNOS protein expression by inhibiting NF-kappaB activation and suggest a negative feed-back mechanism that may be important for limiting excessive or prolonged NO production in pathological events.


Testosterone and cardiovascular disease.
Use of testosterone among men is increasing rapidly. Low serum testosterone is positively associated with cardiovascular disease and its risk factors. No large randomized controlled trial (RCT) has assessed the effects of testosterone on cardiovascular outcomes. Here recent evidence accumulating from other sources - pharmacoepidemiology, Mendelian randomization studies and meta-analysis of small RCTs - is reviewed to inform current testosterone usage. In a large, well conducted pharmacoepidemiology study specifically testosterone prescription was associated with myocardial infarction. Two Mendelian randomization studies did not corroborate beneficial effects of higher endogenous testosterone on cardiovascular risk factors, but suggested higher endogenous testosterone raised LDL cholesterol and lowered HDL cholesterol. A comprehensive meta-analysis of RCTs summarizing 27 trials including 2994 men found increased risk of cardiovascular-related events on testosterone (odds ratio 1.54, 95% confidence interval 1.09-2.18). Contrary to expectations from observational studies, current indications suggest testosterone causes ischemic cardiovascular disease with corresponding implications for practice. A large RCT would undoubtedly settle the issue definitively. Given mounting evidence of harm and the urgency of the situation assembling all the evidence from completed RCTs of testosterone or androgen deprivation therapy and use of Mendelian randomization might generate a definitive answer most quickly.


Weibull analysis and flexural strength of hot-pressed core and veneered ceramic structures.
To test the hypothesis that the Weibull moduli of single- and multilayer ceramics are controlled primarily by the structural reliability of the core ceramic.Methods. Seven groups of 20 bar specimens (25 x 4 x 1.2 mm) were made from the following materials: (1) IPS Empress--a hot-pressed (HP) leucite-based core ceramic; (2) IPS Empress2--a HP lithia-based core ceramic; (3 and 7) Evision--a HP lithia-based core ceramic (ES); (4) IPS Empress2 body--a glass veneer; (5) ES (1.1 mm thick) plus a glaze layer (0.1 mm); and (6) ES (0.8 mm thick) plus veneer (0.3 mm) and glaze (0.1 mm). Each specimen was subjected to four-point flexure loading at a cross-head speed of 0.5 mm/min while immersed in distilled water at 37 degrees C, except for Group 7 that was tested in a dry environment. Failure loads were recorded and the fracture surfaces were examined using SEM. ANOVA and Duncan's multiple range test were used for statistical analysis. No significant differences were found between the mean flexural strength values of Groups 2, 3, 5, and 6 or between Groups 1 and 4 (p>0.05). However, significant differences were found for dry (Group 7) and wet (Groups 1-6) conditions. Glazing had no significant effect on the flexural strength or Weibull modulus. The strength and Weibull modulus of the ES ceramic were similar to those of Groups 5 and 6. The structural reliability of veneered core ceramic is controlled primarily by that of the core ceramic.


Scanning electron microscopy of the channel catfish olfactory lamellae.
The olfactory lamellae of the channel catfish (Ictalurus punctatus) are composed of sensory and indifferent (non-sensory) epithelia organized into two distinct regions on both surfaces of each lamella. The smaller sensory region located adjacent to the midline raphe has fewer cilia per unit surface area than the indifferent epithelium and contains the olfactory neurons whose ciliated dendritic terminals occur at the epithelial surface. The indifferent epithelium, comprising the greater surface area of the olfactory lamella, is covered with a dense mat of non-sensory cilia. Fractured carbon dioxide critical point dried lamellar tissue revealed the underlying cellular structure. The lamellae are composed of two layers of epithelium enclosing a thin stromal layer. Olfactory receptors were observed in the fractured tissue only within the sensory epithelium.


Staphylococcus aureus with inducible clindamycin resistance and methicillin resistance in a tertiary hospital in Nepal.
Staphylococcus aureus is a global public health issue in both community and hospital settings. Management of methicillin-resistant S. aureus (MRSA) infections are tough owing to its resistance to many antibiotics. Macrolide-lincosamide-streptogramin B (MLSB) antibiotics are commonly used for the management of MRSA. This study was aimed to determine the occurrence of inducible clindamycin- and methicillin-resistant S. aureus at a tertiary care hospital in Kathmandu, Nepal. A total of 1027 clinical samples were processed following standard laboratory procedures and antibiotic susceptibility testing of S. aureus was performed by disc diffusion method. MRSA isolates were detected phenotypically using cefoxitin disc, and inducible clindamycin resistance was detected phenotypically using the D-zone test. Of 1027 samples, 321 (31.2%) were culture positive, of which 38 (11.8%) were S. aureus. All S. aureus isolates were susceptible to vancomycin, and 25 (67%) of S. aureus isolates were multidrug-resistant. Similarly, 15 (39.5%) of S. aureus were MRSA and 14 (36.5%) were inducible clindamycin-resistant phenotypes. Inducible clindamycin and methicillin resistance were common in S. aureus. This emphasizes that the methicillin resistance test and the D-zone test should be incorporated into the routine antibiotic susceptibility testing in hospital settings.


Nitrogen cycling of atmosphere-plant-soil system in the typical Calamagrostis angustifolia wetland in the Sanjiang Plain, northeast China.
The nitrogen (N) distribution and cycling of atmosphere-plant-soil system in the typical meadow Calamagrostis angustifolia wetland (TMCW) and marsh meadow Calamagrostis angustifolia wetland (MMCW) in the Sanjiang plain were studied by a compartment model. The results showed that the N wet deposition amount was 0.757 gN/(m2 x a), and total inorganic N (TIN) was the main body (0.640 gN/(m2 x a). The ammonia volatilization amounts of TMCW and MMCW soils in growing season were 0.635 and 0.687 gN/m2, and the denitrification gaseous lost amounts were 0.617 and 0.405 gN/m2, respectively. In plant subsystem, the N was mainly stored in root and litter. Soil organic N was the main N storage of the two plant-soil systems and the proportions of it were 93.98% and 92.16%, respectively. The calculation results of N turnovers among compartments of TMCW and MMCW showed that the uptake amounts of root were 23.02 and 28.18 gN/(m2 x a) and the values of aboveground were 11.31 and 6.08 gN/(m2 x a), the re-translocation amounts from aboveground to root were 5.96 and 2.70 gN/(m2 x a), the translocation amounts from aboveground living body to litter were 5.35 and 3.38 gN/(m2 x a), the translocation amounts from litter to soil were larger than 1.55 and 3.01 gN/(m2 x a), the translocation amounts from root to soil were 14.90 and 13.17 gN/(m2 x a), and the soil (0-15 cm) N net mineralization amounts were 1.94 and 0.55 gN/(m2 x a), respectively. The study of N balance indicated that the two plant-soil systems might be situated in the status of lacking N, and the status might induce the degradation of C. angustifolia wetland.


[Intestinal disease due to Mycobacterium avium in a patient with HIV/AIDS].
We report the first case of colitis due to Mycobacterium avium in a Peruvian patient with HIV/AIDS.


[Cloning and identification of the variable region gene of mouse anti-human BAFF mAb].
To obtain the variable region gene sequence of heavy and light chain of mouse anti-human BAFF monoclonal antibody (mAb) on base of BAFF mAb which was cloned in our laboratory. The total RNA was extracted from mouse anti-human BAFF mAb hybridoma cell line FMMUB(4);, and then the RNA was reverse transcribed into cDNA. Specific primers were designed to amplify the targeted gene. The targeted gene fragments were inserted into vectors to construct the clone vectors. The gene sequences were analyzed after identified by positive clones screening and restrictive enzyme digestion. The variable region gene sequences of mouse anti-human BAFF mAb were obtained. The variable region gene sequences of mouse anti-human BAFF mAb will provide experimental basis for further study on constructing engineered antibodies.


Evidence for a functional relationship between noradrenaline and neurohypophyseal peptides in the brainstem of rats.
The possibility of a functional relationship between noradrenaline and neurohypophyseal peptides in the control of cardiovascular function in the nucleus tractus solitarius of rats has been investigated. The hypotensive response to microinjections of noradrenaline (20 nmol) was abolished by simultaneous (but not prior) microinjections of [Arg8]vasopressin (AVP) and oxytocin at doses (0.9 pmol) which alone had no effects on cardiovascular parameters. AVP plus noradrenaline actually resulted in a transient pressor effect. Simultaneous administration of [deamino-D-Arg8]vasopressin, a selective agonist of AVP V2 receptors, did not modify the effect of noradrenaline, whereas the specific V1 antagonist D-(CH2)5-Tyr(Me)-AVP partially decreased its intensity. When subthreshold doses of both AVP (0.9 pmol) and noradrenaline (10 pmol) were administered simultaneously, a pressor response was observed. In vasopressin-deficient Brattleboro rats, microinjections of 0.9 pmol AVP had no effects, but a marked pressor response was observed after the administration of a higher dose (9 pmol). In parent strain Long-Evans rats, noradrenaline (20 nmol) also produced a hypotensive response, but in Brattleboro rats microinjections of this amine elicited a marked pressor effect. In these rats, simultaneous administration of a subthreshold dose of AVP (0.9 pmol) reversed this response in such a way that a fall in blood pressure, similar to that observed in Long-Evans rats after injection of noradrenaline alone, was registered. These results provide evidence for a functional interaction between noradrenaline and neurohypophyseal peptides in the control of cardiovascular function in the brainstem.


1H- and 13C-n.m.r. assignments for structural elements of xylose-containing N-linked oligosaccharides, using 1D-and 2D-n.m.r. experiments.
1H-N.m.r. and 13C-n.m.r. spectral assignments for synthetic beta-D-Xyl-(1----2)-beta-D-Man-OMe, beta-D-Xyl-(1----2)-[alpha-D-Man-(1----3)]-beta-D-Man-OMe, beta-D-Xyl-(1----2)-[alpha-D-Man-(1----6)]-beta-D-Man-OMe, and beta-D-Xyl-(1----2)-[alpha-D-Man-(1----3)]-[alpha-D-Man-(1----6)]- beta-D-Man-OMe, which are structural elements of xylose-containing carbohydrate chains from N-glycoproteins, have been made on the basis of 1D and 2D (DQF 1H-1H COSY, HOHAHA) 500-MHz 1H-n.m.r. spectroscopy and 1D 50-MHz 13C-n.m.r. spectroscopy, respectively.


A cross-sectional examination of the physical fitness and selected health attributes of recreational all-terrain vehicle riders and off-road motorcyclists.
The aims of this study were: (1) to characterize selected fitness and health attributes of two types of habitual recreational off-road vehicle riders - off-road motorcyclists and all-terrain vehicle riders; (2) to explore differences among riders in terms of vehicle type, age, and gender; and (3) to compare the fitness and health of riders to population norms and clinical health standards. Canadian off-road riders (n = 141) of both sexes aged 16 years and over were recruited through local and national off-road riding organizations. Anthropometry, fitness, and health measures of off-road motorcycle and all-terrain vehicle riders were compared with population norms, health standards, and physical activity guidelines. Off-road motorcycle riders had above average aerobic fitness (79th percentile), while all-terrain vehicle riders were lower than average (40th percentile). All riders had a healthy blood lipid profile and a low incidence of the metabolic syndrome (12.9%) compared with members of the general population. Off-road motorcycle riders had healthier body composition and fitness than all-terrain vehicle riders; however, the body composition of off-road motorcycle riders was no healthier than that of the general population and all-terrain vehicle riders were worse than the general population. Off-road motorcycle riders had healthier anthropometry and fitness than all-terrain vehicle riders and thus fewer health risk factors for future disease, demonstrating that the physiological profiles of off-road riders are dependent on vehicle type.


Selective synthesis of [2-(11)C]2-iodopropane and [1-(11)C]iodoethane using the loop method by reacting methylmagnesium bromide with [11C]carbon dioxide.
[2-(11)C]2-iodopropane ([2-(11)C]i-PrI) and [1-(11)C]iodoethane ([1-(11)C]EtI) were selectively synthesized using the loop method by reacting methylmagnesium bromide (MeMgBr) with [11C]carbon oxide ([11C]CO2), followed by treatment with LiAlH4 and then HI. The loop method, in which a low amount of MeMgBr was used for the Grignard reaction, diminished the formation of non-radioactive iodomethane (MeI) and improved the specific activity of [2-(11)C]i-PrI and [1-(11)C]EtI. By examining the reaction temperature and time of MeMgBr with [11C]CO2 in the loop, we determined the optimal respective conditions of forming [2-(11)C]i-PrI and [1-(11)C]EtI. Moreover, [2-(11)C]i-PrI and [1-(11)C]EtI could be simultaneously synthesized at a designated ratio in one production run. These substances were obtained by gas chromatographic purification as two radiochemically pure products. All the processes from the production of [11C]CO2 to the purification of [11C]RI were automated. When we started from about 37 GBq of [11C]CO2, 3.9-5.3 GBq of [1-(11)C]EtI or 3.7-4.4 GBq of [2-(11)C]i-PrI was obtained with a specific activity of 37-99 GBq/micromol at EOS (n=3). This amount of radioactivity is sufficient for the synthesis of [11C]radioligands.


An Isolated Metastasis From Clear Cell Renal Cell Carcinoma to the Uterus: A Case Report and Review of Literature.
Ovaries are a favored site for metastatic tumors arising in the female genital tract. Other organs of the mullerian system, that is, the uterine corpus as well as the fallopian tubes, cervix, and the vagina are less commonly involved by metastases. If there is no clinical history of a known extramullerian primary tumor, suspicion that a uterine mass represents metastatic disease is low. We report the case of a renal clear cell carcinoma presenting as an isolated uterine mass and morphologically mimicking a primary endometrial clear cell adenocarcinoma. A review of the English literature yielded only a recent abstract describing 3 cases of renal clear cell carcinoma metastasizing to the endometrium.


Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study.
This multicenter, double-blind study evaluated the effects of three doses of adalimumab in Japanese patients with rheumatoid arthritis (RA). Patients were randomized to placebo (n = 87) or adalimumab 20 mg (n = 87), 40 mg (n = 91), or 80 mg (n = 87) every other week for 24 weeks. The primary efficacy endpoint was the American College of Rheumatology criteria for 20% improvement (ACR20) at Week 24. At Week 24, all adalimumab treatment groups achieved statistically significantly better ACR20 response rates (20 mg: 28.7%, P < 0.05; 40 mg: 44.0%, P < 0.001; and 80 mg: 50.6%, P < 0.001) versus placebo (13.8%), as well as statistically significantly greater ACR50 and ACR70 responses for the two higher adalimumab doses versus placebo. Rates of adverse events were comparable between the adalimumab groups and the placebo group, except for injection-site reactions, which occurred in more adalimumab-treated patients. Adalimumab 20, 40, and 80 mg were safe and effective in Japanese patients; however, the greatest responses occurred with the 40 and 80 mg doses. These results and comparable ACR20 responses in Western patients support adalimumab 40 mg every other week as the appropriate dosage to treat RA in Japanese patients.


Impact of Neighborhood Disadvantage on High-Risk Oncotype DX Recurrence Scores and Breast Cancer Survival.
Evaluate the association between neighborhood disadvantage and Oncotype DX score, a surrogate for tumor biology, among a national cohort. Women living in disadvantaged neighborhoods have shorter breast cancer (BC) survival, even after accounting for individual-level, tumor, and treatment characteristics. This suggests unaccounted social and biological mechanisms by which neighborhood disadvantage may impact BC survival. This cross-sectional study included Stage I and II, ER+ /HER2- BC patients with Oncotype DX score data from the National Cancer Database from 2004-2019. Multivariate regression models tested the association of neighborhood-level income on Oncotype DX score controlling for age, race/ethnicity, insurance, clinical stage, and education. Cox regression assessed overall survival. Of the 294,283 total BC patients selected, the majority were non-Hispanic White (n=237,197, 80.6%) with 7.6% non-Hispanic Black (n=22,495) and 4.5% Other (n=13,383). 27.1% (n=79,7254) of the population lived in the most disadvantaged neighborhoods with an annual neighborhood-level income of <$48,000 while 59.62% (n=175,305) lived in neighborhoods with a median-level income of >$48,000. On multivariate analysis controlling for age, race/ethnicity, insurance status, neighborhood-level education, and pathologic stage, patients in disadvantaged neighborhoods had a greater risk of high- versus low-risk Oncotype DX scores compared to those in advantaged neighborhoods [OR=1.04 (1.01-1.07), P=0.0067]. This study takes a translational epidemiologic approach to identify that women living in the most disadvantaged neighborhoods have more aggressive tumor biology, as determined by the Oncotype DX score.


Selective amino acid restriction differentially affects the motility and directionality of DU145 and PC3 prostate cancer cells.
We previously found that selective restriction of amino acids inhibits invasion of two androgen-independent human prostate cancer cell lines, DU145 and PC3. Here we show that the restriction of tyrosine (Tyr) and phenylalanine (Phe), methionine (Met) or glutamine (Gln) modulates the activity of G proteins and affects the balance between two actin-binding proteins, cofilin and profilin, in these two cell lines. Selective amino acid restriction differentially reduces G protein binding to GTP in DU145 cells. Tyr/Phe deprivation reduces the amount of Rho-GTP and Rac1-GTP. Met deprivation reduces the amount of Ras-GTP and Rho-GTP, and Gln deprivation decreases Ras-GTP, Rac-GTP, and Cdc42-GTP. Restriction of these amino acids increases the amount of profilin, cofilin and phosphorylation of cofilin-Ser(3). Increased PAK1 expression and phosphorylation of PAK1-Thr(423), and Ser(199/204) are consistent with the increased phosphorylation of LIMK1-Thr(508). In PC3 cells, Tyr/Phe or Gln deprivation reduces the amount of Ras-GTP, and all of the examined amino acid restrictions reduce the amount of profilin. PAK1, LIMK1 and cofilin are not significantly altered. These data reveal that specific amino acid deprivation differentially affects actin dynamics in DU145 and PC3. Modulation on Rho, Rac, PAK1, and LIMK1 likely alter the balance between cofilin and profilin in DU145 cells. In contrast, profilin is inhibited in PC3 cells. These effects modulate directionality and motility to inhibit invasion.


Electrical stimulation of rhesus monkey nucleus reticularis gigantocellularis. II. Effects on metrics and kinematics of ongoing gaze shifts to visual targets.
Saccade kinematics are altered by ongoing head movements. The hypothesis that a head movement command signal, proportional to head velocity, transiently reduces the gain of the saccadic burst generator (Freedman 2001, Biol Cybern 84:453-462) can account for this observation. Using electrical stimulation of the rhesus monkey nucleus reticularis gigantocellularis (NRG) to alter the head contribution to ongoing gaze shifts, two critical predictions of this gaze control hypothesis were tested. First, this hypothesis predicts that activation of the head command pathway will cause a transient reduction in the gain of the saccadic burst generator. This should alter saccade kinematics by initially reducing velocity without altering saccade amplitude. Second, because this hypothesis does not assume that gaze amplitude is controlled via feedback, the added head contribution (produced by NRG stimulation on the side ipsilateral to the direction of an ongoing gaze shift) should lead to hypermetric gaze shifts. At every stimulation site tested, saccade kinematics were systematically altered in a way that was consistent with transient reduction of the gain of the saccadic burst generator. In addition, gaze shifts produced during NRG stimulation were hypermetric compared with control movements. For example, when targets were briefly flashed 30 degrees from an initial fixation location, gaze shifts during NRG stimulation were on average 140% larger than control movements. These data are consistent with the predictions of the tested hypothesis, and may be problematic for gaze control models that rely on feedback control of gaze amplitude, as well as for models that do not posit an interaction between head commands and the saccade burst generator.


Diagnostic tools for assessment of urinary dysfunction in MS patients without urinary disturbances.
Many guidelines are available for the management of lower urinary tract symptoms (LUTSs) in multiple sclerosis (MS) patients, but no agreement exists on the best approach for subjects without LUTSs. The objective of this study was to evaluate whether LUTSs can be detected in MS patients asymptomatic for urinary dysfunction, comparing three different tools [measure of post-void residual volume (PRV), bladder diary (BD), a focused questionnaire (IPSS)], and whether disability, disease duration and signs of pyramidal involvement are linked to their subclinical presence. 178 MS patients (118 women) have been included (mean age 41.2 years, mean disease duration 11.3 years, mean EDSS 2.2), and tested with the above-mentioned tools. PRV was abnormal in 14 subjects (7.8%), associated to abnormal findings at IPSS in 3 cases, at BD in 2 cases, at both in 1. BD was abnormal in 37 subjects (20.8%), with concomitant abnormal PRV in 2, abnormal IPSS in 10 cases, abnormal IPSS and BD in 1. IPSS was ≥ 9 in 43 subjects (24.1%). At least one test was abnormal in 76 patients (42.7%): 1 in 57 patients (32.0%), 2 in 17 (9.5%), and 3 tests in 2 (1.1%). Patients with at least one abnormal urinary variable, compared to patients without urinary abnormalities, had a more frequent pyramidal involvement (69.5 vs. 16.8%, χ(2) = 48.6, p < 0.00001), a more frequent occurrence of EDSS ≥2 (83.1 vs. 23.5%, χ(2) = 56.9, p < 0.00001), and a longer disease duration (15.7 ± 7.3 vs. 9.1 ± 7.1, t = 5.7, p < 0.00001). Asymptomatic LUTS were frequent but none of the tests used permitted to better identify asymptomatic patients.


Theoretical study of tautomers and photoisomers of avobenzone by DFT methods.
Organic ultraviolet (UV) filters such as cinnamates, benzophenones, p-aminobenzoic derivatives, and avobenzone (which have well-established and recognized UV-filtering efficacies) are employed in cosmetic/pharmaceutical products to minimize the harm caused by exposure of the skin to sunlight. In this study, a detailed investigation of the photostability and tautomerism mechanisms of avobenzone was performed utilizing DFT methods. The UV spectral profile of avobenzone was also simulated, and the results showed good agreement with experimental data. Furthermore, the calculations were able to distinguish tautomers and photoisomers of the studied organic filter based on their properties, thus showing the potential to develop new organic UV filters. Graphical Abstract Theoretical studies of avobenzone and its tautomers by TD-DFT.


Interleukin-1beta and tumor necrosis factor-alpha are expressed by different subsets of microglia and macrophages after ischemic stroke in mice.
Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are expressed by microglia and infiltrating macrophages following ischemic stroke. Whereas IL-1beta is primarily neurotoxic in ischemic stroke, TNF-alpha may have neurotoxic and/or neuroprotective effects. We investigated whether IL-1beta and TNF-alpha are synthesized by overlapping or segregated populations of cells after ischemic stroke in mice. We used flow cytometry and immunohistochemistry to examine cellular co-expression of IL-1beta and TNF-alpha at 6, 12 and 24 hours after permanent middle cerebral artery occlusion in mice, validating the results by the use of bone marrow chimeric mice. We found that IL-1beta and TNF-alpha were expressed in largely segregated populations of CD11b+CD45dim microglia and CD11b+CD45high macrophages, with cells expressing both cytokines only rarely. The number of Gr1+ granulocytes producing IL-1beta or TNF-alpha was very low, and we observed no IL-1beta- or TNF-alpha-expressing T cells or astrocytes. Taken together, the results show that IL-1beta and TNF-alpha are produced by largely segregated populations of microglia and macrophages after ischemic stroke in mice. Our findings provide evidence of a functional diversity among different subsets of microglia and macrophages that is potentially relevant to future design of anti-inflammatory therapies in stroke.


Research on predicting early Fusarium head blight with asymptomatic wheat grains by micro-near infrared spectrometer.
Fusarium head blight (FHB) is considered one of the most serious fungal diseases of wheat. Fusarium resulted in yield losses and contamination of harvested grains with mycotoxins. Therefore, diagnosing Fusarium head blight in early asymptomatic wheat is vital. To detect early FHB, a micro-near-infrared spectrometer was used to collect the spectrum of wheat grains, and FHB infection of wheat was detected by combining chemometrics in the 900-1700 nm near-infrared spectral region. First, the obtained spectra were analysed accordingly, and the pre-processed data were compared. The modelling analysis was then performed using the support vector machine (SVM), random forest (RF), extreme gradient descent (XGBoost), Autokeras, and Autogluon (with SVM) algorithms. The results showed that SG smoothing with standard normal variate (SG + SNV) was the best pre-treatment method. In addition, after SG + SNV was combined with the Autogluon (with SVM) model, the optimal classification results were obtained, with an accuracy of 73.33 % and an F1 value of 72.86 %. Autogluon (with SVM) could prevent overfitting and optimize generalization. Then, this manuscript discusses the performance of the Autogluon (with SVM) model with different stacking layers. The results show that one stacking layer can obtain a classification model with excellent performance. These results indicated that the near infrared spectrum (NIR) has the potential for early detection of Fusarium head blight with asymptomatic early statements.


Exercise testing in survivors of intensive care--is there a role for cardiopulmonary exercise testing?
The aims of this study were to assess the feasibility of cardiopulmonary exercise testing (CPET) for the early assessment of cardiorespiratory fitness in general adult intensive care unit (ICU) survivors and to characterize the pathophysiology of exercise limitation in this population. Fifty general ICU survivors (ventilated for ≥ 5 days) performed a maximal cycle ergometer CPET within 6 weeks of hospital discharge. Health-related quality of life was measured by the Medical Outcome Study Short Form 36 version 2.0 questionnaire. Fifty patients (median age, 57 years; median Acute Physiology And Chronic Health Evaluation II score, 16) completed a CPET 24 ± 14 days after hospital discharge with no adverse events. Significant exercise limitation was present with peak Vo(2) 56% ± 16% predicted and anaerobic threshold (AT) 41% ± 13% of peak predicted Vo(2). Prospectively stratified subgroup comparison showed that patients ventilated for 14 days or more had a significantly lower AT and peak Vo(2) than those ventilated for 5 to 14 days (AT: 9.6 vs 11.7 mL/kg per minute O(2), P = .009; peak Vo(2): 12.9 vs 15.3 mL/kg per minute O(2), P = .022). At peak exercise, heart rate reserve was 25% ± 14%, breathing reserve was 47% ± 19%, and the respiratory exchange ratio was 0.96 ± 0.11. Ventilatory equivalents for CO(2) (Eqco(2)) were 39 ± 9. Significant exercise limitation is evident in patients who have had critical illness. Etiology of exercise limitation appears multifactorial, with general deconditioning and muscle weakness as major contributory factors. Early CPET appears a practical method of assessing exercise capacity in ICU survivors. Cardiopulmonary exercise testing could be used to select patients who may benefit most from a targeted physical rehabilitation program, aid in exercise prescription, and help assess the response to intervention.


The reliability and validity of the brief symptom inventory-18 in persons with traumatic brain injury.
To investigate the psychometric properties of the Brief Symptom Inventory-18 (BSI-18) among persons with traumatic brain injury (TBI). Inception cohort design with cross-sectional follow-up of 6 months to 15 years. Rehabilitation hospital. Adults (N=257) with moderate to severe TBI (81 inpatients and 176 follow-up participants, analyzed separately). Not applicable. The BSI-18 is a brief screen of psychologic distress with a Global Severity Index (GSI), and 3 clinical subscales: somatization, anxiety, and depression. Internal consistency of the GSI was high in both follow-up participants (alpha=.91) and inpatients (alpha=.84), whereas estimates for the somatization, anxiety, and depression subscales were more variable (alpha range, .61-.84). As would be expected for a measure of affective state, retest reliability estimates were only moderate. The BSI-18 GSI correlated with multiple measures of psychosocial adjustment. After accounting for demographics, injury severity, inpatient functional status, years since injury, and various psychosocial factors, the BSI-18 showed incremental validity in predicting concurrent functional, psychosocial, and psychologic status. The BSI-18 GSI had excellent reliability and validity among inpatients and follow-up participants. Modest reliability estimates may place an upper bound on the validity of the BSI-18 clinical subscales in inpatient TBI populations.


Analysis of the carbohydrate composition of the pancreatic plasmalemmal glycoprotein affinity labeled by short probes for the cholecystokinin receptor.
Affinity labeling of the rat pancreatic cholecystokinin (CCK) receptor with decapeptide probes has identified an Mr = 85,000-95,000 protein, distinct from the Mr = 80,000 component previously labeled with 125I-Bolton Hunter-CCK-33. We have characterized the carbohydrate composition of this novel protein labeled with 125I-D-Tyr-Gly-[(Nle28,31)-CCK-26-33] and disuccinimidyl suberate by using chemical and enzymatic deglycosylation and lectin chromatography. The Mr = 85,000-95,000 component was demonstrated to be an N-linked sialoglycoprotein based on neuraminidase digestion to Mr = 75,000-85,000 and endo-beta-N-acetylglucosaminidase F (Endo F) digestion to Mr = 42,000. This was distinct from the Mr = 65,000 product of Endo F digestion of the protein labeled with 125I-Bolton Hunter-CCK-33. Lack of an effect of endo-beta-N-acetylglucosaminidase H demonstrated the absence of N-linked simple oligosaccharides, while products of chemical deglycosylation with hydrogen fluoride and endo-alpha-N-acetylgalactosaminidase supported the absence of O-linked carbohydrate. The presence of at least four oligosaccharide chains on the core protein was suggested by Endo F digestion of the Mr = 85,000-95,000 protein using limiting enzyme conditions. This glycoprotein was retained on wheat germ agglutininagarose and eluted by N,N',N"-triacetylchitotriose. Identification of the Mr = 85,000-95,000 component on the ectodomain of the plasmalemma of intact pancreatic acini confirmed this to be the fully processed form of the CCK-binding protein.


A "Grave" Case of Mitral Regurgitation: Cardio-Obstetric Approach to Severe Mitral Regurgitation With Cardiogenic Shock.
A 26-year-old woman presented at 26 weeks of pregnancy with severe mitral regurgitation (MR) and cardiogenic shock in the setting of profound hyperthyroidism. An intra-aortic balloon pump was placed, and surgical intervention was considered. However, with management of thyrotoxicosis and delivery, complete resolution of MR and cardiogenic shock was achieved. (Level of Difficulty: Intermediate.).


Interactions in self-assembled microbial communities saturate with diversity.
How the diversity of organisms competing for or sharing resources influences community function is an important question in ecology but has rarely been explored in natural microbial communities. These generally contain large numbers of species making it difficult to disentangle how the effects of different interactions scale with diversity. Here, we show that changing diversity affects measures of community function in relatively simple communities but that increasing richness beyond a threshold has little detectable effect. We generated self-assembled communities with a wide range of diversity by growth of cells from serially diluted seawater on brown algal leachate. We subsequently isolated the most abundant taxa from these communities via dilution-to-extinction in order to compare productivity functions of the entire community to those of individual taxa. To parse the effect of different types of organismal interactions, we defined relative total function (RTF) as an index for positive or negative effects of diversity on community function. Our analysis identified three overall regimes with increasing diversity. At low richness (<12 taxa), positive and negative effects of interactions were both weak, while at moderate richness (12-26 taxa), community resource uptake increased but the carbon use efficiency decreased. Finally, beyond 26 taxa, the effect of interactions on community function saturated and further diversity increases did not affect community function. Although more diverse communities had overall greater access to resources, on average individual taxa within these communities had lower resource availability and reduced carbon use efficiency. Our results thus suggest competition and complementation simultaneously increase with diversity but both saturate at a threshold.


Gestational exposure to phenanthrene induces follicular atresia and endocrine dyscrasia in F1 adult female.
Epidemiological investigations and animal studies demonstrate a significantly positive relationship between polycyclic aromatic hydrocarbons (PAHs) exposure and reproductive disorders. However, few researches are focused on the reproductive toxicity of low-molecular-weight PAHs (number of benzene ring ≤ 3) which occupy a large part of PAHs. Phenanthrene (Phe), a typical low-molecular-weight PAH, is one of the most abundant PAHs detected in foods. In the present study, oral treatment with Phe at a human exposure related level during gestation (60 μg/kg body weight every three days, six times in total) induced reproductive disorders in F1 adult female mice: the number of antral follicles (an immature stage of follicular development) were significantly increased, while the maturation of oocytes was inhibited and aggravated follicular atresia was observed; the serum levels of luteinizing hormone (LH), testosterone and estradiol were significantly reduced; the receptor of follicle-stimulating hormone (FSHR) and aromatase in the ovary were significantly upregulated; transcriptome analysis demonstrated that the phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt) signal pathway was upregulated, and the calcium signal pathway was disturbed, which probably accounts for the exacerbated atresia of the growing follicles and the excessive consumption of follicles. The reproductive toxicity of low-molecular-weight PAHs could not be neglected.


The site of settlement indicates commensalism between bluemussel and its epibiont.
The site of settlement of barnacles (Balanus improvisus) attached on shells of bluemussels (Mytilus edulis) was mapped from a sample of mussels collected in the Baltic Sea. Most barnacles had settled near the siphonal apertures of the mussel. An experiment was made to measure the disadvantages and advantages that living in close association brings to barnacles and mussels. The barnacles on shells of living mussels were shown to grow significantly faster than those on empty mussel shells. Presence of barnacles had no effects on growth of mussels. The two-species association under study was demonstrated to be a case of commensalism.


Expression of a rice glutaredoxin in aleurone layers of developing and mature seeds: subcellular localization and possible functions in antioxidant defense.
A rice glutaredoxin isoform (OsGrxC2;2) with antioxidant capacity is expressed abundantly in seed tissues and is localized to storage vacuoles in aleurone layers in developing and mature seeds. Seed tissues undergo drastic water loss at the late stage of seed development, and thus need to tolerate oxidative injuries associated with desiccation. We previously found a rice glutaredoxin isoform, OsGrxC2;2, as a gene expressed abundantly in developing seeds. Since glutaredoxin is involved in antioxidant defense, in the present study we investigated the subcellular localization and expression profile of OsGrxC2;2 and whether OsGrxC2;2 has a role in the defense against reactive oxygen species. Western blotting and immunohistochemistry revealed that the OsGrxC2;2 protein accumulated at a high level in the embryo and aleurone layers of developing and mature seeds. The OsGrxC2;2 in developing seeds was particularly localized to aleurone grains, which are storage organelles derived from vacuoles. Overexpression of OsGrxC2;2 resulted in an enhanced tolerance to menadione in yeast and methyl viologen in green leaves of transgenic rice plants. These results suggest that OsGrxC2;2 participates in the defense against oxidative stress in developing and mature seeds.


Standardizing the double-observer survey method for estimating mountain ungulate prey of the endangered snow leopard.
Mountain ungulates around the world have been threatened by illegal hunting, habitat modification, increased livestock grazing, disease and development. Mountain ungulates play an important functional role in grasslands as primary consumers and as prey for wild carnivores, and monitoring of their populations is important for conservation purposes. However, most of the several currently available methods of estimating wild ungulate abundance are either difficult to implement or too expensive for mountainous terrain. A rigorous method of sampling ungulate abundance in mountainous areas that can allow for some measure of sampling error is therefore much needed. To this end, we used a combination of field data and computer simulations to test the critical assumptions associated with double-observer technique based on capture-recapture theory. The technique was modified and adapted to estimate the populations of bharal (Pseudois nayaur) and ibex (Capra sibirica) at five different sites. Conducting the two double-observer surveys simultaneously led to underestimation of the population by 15%. We therefore recommend separating the surveys in space or time. The overall detection probability for the two observers was 0.74 and 0.79. Our surveys estimated mountain ungulate populations (± 95% confidence interval) of 735 (± 44), 580 (± 46), 509 (± 53), 184 (± 40) and 30 (± 14) individuals at the five sites, respectively. A detection probability of 0.75 was found to be sufficient to detect a change of 20% in populations of >420 individuals. Based on these results, we believe that this method is sufficiently precise for scientific and conservation purposes and therefore recommend the use of the double-observer approach (with the two surveys separated in time or space) for the estimation and monitoring of mountain ungulate populations.


An efficient single-cell based method for linking human T cell phenotype to T cell receptor sequence and specificity.
Single-cell antigen-receptor gene amplification and sequencing platforms have been used to characterize T cell receptor (TCR) repertoires but typically fail to generate paired full-length gene products for direct expression cloning and do not enable linking this data to cell phenotype information. To overcome these limitations, we established a high-throughput platform for the quantitative and qualitative analysis of human TCR repertoires that provides insights into the clonal and functional composition of human CD4+ and CD8+ αβ T cells at the molecular and cellular level. The strategy is a powerful tool to qualitatively assess differences between antigen receptors of phenotypically defined αβ T cell subsets, e.g. in immune responses to cancer, vaccination, or infection, and in autoimmune diseases.